ORCID Profile
0000-0001-8618-7950
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UNSW Sydney
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Publisher: Wiley
Date: 07-10-2010
Publisher: Society for Neuroscience
Date: 18-01-2012
DOI: 10.1523/JNEUROSCI.4806-11.2012
Abstract: The role of the amygdala central nucleus (CeN) in habit learning was assessed in two experiments. First, we examined the effects of bilateral lesions of the anterior CeN on an overtraining-induced lever press habit evaluated using an outcome devaluation protocol. Overtraining generated habitual performance and rendered sham lesioned rats insensitive to outcome devaluation, an effect that was also found in rats given control lesions of the posterior CeN. In contrast, rats with lesions of the anterior CeN did not show normal habit acquisition and their performance remained goal-directed and sensitive to outcome devaluation. Nevertheless, lesions of either the posterior or the anterior CeN abolished the general excitatory influence of a Pavlovian conditioned stimulus on instrumental performance. Second, we assessed the functional interaction between the CeN and dorsolateral striatum (DLS), a region previously implicated in the acquisition of habits, using asymmetrical lesions to disconnect these structures. Rats were given a unilateral lesion of anterior CeN and a unilateral lesion of the DLS, made either ipsilateral (control) or contralateral (disconnection) to the CeN lesion, and given overtraining followed by outcome devaluation. Although the ipsilateral lesioned rats were insensitive to devaluation, the contralateral CeN–DLS lesion impaired habit acquisition, rendering performance sensitive to the devaluation treatment. These results are the first to implicate the CeN and its connection with a circuit involving DLS in habit learning. They imply that, in instrumental conditioning, regions of amygdala parse the instrumental outcome into the reward and reinforcement signals mediating goal-directed and habitual actions, respectively.
Publisher: Society for Neuroscience
Date: 17-08-2011
DOI: 10.1523/JNEUROSCI.2711-11.2011
Abstract: Tests of Pavlovian–instrumental transfer (PIT) demonstrate that reward-predictive stimuli can exert a powerful motivational influence on the performance of instrumental actions. Recent evidence suggests that predictive stimuli produce this effect through either the general arousal (general PIT) or the specific predictions (outcome-specific PIT) produced by their association with reward. In two experiments, we examined the effects of pretraining lesions (Experiment 1) or muscimol-induced inactivation (Experiment 2) of either the core or shell regions of the nucleus accumbens (NAC) on these forms of PIT. Rats received Pavlovian training in which three auditory stimuli each predicted the delivery of a distinct food outcome. Separately, the rats were trained to perform two instrumental actions, each of which earned one of the outcomes used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Here we report evidence of a double dissociation between general and outcome-specific PIT at the level of the accumbens. Shell lesions eliminated outcome-specific PIT but spared general PIT, whereas lesions of the core abolished general PIT but spared outcome-specific PIT. Importantly, the infusion of muscimol into core or shell made immediately before the PIT tests produced a similar pattern of results. These results suggest that whereas the NAC core mediates the general excitatory effects of reward-related cues, the NAC shell mediates the effect of outcome-specific reward predictions on instrumental performance, and thereby serve to clarify reported discrepancies regarding the role of the NAC core and shell in PIT.
Publisher: Society for Neuroscience
Date: 25-03-2015
DOI: 10.1523/JNEUROSCI.4837-14.2015
Abstract: Outcome-specific Pavlovian-instrumental transfer (PIT) demonstrates the way that reward-related cues influence choice between instrumental actions. The nucleus accumbens shell (NAc-S) contributes critically to this effect, particularly through its output to the rostral medial ventral pallidum (VP-m). Using rats, we investigated in two experiments the role in the PIT effect of the two major outputs of this VP-m region innervated by the NAc-S, the mediodorsal thalamus (MD) and the ventral tegmental area (VTA). First, two retrograde tracers were injected into the MD and VTA to compare the neuronal activity of the two populations of projection neurons in the VP-m during PIT relative to controls. Second, the functional role of the connection between the VP-m and the MD or VTA was assessed using asymmetrical pharmacological manipulations before a PIT test. It was found that, whereas neurons in the VP-m projecting to the MD showed significantly more neuronal activation during PIT than those projecting to the VTA, neuronal activation of these latter neurons correlated with the size of the PIT effect. Disconnection of the two pathways during PIT also revealed different deficits in performance: disrupting the VP-m to MD pathway removed the response biasing effects of reward-related cues, whereas disrupting the VP-m to VTA pathway preserved the response bias but altered the overall rate of responding. The current results therefore suggest that the VP-m exerts distinct effects on the VTA and MD and that these latter structures mediate the motivational and cognitive components of specific PIT, respectively.
Publisher: American Psychological Association (APA)
Date: 04-2021
DOI: 10.1037/BNE0000443
Publisher: Center for Open Science
Date: 20-03-2021
Abstract: It has been suggested that there are two distinct and parallel mechanisms for controlling instrumental behavior in mammals: goal-directed actions and habits. To gain an understanding of how these two systems interact to control behavior, it is essential to characterize the mechanisms by which the balance between these systems is influenced by experience. Studies in rodents have shown that the amount of training governs the relative expression of these two systems: behavior is goal-directed following moderate training, but the more extensively an instrumental action is trained, the more it becomes habitual. It is less clear whether humans exhibit similar training effects on the expression of goal-directed and habitual behavior, as human studies have reported contradictory findings. To tackle these contradictory findings, we formed a consortium, where four laboratories undertook a pre-registered experimental induction of habits by manipulating the amount of training. There was no statistical evidence for a main effect of the amount of training on the formation and expression of habits. However, exploratory analyses suggest a moderating effect of the affective component of stress on the impact of training over habit expression. Participants who were lower in affective stress appeared to be initially goal-directed, but became habitual with increased training, whereas participants who were high in affective stress were already habitual even after moderate training, thereby manifesting insensitivity to overtraining effects. Our findings highlight the importance of the role of moderating variables such as in idual differences in stress and anxiety when studying the experimental induction of habits in humans.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.IJCARD.2016.11.030
Abstract: The EQ-5D-3L, a generic multi-attribute utility instrument (MAUI), is widely employed to assist in economic evaluations in health care. The EQ-5D-3L lacks sensitivity when used in conditions such as cardiovascular disease (CVD). Although there are number of CVD specific quality of life instruments, currently, there are no CVD specific MAUIs. The aim of this study is to investigate the discriminative ability and responsiveness of the EQ-5D-3L and the Minnesota Living with Heart Failure Questionnaire (MLHF), a CVD specific quality of life instrument in a group of heart failure patients. The psychometric performance of the EQ-5D-3L and the MLHF was assessed using data from a randomised trial for a heart failure management intervention. The two instruments were compared for discrimination, responsiveness and agreement. The severity groups were defined using New York Heart Association functional classes. The effect sizes for severe classes were generally similar showing good discrimination. The MLHF recorded better responsiveness between the time points than the EQ-5D-3L which was indicated by higher effect sizes and standardised response means. The change in MLHF summary scores between the time points was significant (p<0.005 paired t-test). The overall agreement between the two measures was low. The low correlation indicates that the two classification systems cover different aspects of health space. Comparison of CVD specific instruments with other generic MAUIs such as EQ-5D-3L and AQOL-8D is recommended for further research.
Publisher: Elsevier BV
Date: 12-1994
DOI: 10.1016/0166-4328(94)90104-X
Abstract: In a series of studies, we assessed the effects of ibotenic acid lesions of the nucleus accumbens on instrumental performance in hungry rats. Although these lesions were found to generally impair lever press performance for both food pellets and a sucrose solution, they did not affect sensitivity to changes in the incentive value of the outcome induced either by a shift in food deprivation or a shift in the sucrose concentration. Further, these lesions did not affect sensitivity to a change in the instrumental contingency from response-contingent to non-contingent outcome delivery. In contrast, concurrent assessment of food magazine approach responses found that the lesion induced both a deficit in magazine entry and marked insensitivity to shifts in the incentive value of the outcome and to the changed situation that accompanied the change in instrumental contingency. These results are interpreted as suggesting (1) that nucleus accumbens lesions produce a general deficit in affective arousal and (2) that the influence of affective mechanisms on instrumental performance may be structurally dissociated from the control of performance mediated by the action-outcome relation.
Publisher: Society for Neuroscience
Date: 04-01-2018
DOI: 10.1523/JNEUROSCI.2850-17.2017
Abstract: The acquisition of goal-directed action requires encoding of the association between an action and its specific consequences or outcome. At a neural level, this encoding has been hypothesized to involve a prefrontal corticostriatal circuit involving the projection from the prelimbic cortex (PL) to the posterior dorsomedial striatum (pDMS) however, no direct evidence for this claim has been reported. In a series of experiments, we performed functional disconnection of this pathway using targeted lesions of the anterior corpus callosum to disrupt contralateral corticostriatal projections with asymmetrical lesions of the PL and/or pDMS to block plasticity in this circuit in rats. We first demonstrated that unilaterally blocking the PL input to the pDMS prevented the phosphorylation of extracellular signal-related kinase/mitogen activated protein kinase (pERK MAPK) induced by instrumental training. Next, we used a full bilateral disconnection of the PL from the pDMS and assessed goal-directed action using an outcome-devaluation test. Importantly, we found evidence that rats maintaining an ipsilateral and/or contralateral connection between the PL and the pDMS were able to acquire goal-directed actions. In contrast, bilateral PL–pDMS disconnection abolished the acquisition of goal-directed actions. Finally, we used a temporary pharmacological disconnection to disrupt PL inputs to the pDMS by infusing the NMDA antagonist dl -2-amino-5-phosphonopentanoic acid into the pDMS during instrumental training and found that this manipulation also disrupted goal-directed learning. These results establish that, in rats, the acquisition of new goal-directed actions depends on a prefrontal–corticostriatal circuit involving a connection between the PL and the pDMS. SIGNIFICANCE STATEMENT It has been hypothesized that the prelimbic cortex (PL) and posterior dorsomedial striatum (pDMS) in rodents interact in a corticostriatal circuit to mediate goal-directed learning. However, no direct evidence supporting this claim has been reported. Using targeted lesions, we performed functional disconnection of the PL–pDMS pathway to assess its role in goal-directed learning. In the first experiment, we demonstrated that PL input to the pDMS is necessary for instrumental training-induced neuronal activity. Next, we disrupted ipsilateral, contralateral, or bilateral PL–pDMS connections and found that only bilateral PL–pDMS disconnection disrupted the acquisition of goal-directed actions, a finding we replicated in our final study using a pharmacological disconnection procedure.
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0028-3908(98)00033-1
Abstract: Instrumental behaviour is controlled by two systems: a stimulus-response habit mechanism and a goal-directed process that involves two forms of learning. The first is learning about the instrumental contingency between the response and reward, whereas the second consists of the acquisition of incentive value by the reward. Evidence for contingency learning comes from studies of reward devaluation and from demonstrations that instrumental performance is sensitive not only the probability of contiguous reward but also to the probability of unpaired rewards. The process of incentive learning is evident in the acquisition of control over performance by primary motivational states. Preliminary lesion studies of the rat suggest that the prelimbic area of prefrontal cortex plays a role in the contingency learning, whereas the incentive learning for food rewards involves the insular cortex.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2021
DOI: 10.1186/S12974-021-02288-8
Abstract: Changes in dopaminergic neural function can be induced by an acute inflammatory state that, by altering the integrity of the neurovasculature, induces neuronal stress, cell death and causes functional deficits. Effectively blocking these effects of inflammation could, therefore, reduce both neuronal and functional decline. To test this hypothesis, we inhibited vascular adhesion protein 1 (VAP-1), a membrane-bound protein expressed on the endothelial cell surface, that mediates leukocyte extravasation and induces oxidative stress. We induced dopaminergic neuronal loss by infusing lipopolysaccharide (LPS) directly into the substantia nigra (SN) in rats and administered the VAP-1 inhibitor, PXS-4681A, daily. LPS produced: an acute inflammatory response, the loss of dopaminergic neurons in the SN, reduced the dopaminergic projection to SN target regions, particularly the dorsolateral striatum (DLS), and a deficit in habit learning, a key function of the DLS. In an attempt to protect SN neurons from this inflammatory response we found that VAP-1 inhibition not only reduced neutrophil infiltration in the SN and striatum, but also reduced the associated striatal microglia and astrocyte response. We found VAP-1 inhibition protected dopamine neurons in the SN, their projections to the striatum and promoted the functional recovery of habit learning. Thus, we reversed the loss of habitual actions, a function usually dependent on dopamine release in DLS and sensitive to striatal dysfunction. We establish, therefore, that VAP-1 inhibition has an anti-inflammatory profile that may be beneficial in the treatment of dopamine neuron dysfunction caused by an acute inflammatory state in the brain.
Publisher: Society for Neuroscience
Date: 22-02-2012
DOI: 10.1523/JNEUROSCI.5780-11.2012
Abstract: The ability to make rapid, informed decisions about whether or not to engage in a sequence of actions to earn reward is essential for survival. Modeling in rodents has demonstrated a critical role for the basolateral amygdala (BLA) in such reward-seeking actions, but the precise neurochemical underpinnings are not well understood. Taking advantage of recent advancements in biosensor technologies, we made spatially discrete near-real-time extracellular recordings of the major excitatory transmitter, glutamate, in the BLA of rats performing a self-paced lever-pressing sequence task for sucrose reward. This allowed us to detect rapid transient fluctuations in extracellular BLA glutamate time-locked to action performance. These glutamate transients tended to precede lever-pressing actions and were markedly increased in frequency when rats were engaged in such reward-seeking actions. Based on muscimol and tetrodotoxin microinfusions, these glutamate transients appeared to originate from the terminals of neurons with cell bodies in the orbital frontal cortex. Importantly, glutamate transient litude and frequency fluctuated with the value of the earned reward and positively predicted lever-pressing rate. Such novel rapid glutamate recordings during instrumental performance identify a role for glutamatergic signaling within the BLA in instrumental reward-seeking actions.
Publisher: American Psychological Association (APA)
Date: 10-2022
DOI: 10.1037/XAN0000340
Abstract: The present article explored the fate of previously formed response-outcome associations when the relation between R and O was disrupted by arranging for O to occur independently of R. In each of three experiments response independent outcome delivery selectively reduced the R earning that O. Nevertheless, in Experiments 1 and 2, the R continued to show sensitivity to outcome devaluation, suggesting that the strength of the R-O association was undiminished by this treatment. These experiments used a two-lever, two-outcome design introducing the possibility that devaluation reflected the influence of specific Pavlovian lever-outcome associations. In an attempt to nullify the influence of these incidental Pavlovian cues Experiment 3 used a single bidirectional vertical lever that rats could press left or right for different outcomes. Again, response-independent outcome presentations selectively depressed the performance of the R that delivered the response-independent O. However, in this situation, the response independent O also reduced the sensitivity of R to outcome devaluation whereas the nondegraded R was sensitive to devaluation, the degraded R was not. We conclude that selective degradation of the instrumental contingency can weaken a specific R-O association while leaving other R-O associations intact. Furthermore, the use of a bidirectional vertical lever in Experiment 3 revealed that unidirectional and spatially separated instrumental manipulanda, such as levers or chains, may produce Pavlovian cues capable of forming incidental associations with the instrumental outcome that can obscure the relative influence of R-O associations after various manipulations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Publisher: SAGE Publications
Date: 07-2004
DOI: 10.1080/02724990344000105
Abstract: In two experiments rats were preexposed to neutral stimuli. Both experiments used a between-subjects design in which a paired group was preexposed to intermixed presentations of A→ Band AX, and an unpaired control group was preexposed to intermixed presentations of A, B, and AX. After the conditioning of B, in Experiment 1, conditioned responding to X was acquired more slowly in the paired than in the unpaired group. Furthermore, in Experiment 2, Xreduced conditioned responding to a separately trained excitor in a summation test but only in the paired group. Together, these results provide evidence of an inhibitory form of sensory preconditioning.
Publisher: eLife Sciences Publications, Ltd
Date: 20-11-2020
DOI: 10.7554/ELIFE.58544
Abstract: The posterior dorsomedial striatum (pDMS) is necessary for goal-directed action however, the role of the direct (dSPN) and indirect (iSPN) spiny projection neurons in the pDMS in such actions remains unclear. In this series of experiments, we examined the role of pDMS SPNs in goal-directed action in rats and found that whereas dSPNs were critical for goal-directed learning and for energizing the learned response, iSPNs were involved in updating that learning to support response flexibility. Instrumental training elevated expression of the plasticity marker Zif268 in dSPNs only, and chemogenetic suppression of dSPN activity during training prevented goal-directed learning. Unilateral optogenetic inhibition of dSPNs induced an ipsilateral response bias in goal-directed action performance. In contrast, although initial goal-directed learning was unaffected by iSPN manipulations, optogenetic inhibition of iSPNs, but not dSPNs, impaired the updating of this learning and attenuated response flexibility after changes in the action-outcome contingency.
Publisher: Elsevier BV
Date: 11-1989
DOI: 10.1016/0031-9384(89)90057-7
Abstract: Rats received noncontingent electrical stimulation of the lateral hypothalamus on one side of a place preference apparatus and no stimulation on the other side. Subsequently, when allowed access to both sides, the rats spent more time on the side associated with stimulation. This change in preference was only found in rats receiving stimulation in the side least preferred prior to conditioning trials. It was further shown that the place preference conditioning procedure produces increased locomotor activity. Thus, the place preference obtained was not an artifact produced by a conditioned freezing response. These data suggest that both the reinforcing and activating effects of lateral hypothalamic stimulation may be conditioned to a specific environment. Some methodological problems of the place preference paradigm are discussed.
Publisher: SAGE Publications
Date: 03-2009
DOI: 10.1080/17470210802008805
Abstract: Two experiments assessed whether similarity between the two elements of a compound would influence the degree of mediated extinction versus recovery from overshadowing in human causal judgements. In both Experiments 1 and 2, we assessed the influence of extinguishing one element of a two-element compound on judgements about the other element. In Experiment 1 we manipulated the physical similarity of the two elements of the compound in Experiment 2, we used equivalence and distinctiveness pretraining in order to vary their functional similarity. We found that these procedures influenced mediated extinction and recovery from overshadowing as a function of both physical and acquired similarity and distinctiveness, respectively. The implications of these results for previously reported differences between humans and nonprimate animals are discussed.
Publisher: Cold Spring Harbor Laboratory
Date: 19-02-2020
DOI: 10.1101/2020.02.18.955385
Abstract: The posterior dorsomedial striatum (pDMS) is necessary for goal-directed action, however the role of the direct (dSPN) and indirect (iSPN) spiny projection neurons in the pDMS in such action remains unclear. In this series of experiments, we examined the role of pDMS SPNs in goal-directed action and found that, whereas dSPNs were critical for goal-directed learning and for energizing the learned response, iSPNs were involved in updating that learning to support response flexibility. Instrumental training elevated expression of the plasticity marker Zif268 in dSPNs only, and chemogenetic suppression of dSPN activity during training prevented goal-directed learning. Unilateral optogenetic inhibition of dSPNs induced an ipsilateral response bias in goal-directed action performance. In contrast, although initial goal-directed learning was unaffected by iSPN manipulations, optogenetic inhibition of iSPNs, but not dSPNs, impaired the updating of this learning and attenuated response flexibility after changes in the action-outcome contingency.
Publisher: Wiley
Date: 23-12-2014
DOI: 10.1111/BPH.12818
Publisher: Wiley
Date: 24-06-2016
Publisher: Elsevier BV
Date: 02-2016
Publisher: Elsevier BV
Date: 06-2017
Publisher: Proceedings of the National Academy of Sciences
Date: 28-07-2009
Abstract: It generally is assumed that a common neural substrate mediates both the palatability and the reward value of nutritive events. However, recent evidence suggests this assumption may not be true. Whereas opioid circuitry in both the nucleus accumbens and ventral pallidum has been reported to mediate taste-reactivity responses to palatable events, the assignment of reward or inventive value to goal-directed actions has been found to involve the basolateral amygdala. Here we found that, in rats, the neural processes mediating palatability and incentive value are indeed dissociable. Naloxone infused into either the ventral pallidum or nucleus accumbens shell blocked the increase in sucrose palatability induced by an increase in food deprivation without affecting the performance of sucrose-related actions. Conversely, naloxone infused into the basolateral amygdala blocked food deprivation-induced changes in sucrose-related actions without affecting sucrose palatability. This double dissociation of opioid-mediated changes in palatability and incentive value suggests that the role of endogenous opioids in reward processing does not depend on a single neural circuit. Rather, changes in palatability and in the incentive value assigned to rewarding events seem to be mediated by distinct neural processes.
Publisher: Springer Science and Business Media LLC
Date: 20-12-2022
Publisher: Society for Neuroscience
Date: 15-05-2013
DOI: 10.1523/JNEUROSCI.5071-12.2013
Abstract: Choice between goal-directed actions is determined by the relative value of their consequences. Such values are encoded during incentive learning and later retrieved to guide performance. Although the basolateral amygdala (BLA) and the gustatory region of insular cortex (IC) have been implicated in these processes, their relative contribution is still a matter of debate. Here we assessed whether these structures interact during incentive learning and retrieval to guide choice. In these experiments, rats were trained on two actions for distinct outcomes after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed that, relative to appropriate controls, outcome devaluation recruited both the BLA and IC based on activation of the immediate early gene Arc however, we found that infusion of the NMDAr antagonist ifenprodil into the BLA only abolished outcome devaluation when given before devaluation. In contrast, ifenprodil infusion into the IC was effective whether made before devaluation or test. We hypothesized that the BLA encodes and the IC retrieves incentive value for choice and, to test this, developed a novel sequential disconnection procedure. Blocking NMDAr activation unilaterally in the BLA before devaluation and then contralaterally in the IC before test abolished selective devaluation. In contrast, reversing the order of these infusions left devaluation intact. These results confirm that the BLA and IC form a circuit mediating the encoding and retrieval of outcome values, with the BLA encoding and the IC retrieving such values to guide choice.
Publisher: Wiley
Date: 09-2003
DOI: 10.1046/J.1460-9568.2003.02833.X
Abstract: Two experiments examined the effects of bilateral excitotoxic lesions of either the mediodorsal (MD) or anterior (ANT) thalamic nuclei on instrumental acquisition and performance, sensitivity to changes in the value of the instrumental outcome, and sensitivity to changes in the instrumental contingency. Rats were food deprived and trained to press two levers, each earning a unique food outcome (pellets or sucrose). All rats acquired the instrumental response although ANT lesions appear slightly to increase and MD lesions slightly to suppress instrumental performance. After training, specific satiety-induced devaluation of one of the two instrumental outcomes produced a selective reduction in responding on the lever that in training had earned the now devalued outcome but only in the SHAM and ANT groups. In contrast, MD animals failed to show evidence of a selective devaluation effect when tested in extinction. Additionally, SHAM and ANT animals selectively decreased responding when one action-outcome contingency was degraded, whereas MD animals reduced responding nonselectively on the two levers. Subsequent tests established that an inability to discriminate between either the two actions or the two outcomes cannot account for the lack of selective responding observed in the MD animals. Together these data suggest that MD lesions produce a profound deficit in the ability of rats to utilize specific action-outcome associations and appear to render rats relatively insensitive to the causal consequences of their instrumental actions. In contrast, far from producing a deficit, ANT lesioned rats were as sensitive to the effects of these behavioural manipulations as the sham lesioned controls.
Publisher: Wiley
Date: 06-2009
Publisher: Oxford University Press (OUP)
Date: 16-05-2015
Abstract: The reported cost effectiveness of cardiovascular disease management programs (CVD-MPs) is highly variable, potentially leading to different funding decisions. This systematic review evaluates published modeled analyses to compare study methods and quality. Articles were included if an incremental cost-effectiveness ratio (ICER) or cost-utility ratio (ICUR) was reported, it is a multi-component intervention designed to manage or prevent a cardiovascular disease condition, and it addressed all domains specified in the American Heart Association Taxonomy for Disease Management. Nine articles (reporting 10 clinical outcomes) were included. Eight cost-utility and two cost-effectiveness analyses targeted hypertension (n=4), coronary heart disease (n=2), coronary heart disease plus stoke (n=1), heart failure (n=2) and hyperlipidemia (n=1). Study perspectives included the healthcare system (n=5), societal and fund holders (n=1), a third party payer (n=3), or was not explicitly stated (n=1). All analyses were modeled based on interventions of one to two years' duration. Time horizon ranged from two years (n=1), 10 years (n=1) and lifetime (n=8). Model structures included Markov model (n=8), 'decision analytic models' (n=1), or was not explicitly stated (n=1). Considerable variation was observed in clinical and economic assumptions and reporting practices. Of all ICERs/ICURs reported, including those of subgroups (n=16), four were above a US$50,000 acceptability threshold, six were below and six were dominant. The majority of CVD-MPs was reported to have favorable economic outcomes, but 25% were at unacceptably high cost for the outcomes. Use of standardized reporting tools should increase transparency and inform what drives the cost-effectiveness of CVD-MPs.
Publisher: Wiley
Date: 2004
DOI: 10.1111/J.1460-9568.2004.03095.X
Abstract: Habits are controlled by antecedent stimuli rather than by goal expectancy. Interval schedules of feedback have been shown to generate habits, as revealed by the insensitivity of behaviour acquired under this schedule to outcome devaluation treatments. Two experiments were conducted to assess the role of the dorsolateral striatum in habit learning. In Experiment 1, sham operated controls and rats with dorsolateral striatum lesions were trained to press a lever for sucrose under interval schedules. After training, the sucrose was devalued by inducing taste aversion to it using lithium chloride, whereas saline injections were given to the controls. Only rats given the devaluation treatment reduced their consumption of sucrose and this reduction was similar in both the sham and the lesioned groups. All rats were then returned to the instrumental chamber for an extinction test, in which the lever was extended but no sucrose was delivered. In contrast to sham operated controls, rats with dorsolateral striatum lesions refrained from pressing the lever if the outcome was devalued. To assess the specificity of the role of dorsolateral striatum in this effect a second experiment was conducted in which a group with lesions of dorsomedial striatum was added. In relation now to both the sham and the dorsomedial lesioned groups, only rats with lesions of dorsolateral striatum significantly reduced responding after outcome devaluation. In conclusion, this study provides direct evidence that the dorsolateral striatum is necessary for habit formation. Furthermore, it suggests that, when the habit system is disrupted, control over instrumental performance reverts to the system controlling the performance of goal-directed instrumental actions.
Publisher: Springer International Publishing
Date: 2015
Abstract: Pavlovian stimuli exert a range of effects on behavior from simple conditioned reflexes, such as salivation, to altering the vigor and direction of instrumental actions. It is currently accepted that these distinct behavioral effects stem from two sources (i) the various associative connections between predictive stimuli and the component features of the events that these stimuli predict and (ii) the distinct motivational and cognitive functions served by cues, particularly their arousing and informational effects on the selection and performance of specific actions. Here, we describe studies that have assessed these latter phenomena using a paradigm that has come to be called Pavlovian-instrumental transfer. We focus first on behavioral experiments that have described distinct sources of stimulus control derived from the general affective and outcome-specific predictions of conditioned stimuli, referred to as general transfer and specific transfer, respectively. Subsequently, we describe research efforts attempting to establish the neural bases of these transfer effects, largely in the afferent and efferent connections of the nucleus accumbens (NAc) core and shell. Finally, we examine the role of predictive cues in ex les of aberrant stimulus control associated with psychiatric disorders and addiction.
Publisher: eLife Sciences Publications, Ltd
Date: 04-10-2017
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.BBR.2008.10.034
Abstract: Recent research in instrumental conditioning has focused on the striatum, particularly the role of the dorsal striatum in the learning processes that contribute to instrumental performance in rats. This research has found evidence of what appear to be parallel, functionally and anatomically distinct circuits involving dorsomedial striatum (DMS) and dorsolateral striatum (DLS) that contribute to two independent instrumental learning processes. Evidence suggests that the formation of the critical action-outcome associations mediating goal-directed action are localized to the dorsomedial striatum, whereas the sensorimotor connections that control the performance of habitual actions are localized to the dorsolateral striatum. In addition to the dorsal striatum, these learning processes appear to engage distinct cortico-striatal networks and to be embedded in a complex of converging and partially segregated loops that constitute the cortico-striatal thalamo-cortical feedback circuit. As the entry point for the basal ganglia, cortical circuits involving the dorsal striatum are clearly in a position to control a variety of motor functions but, as recent studies of various neurodegenerative disorders have made clear, they are also involved in a number of cognitive and executive functions including action selection, planning, and decision-making.
Publisher: Informa UK Limited
Date: 14-05-2015
DOI: 10.1586/14737167.2015.1046842
Abstract: Substantial variation in economic analyses of cardiovascular disease management programs hinders not only the proper assessment of cost-effectiveness but also the identification of heterogeneity of interest such as patient characteristics. The authors discuss the impact of reporting and methodological variation on the cost-effectiveness of cardiovascular disease management programs by introducing issues that could lead to different policy or clinical decisions, followed by the challenges associated with net intervention effects and generalizability. The authors conclude with practical suggestions to mitigate the identified issues. Improved transparency through standardized reporting practice is the first step to advance beyond one-off experiments (limited applicability outside the study itself). Transparent reporting is a prerequisite for rigorous cost-effectiveness analyses that provide unambiguous implications for practice: what type of program works for whom and how.
Publisher: Alcohol Research Documentation, Inc.
Date: 2005
Abstract: Recent treatment approaches to substance use disorders have focused on reducing drug use by modifying drug-seeking behaviors in response to drug-associated cues. Understanding the effect of alcohol-related stimuli on alcohol-seeking responses is therefore of interest in the study of alcoholism. The present study examined the impact of ethanol- (ETOH) associated cues on selective ETOH-seeking behavior, using a Pavlovian-instrumental transfer design in groups of alcohol-dependent and nondependent rats. Rats (N = 24) received Pavlovian conditioning in which each of two stimuli, a tone and white noise, was paired alternately with a 10% sweetened ETOH solution and a polycose-quinine solution. The rats were trained to perform two instrumental actions, with one action earning access to the sweetened ETOH and the other to the polycose-quinine. After training, half of the animals were made ETOH-dependent by intragastric administration of 36 g/kg of ETOH over 4 days, whereas the remainder received intragastric administration of an isocaloric polycose solution. On the following day, subjects were given a choice extinction test in which they were free to choose between both actions with no outcomes being delivered. During this test, the ETOH- and polycose-associated Pavlovian cues were presented to assess performance of the two instrumental actions both in the presence and absence of these stimuli. Pavlovian cues associated with both the ETOH or the polycose exerted a nonspecific excitatory influence on reward-seeking behavior in both nondependent and alcohol-dependent rats. Responses through which rats gain access to ETOH appear to be subject to the general excitatory influence of the general motivational arousal induced by reward-related cues. It appears the rats' performance did not depend on encoding the specific consequences of their actions and thus was not affected by the selective retrieval or priming of those consequences in memory.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Cold Spring Harbor Laboratory
Date: 15-12-2021
Abstract: It has been suggested that there are two distinct and parallel mechanisms for controlling instrumental behavior in mammals: goal-directed actions and habits. To gain an understanding of how these two systems interact to control behavior, it is essential to characterize the mechanisms by which the balance between these systems is influenced by experience. Studies in rodents have shown that the amount of training governs the relative expression of these two systems: Behavior is goal-directed following moderate training, but the more extensively an instrumental action is trained, the more it becomes habitual. It is less clear whether humans exhibit similar training effects on the expression of goal-directed and habitual behavior, as human studies have reported contradictory findings. To tackle these contradictory findings, we formed a consortium, where four laboratories undertook a preregistered experimental induction of habits by manipulating the amount of training. There was no statistical evidence for a main effect of the amount of training on the formation and expression of habits. However, exploratory analyses suggest a moderating effect of the affective component of stress on the impact of training over habit expression. Participants who were lower in affective stress appeared to be initially goal-directed, but became habitual with increased training, whereas participants who were high in affective stress were already habitual even after moderate training, thereby manifesting insensitivity to overtraining effects. Our findings highlight the importance of the role of moderating variables such as in idual differences in stress and anxiety when studying the experimental induction of habits in humans.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEURON.2019.01.004
Abstract: Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.
Publisher: Wiley
Date: 20-06-2013
DOI: 10.1111/J.1465-3362.2012.00482.X
Abstract: Increasing the price of alcohol is consistently shown to reduce the average level of consumption. However, the evidence for the effect of increasing the price on high-intensity drinking is both limited and equivocal. The aim of this analysis is to estimate the effect of changes in price on patterns of consumption. Self-reported patterns of alcohol consumption and demographic data were obtained from the Australian National Drug Strategy Household Surveys, conducted in 2001, 2004 and 2007. A pooled three-stage least-squares estimator was used to simultaneously model the impact of the price on the frequency (measured in days) of consuming no, low, moderate and high quantities of alcohol. A 1% increase in the price of alcohol was associated with a statistically significant increase of 6.41 days per year on which no alcohol is consumed (P ≤ 0.049), and a statistically significant decrease of 7.30 days on which 1-4 standard drinks are consumed (P ≤ 0.021). There was no statistically significant change for high or moderate-intensity drinking. For Australia, and countries with a similar pattern of predominant high-intensity drinking, taxation policies that increase the price of alcohol and are very efficient at decreasing harms associated with reduced average consumption may be relatively inefficient at decreasing alcohol harms associated with high-intensity drinking.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2020
DOI: 10.1101/2020.02.28.970616
Abstract: The acquisition of goal-directed action requires the encoding of specific action-outcome associations involving plasticity in the posterior dorsomedial striatum (pDMS). We first investigated the relative involvement of the major inputs to the pDMS argued to be involved in this learning-related plasticity, from prelimbic prefrontal cortex (PL) and from the basolateral amygdala (BLA). Using ex vivo optogenetic stimulation of PL or BLA terminals in pDMS, we found that goal-directed learning potentiated the PL input to direct pathway spiny projection neurons (dSPNs) bilaterally but not to indirect pathway neurons (iSPNs). In contrast, learning-related plasticity was not observed in the direct BLA-pDMS pathway. Using toxicogenetics, we ablated BLA projections to either pDMS or PL and found that only the latter was necessary for goal-directed learning. Importantly, transient inactivation of the BLA during goal-directed learning prevented the PL-pDMS potentiation of dSPNs, establishing that the BLA input to the PL is necessary for the corticostriatal plasticity underlying goal-directed learning.
Publisher: American Psychological Association (APA)
Date: 07-1995
Publisher: Elsevier BV
Date: 2020
Publisher: Society for Neuroscience
Date: 05-01-2011
DOI: 10.1523/JNEUROSCI.4759-10.2011
Abstract: Tonic dopamine (DA) signaling is widely regarded as playing a central role in effort-based decision making and in the motivational control of instrumental performance. The current study used microdialysis to monitor changes in extracellular DA levels across subregions of the nucleus accumbens and dorsal striatum of rats as they lever pressed for food reward on a probabilistic schedule of reinforcement, a procedure that ensured they would experience variation in the amount of effort needed to earn rewards across tests. Each rat was given three tests. Rats were hungry for the first and last test, but were sated on food before the middle test, allowing us to assess the effects of a downshift in motivational state on task performance and conditioning-induced DA efflux. During hungry tests, DA levels rose in both the shell and core of the accumbens and, to a lesser degree, in both the medial and lateral isions of the dorsal striatum. Interestingly, changes in DA efflux across hungry tests in the accumbens core were negatively correlated with changes in the effort required to obtain rewards. We also found that—across regions—the DA response to instrumental conditioning was attenuated when rats were sated before testing. Furthermore, the effect of satiety on DA efflux in the accumbens shell was positively correlated with its effect on task performance. Together, the results indicate that tonic DA contributes to the control of instrumental performance by conveying information about the costs and benefits of responding to different striatal subregions.
Publisher: Wiley
Date: 07-2005
DOI: 10.1111/J.1460-9568.2005.04219.X
Abstract: Although there is consensus that instrumental conditioning depends on the encoding of action-outcome associations, it is not known where this learning process is localized in the brain. Recent research suggests that the posterior dorsomedial striatum (pDMS) may be the critical locus of these associations. We tested this hypothesis by examining the contribution of N-methyl-D-aspartate receptors (NMDARs) in the pDMS to action-outcome learning. Rats with bilateral cannulae in the pDMS were first trained to perform two actions (left and right lever presses), for sucrose solution. After the pre-training phase, they were given an infusion of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (APV, 1 mg/mL) or artificial cerebral spinal fluid (ACSF) before a 30-min session in which pressing one lever delivered food pellets and pressing the other delivered fruit punch. Learning during this session was tested the next day by sating the animals on either the pellets or fruit punch before assessing their performance on the two levers in extinction. The ACSF group selectively reduced responding on the lever that, in training, had earned the now devalued outcome, whereas the APV group did not. Experiment 2 replicated the effect of APV during the critical training session but found no effect of APV given after acquisition and before test. Furthermore, Experiment 3 showed that the effect of APV on instrumental learning was restricted to the pDMS infusion into the dorsolateral striatum did not prevent learning. These experiments provide the first direct evidence that, in instrumental conditioning, NMDARs in the dorsomedial striatum are involved in encoding action-outcome associations.
Publisher: Society for Neuroscience
Date: 23-04-2008
DOI: 10.1523/JNEUROSCI.5472-07.2008
Abstract: Although it has been shown that the basolateral amygdala (BLA) and the mediodorsal thalamus (MD) are critical for goal-directed instrumental performance, much remains unknown about the respective contributions of these structures to action selection. The current study assessed the effects of post-training BLA and MD lesions on several tests of instrumental action selection. We found that MD damage disrupted the influence of pavlovian cues over action selection but left intact rats' ability to select actions based on either the expected value or the discriminative stimulus properties of the outcome. In contrast, BLA lesions impaired performance on all three tests of action selection. Because both lesion types disrupted the influence of cues that signal reward over instrumental performance, we then investigated the involvement of these structures in pavlovian contingency learning using a task in which the predictive status of one of two cues is degraded by delivering its outcome noncontingently during the intertrial interval. As expected, the sham group selectively suppressed their conditioned approach performance to the cue that no longer signaled its outcome but continued to respond to the control stimulus. In contrast, both lesioned groups were impaired on this task. Interestingly, whereas the MD group displayed a nonspecific reduction in responding to both cues, the BLA group continued to show high levels of responding to both cues as if their performance was completely insensitive to this contingency manipulation. These findings demonstrate that the BLA and MD make important yet distinct contributions to instrumental action selection.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.CUB.2015.02.044
Abstract: The capacity to extract causal knowledge from the environment allows us to predict future events and to use those predictions to decide on a course of action. Although evidence of such causal reasoning has long been described, recent evidence suggests that using predictive knowledge to guide decision-making in this way is predicated on reasoning about causes in two quite distinct ways: choosing an action can be based on the interaction between predictive information and the consequences of that action, or, alternatively, actions can be selected based on the consequences that they do not produce. The latter counterfactual reasoning is highly adaptive because it allows us to use information about both present and absent events to guide decision-making. Nevertheless, although there is now evidence to suggest that animals other than humans, including rats and birds, can engage in causal reasoning of one kind or another, there is currently no evidence that they use counterfactual reasoning to guide choice. To assess this question, we gave rats the opportunity to learn new action-outcome relationships, after which we probed the structure of this learning by presenting excitatory and inhibitory cues predicting that the specific outcomes of their actions would either occur or would not occur. Whereas the excitors biased choice toward the action delivering the predicted outcome, the inhibitory cues selectively elevated actions predicting the absence of the inhibited outcome, suggesting that rats encoded the counterfactual action-outcome mappings and were able to use them to guide choice.
Publisher: American Psychological Association (APA)
Date: 1991
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-01-2020
Abstract: An intriguing characteristic of the striatum is the random spatial distribution and high degree of intermingling between expression of dopamine receptor types 1 (D1) and 2 (D2) within striatal projection neurons (SPNs). The resulting highly entropic mosaic extends through a homogeneous space and is mostly devoid of histological boundaries. The rules established locally by D1- and D2-expressing SPNs (D1-SPNs and D2-SPNs) are thus likely critical in defining how functional territories develop throughout the striatum. Matamales et al. found that activated D2-SPNs access and modify developing behavioral programs encoded by regionally defined ensembles of transcriptionally active D1-SPNs. This process is slow because it depends on the molecular integration of additive neuro-modulatory signals. However, with time, it creates the regional functional boundaries that are necessary to identify and shape specific learning in the striatum. Science , this issue p. 549
Publisher: Society for Neuroscience
Date: 24-08-2005
DOI: 10.1523/JNEUROSCI.1921-05.2005
Abstract: Several studies have established that pretraining lesions of the medial prefrontal cortex (mPFC) render instrumental actions insensitive to devaluation of the instrumental outcome and degradation of the action-outcome contingency. Nevertheless, it remains to be assessed whether the involvement of the mPFC in goal-directed action is limited to the acquisition or to the expression of the action-outcome association in performance. The current series of experiments investigated this issue by comparing the effects of mPFC lesions made either before or after initial training using sensitivity to outcome devaluation as an assay of goal-directed performance. Whereas pretraining lesions left performance insensitive to outcome devaluation, posttraining lesions spared this effect. To determine whether the effect of mPFC lesions on outcome devaluation was the result of a more fundamental deficit in response selection, experiment 2 assessed the impact of pretraining and posttraining lesions on the ability of the instrumental outcome to selectively reinstate the performance of its associated action after a period of extinction. Although both lesions attenuated the magnitude of instrumental reinstatement generally, they left intact the ability of the instrumental outcome to influence response selection. Experiment 3 investigated the relationship between the outcome-selective devaluation and reinstatement effects and found evidence that these effects are both behaviorally and neurally dissociable at the level of the mPFC. These results indicate that the mPFC is selectively involved in the acquisition, but not the permanent storage or expression, of action-outcome associations in instrumental conditioning.
Publisher: Elsevier BV
Date: 30-01-2006
DOI: 10.1016/J.BBR.2005.07.012
Abstract: Actions become compulsive when they are no longer controlled by their consequences. Compulsivity can be assessed using the omission procedure in which animals are required to withhold a previously reinforced action to earn reward. The current study tested the hypothesis that inactivation of the dorsolateral striatum (DLS), a structure implicated in habitual behavior, can enhance sensitivity to changes in the action-outcome contingency during omission training, thus leading to a reduction in compulsive responding. Over 10 days rats were trained to press a freely available lever for sucrose reward delivered on interval schedules of reinforcement. After learning to press the lever at a stable and high rate, rats in the omission group received a session in which the rewards were now delayed by pressing the lever i.e. withholding lever pressing resulted in increased access to reward. A control group was yoked to the omission group and received the same number and pattern of reward delivery but without the omission contingency. Half the rats in each group received infusions of vehicle into the DLS prior to this training whereas the remainder received an infusion of the GABA-A receptor agonist muscimol. On the next day, the effect of these treatments was assessed on a probe test in which the tendency of the various groups to press the lever was assessed in extinction and without drug infusion. Rats that received vehicle infusions prior to the omission session showed complete insensitivity to the newly imposed omission contingency. In contrast, rats given the infusion of muscimol selectively reduced lever pressing compared to yoked controls. Thus, extended training with interval schedules resulted in compulsive lever pressing that prevented the learning of the omission contingency, whereas inactivation of the DLS appeared to enhance the rats' sensitivity to this change in the action-outcome contingency.
Publisher: Wiley
Date: 10-06-2017
DOI: 10.1111/BPH.13832
Publisher: Springer Science and Business Media LLC
Date: 03-03-2018
DOI: 10.1038/S41398-018-0103-0
Abstract: Learning the causal relation between actions and their outcomes (AO learning) is critical for goal-directed behavior when actions are guided by desire for the outcome. This can be contrasted with habits that are acquired by reinforcement and primed by prevailing stimuli, in which causal learning plays no part. Recently, we demonstrated that goal-directed actions are impaired in schizophrenia however, whether this deficit exists alongside impairments in habit or reinforcement learning is unknown. The present study distinguished deficits in causal learning from reinforcement learning in schizophrenia. We tested people with schizophrenia (SZ, n = 25) and healthy adults (HA, n = 25) in a vending machine task. Participants learned two action–outcome contingencies (e.g., push left to get a chocolate M& M, push right to get a cracker), and they also learned one contingency was degraded by delivery of noncontingent outcomes (e.g., free M& Ms), as well as changes in value by outcome devaluation. Both groups learned the best action to obtain rewards however, SZ did not distinguish the more causal action when one AO contingency was degraded. Moreover, action selection in SZ was insensitive to changes in outcome value unless feedback was provided, and this was related to the deficit in AO learning. The failure to encode the causal relation between action and outcome in schizophrenia occurred without any apparent deficit in reinforcement learning. This implies that poor goal-directed behavior in schizophrenia cannot be explained by a more primary deficit in reward learning such as insensitivity to reward value or reward prediction errors.
Publisher: American Psychological Association (APA)
Date: 2010
DOI: 10.1037/A0016484
Publisher: Society for Neuroscience
Date: 02-02-2011
DOI: 10.1523/JNEUROSCI.3102-10.2011
Abstract: The decision to perform, or not perform, actions known to lead to a rewarding outcome is strongly influenced by the current incentive value of the reward. Incentive value is largely determined by the affective experience derived during previous consumption of the reward—the process of incentive learning. We trained rats on a two-lever, seeking–taking chain paradigm for sucrose reward, in which responding on the initial seeking lever of the chain was demonstrably controlled by the incentive value of the reward. We found that infusion of the μ-opioid receptor antagonist, CTOP ( d -Phe-Cys-Tyr- d -Trp-Orn-Thr-Pen-Thr-NH 2 ), into the basolateral amygdala (BLA) during posttraining, noncontingent consumption of sucrose in a novel elevated-hunger state (a positive incentive learning opportunity) blocked the encoding of incentive value information normally used to increase subsequent sucrose-seeking responses. Similar treatment with δ [ N , N -diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864)] or κ [5′-guanidinonaltrindole (GNTI)] antagonists was without effect. Interestingly, none of these drugs affected the ability of the rats to encode a decrease in incentive value resulting from experiencing the sucrose in a novel reduced-hunger state. However, the μ agonist, DAMGO ([d-Ala2, NMe-Phe4, Gly5-ol]-enkephalin), appeared to attenuate this negative incentive learning. These data suggest that upshifts and downshifts in endogenous opioid transmission in the BLA mediate the encoding of positive and negative shifts in incentive value, respectively, through actions at μ-opioid receptors, and provide insight into a mechanism through which opiates may elicit inappropriate desire resulting in their continued intake in the face of diminishing affective experience.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.NEUBIOREV.2016.09.020
Abstract: Reward-related cues are an important part of our daily life as they often influence and guide our actions. This paper reviews one of the experimental paradigms used to study the effects of cues, the Pavlovian to Instrumental Transfer paradigm. In this paradigm, cues associated with rewards through Pavlovian conditioning alter motivation and choice of instrumental actions. The first transfer experiments date back to the 1940s, but only in the last decade has it been fully recognised that there are two types of transfer, specific and general. This paper presents a systematic review of both the neural substrates and the behavioral factors affecting both types of transfer. It also examines the recent application of the paradigm to study the effect of cues on human participants, both in normal and pathological conditions, and the interactions of transfer with drugs of abuse. Finally, the paper analyses the theoretical aspects of transfer to build an overall picture of the phenomenon, from early theories to recent hierarchical accounts.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Society for Neuroscience
Date: 02-2012
DOI: 10.1523/JNEUROSCI.4688-11.2012
Abstract: Two motivational processes affect choice between actions: (1) changes in the reward value of the goal or outcome of an action and (2) changes in the predicted value of an action based on outcome-related stimuli. Here, we evaluated the role of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) in the nucleus accumbens in the way these motivational processes influence choice using outcome revaluation and pavlovian-instrumental transfer tests. We first examined the effect of genetic deletion of MOR and DOR in specific knock-out mice. We then assessed the effect of infusing the MOR antagonist d -Phe-Cys-Tyr- d -Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) or the DOR antagonist naltrindole into the core or shell subregions of the nucleus accumbens on these tests in rats. We found that, whereas MOR knock-outs showed normal transfer, they failed to show a selective outcome revaluation effect. Conversely, DOR knock-outs showed normal revaluation but were insensitive to the influence of outcome-related cues on choice. This double dissociation was also found regionally within the nucleus accumbens in rats. Infusion of naltrindole into the accumbens shell abolished transfer but had no effect on outcome revaluation and did not influence either effect when infused into the accumbens core. Conversely, infusion of CTAP into the accumbens core abolished sensitivity to outcome revaluation but had no effect on transfer and did not influence either effect when infused into the accumbens shell. These results suggest that reward-based and stimulus-based values exert distinct motivational influences on choice that can be doubly dissociated both neuroanatomically and neurochemically at the level of the nucleus accumbens.
Publisher: Public Library of Science (PLoS)
Date: 28-12-2012
Publisher: Frontiers Media SA
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 13-01-2023
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.CUB.2016.04.023
Abstract: In many contexts, decision-making requires an accurate representation of outcome variance-otherwise known as "risk" in economics. Conventional economic theory assumes this representation to be perfect, thereby focusing on risk preferences rather than risk perception per se [1-3] (but see [4]). However, humans often misrepresent their physical environment. Perhaps the most striking of such misrepresentations are the many well-known sensory after-effects, which most commonly involve visual properties, such as color, contrast, size, and motion. For ex le, viewing downward motion of a waterfall induces the anomalous biased experience of upward motion during subsequent viewing of static rocks to the side [5]. Given that after-effects are pervasive, occurring across a wide range of time horizons [6] and stimulus dimensions (including properties such as face perception [7, 8], gender [9], and numerosity [10]), and that some evidence exists that neurons show adaptation to variance in the sole visual feature of motion [11], we were interested in assessing whether after-effects distort variance perception in humans. We found that perceived variance is decreased after prolonged exposure to high variance and increased after exposure to low variance within a number of different visual representations of variance. We demonstrate these after-effects occur across very different visual representations of variance, suggesting that these effects are not sensory, but operate at a high (cognitive) level of information processing. These results suggest, therefore, that variance constitutes an independent cognitive property and that prolonged exposure to extreme variance distorts risk perception-a fundamental challenge for economic theory and practice.
Publisher: Society for Neuroscience
Date: 09-07-2014
Publisher: eLife Sciences Publications, Ltd
Date: 23-10-2017
DOI: 10.7554/ELIFE.29908
Abstract: The acquisition of motor skills involves implementing action sequences that increase task efficiency while reducing cognitive loads. This learning capacity depends on specific cortico-basal ganglia circuits that are affected by normal ageing. Here, combining a series of novel behavioural tasks with extensive neuronal mapping and targeted cell manipulations in mice, we explored how ageing of cortico-basal ganglia networks alters the microstructure of action throughout sequence learning. We found that, after extended training, aged mice produced shorter actions and displayed squeezed automatic behaviours characterised by ultrafast oligomeric action chunks that correlated with deficient reorganisation of corticostriatal activity. Chemogenetic disruption of a striatal subcircuit in young mice reproduced age-related within-sequence features, and the introduction of an action-related feedback cue temporarily restored normal sequence structure in aged mice. Our results reveal static properties of aged cortico-basal ganglia networks that introduce temporal limits to action automaticity, something that can compromise procedural learning in ageing.
Publisher: MDPI AG
Date: 27-02-2014
Publisher: Wiley
Date: 07-2014
DOI: 10.1111/BPH.12731
Publisher: Wiley
Date: 19-03-2021
DOI: 10.1111/JNC.15339
Abstract: Predictive learning endows stimuli with the capacity to signal both the sensory‐specific and general motivational properties of their associated rewards or outcomes. These two signals can be distinguished behaviorally by their influence on the selection and performance of instrumental actions, respectively. This review focuses on how sensory‐specific predictive learning guides choice between actions that earn otherwise equally desirable outcomes. We describe evidence that outcome‐specific predictive learning is encoded in the basolateral amygdala and drives the accumulation of delta‐opioid receptors on the surface of cholinergic interneurons located in the nucleus accumbens shell. This accumulation constitutes a novel form of cellular memory, not for outcome‐specific predictive learning per se but for the selection of, and choice between, future instrumental actions. We describe recent evidence regarding the cascade of events necessary for the formation and expression of this cellular memory and point to open questions for future research into this process. Beyond these mechanistic considerations, the discovery of this new form of memory is consistent with recent evidence suggesting that intracellular rather than synaptic changes can mediate learning‐related plasticity to modify brain circuitry to prepare for future significant events. image
Publisher: Society for Neuroscience
Date: 21-08-2013
DOI: 10.1523/JNEUROSCI.1697-13.2013
Abstract: The nucleus accumbens shell (NAc-S) plays an important role in the way stimuli that predict reward affect the performance of, and choice between, goal-directed actions in tests of outcome-specific Pavlovian-instrumental transfer (PIT). The neural processes involved in PIT downstream of the ventral striatum are, however, unknown. The NAc-S projects prominently to the ventral pallidum (VP), and in the current experiments, we assessed the involvement of the NAc-S to VP projection in specific PIT in rats. We first compared expression of the immediate-early gene c-Fos in the medial (VP-m) and lateral (VP-l) regions of the VP and in addition, used the retrograde tracer Fluoro-gold combined with c-Fos to assess the involvement of these pathways during PIT. Although there was no evidence of differential activation in neurons in the VP-l, the VP-m showed a selective increase in activity in rats tested for PIT compared with appropriate controls, as did NAc-S neurons projecting to the VP-m. To confirm that VP-m activity is important for PIT, we inactivated this region before test and found this inactivation blocked the influence of predictive learning on choice. Finally, to confirm the functional importance of the NAc-S to VP-m pathway we used a disconnection procedure, using asymmetrical inactivation of the NAc-S and either the ipsilateral or contralateral VP-m. Specific PIT was blocked but only by inactivation of the NAc-S and VP-m in contralateral hemispheres. These results suggest that the NAc-S and VP-m form part of a circuit mediating the effects of predictive learning on choice.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0896-6273(02)00963-7
Abstract: There is substantial evidence that dopamine is involved in reward learning and appetitive conditioning. However, the major reinforcement learning-based theoretical models of classical conditioning (crudely, prediction learning) are actually based on rules designed to explain instrumental conditioning (action learning). Extensive anatomical, pharmacological, and psychological data, particularly concerning the impact of motivational manipulations, show that these models are unreasonable. We review the data and consider the involvement of a rich collection of different neural systems in various aspects of these forms of conditioning. Dopamine plays a pivotal, but complicated, role.
Publisher: Society for Neuroscience
Date: 06-10-2017
DOI: 10.1523/JNEUROSCI.3415-16.2017
Abstract: Animals can readily learn that stimuli predict the absence of specific appetitive outcomes however, the neural substrates underlying such outcome-specific conditioned inhibition remain largely unexplored. Here, using female and male rats as subjects, we examined the involvement of the lateral habenula (LHb) and of its inputs onto the rostromedial tegmental nucleus (RMTg) in inhibitory learning. In these experiments, we used backward conditioning and contingency reversal to establish outcome-specific conditioned inhibitors for two distinct appetitive outcomes. Then, using the Pavlovian-instrumental transfer paradigm, we assessed the effects of manipulations of the LHb and the LHb–RMTg pathway on that inhibitory encoding. In control animals, we found that an outcome-specific conditioned inhibitor biased choice away from actions delivering that outcome and toward actions earning other outcomes. Importantly, this bias was abolished by both electrolytic lesions of the LHb and selective ablation of LHb neurons using Cre-dependent Caspase3 expression in Cre-expressing neurons projecting to the RMTg. This deficit was specific to conditioned inhibition an excitatory predictor of a specific outcome-biased choice toward actions delivering the same outcome to a similar degree whether the LHb or the LHb–RMTg network was intact or not. LHb lesions also disrupted the ability of animals to inhibit previously encoded stimulus–outcome contingencies after their reversal, pointing to a critical role of the LHb and of its inputs onto the RMTg in outcome-specific conditioned inhibition in appetitive settings. These findings are consistent with the developing view that the LHb promotes a negative reward prediction error in Pavlovian conditioning. SIGNIFICANCE STATEMENT Stimuli that positively or negatively predict rewarding outcomes influence choice between actions that deliver those outcomes. Previous studies have found that a positive predictor of a specific outcome biases choice toward actions delivering that outcome. In contrast, a negative predictor of an outcome biases choice away from actions earning that outcome and toward other actions. Here we reveal that the lateral habenula is critical for negative predictors, but not positive predictors, to affect choice. Furthermore, these effects were found to require activation of lateral habenula inputs to the rostromedial tegmental nucleus. These results are consistent with the view that the lateral habenula establishes inhibitory relationships between stimuli and food outcomes and computes a negative prediction error in Pavlovian conditioning.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2015
DOI: 10.1038/TP.2015.148
Abstract: Cognitive impairment is a functionally disabling feature of depression contributing to maladaptive decision-making, a loss of behavioral control and an increased disease burden. The ability to calculate the causal efficacy of ones actions in achieving specific goals is critical to normal decision-making and, in this study, we combined voxel-based morphometry (VBM), shape analysis and diffusion tensor tractography to investigate the relationship between cortical–basal ganglia structural integrity and such causal awareness in 43 young subjects with depression and 21 demographically similar healthy controls. Volumetric analysis determined a relationship between right pallidal size and sensitivity to the causal status of specific actions. More specifically, shape analysis identified dorsolateral surface vertices where an inward location was correlated with reduced levels of causal awareness. Probabilistic tractography revealed that affected parts of the pallidum were primarily connected with the striatum, dorsal thalamus and hippoc us. VBM did not reveal any whole-brain gray matter regions that correlated with causal awareness. We conclude that volumetric reduction within the indirect pathway involving the right dorsolateral pallidum is associated with reduced awareness of the causal efficacy of goal-directed actions in young depressed in iduals. This causal awareness task allows for the identification of a functionally and biologically relevant subgroup to which more targeted cognitive interventions could be applied, potentially enhancing the long-term outcomes for these in iduals.
Publisher: Cold Spring Harbor Laboratory
Date: 29-03-2022
DOI: 10.1101/2022.03.28.486040
Abstract: Performing several actions in swift succession is often necessary to exploit known contingencies in the environment. However, in order to remain successful when contingency rules change, streamlined action sequences must be adaptable. Here, by combining analyses of behavioural microstructure with circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relies on post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). Using a two-lever instrumental task, we found that mice build successful action sequences by first establishing action scaffolds, from which they dynamically elongate as task requirements extend. Specific interruption of the M1→DLS circuit altered these dynamics, prompting actions that were less variable in their timing, overall reducing opportunities for success. Our results reveal a role for M1→DLS circuitry in setting the exploration/exploitation balance that is required for adaptively guiding the timing and success of instrumental action. Based on evidence from transsynaptic tracing experiments, we propose that such function may involve additional downstream subcortical processing relating to collateralisation of descending motor pathways to multiple basal ganglia centres.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2002
DOI: 10.1007/S00221-002-1031-Y
Abstract: In two experiments the involvement of the nucleus accumbens in instrumental conditioning was investigated using rats as subjects. In experiment 1, extensive bilateral cytotoxic lesions of the nucleus accumbens mildly suppressed instrumental responding reinforced with food, but had no detectable effect on the sensitivity of the rats' performance either to outcome devaluation or to degradation of the instrumental contingency. In experiment 2, restricted accumbens lesions reliably attenuated the excitatory effect of systemically administered d- hetamine on lever pressing for a conditioned reinforcer, and completely abolished Pavlovian-instrumental transfer. Taken together these results give a picture of the involvement of the rat nucleus accumbens in instrumental conditioning. They support the widely held theory that the nucleus accumbens mediates the excitatory effects of appetitively conditioned Pavlovian signals on instrumental performance and refute the hypothesis that the nucleus accumbens is part of the neural circuitry by which incentive value is attached to the representations of instrumental outcomes.
Publisher: Wiley
Date: 07-2005
DOI: 10.1111/J.1460-9568.2005.04218.X
Abstract: Considerable evidence suggests that, in instrumental conditioning, rats learn the relationship between actions and their specific consequences or outcomes. The present study examined the role of the dorsomedial striatum (DMS) in this type of learning after excitotoxic lesions and reversible, muscimol-induced inactivation. In three experiments, rats were first trained to press two levers for distinct outcomes, and then tested after training using a variety of behavioural assays that have been established to detect action-outcome learning. In Experiment 1, pre-training lesions of the posterior DMS abolished the sensitivity of rats' instrumental performance to both outcome devaluation and contingency degradation when tested in extinction, whereas lesions of the anterior DMS had no effect. In Experiment 2, both pre-training and post-training lesions of the posterior DMS were equally effective in reducing the sensitivity of performance both to devaluation and degradation treatments. In Experiment 3, the infusion of muscimol into the posterior DMS selectively abolished sensitivity of performance to devaluation and contingency degradation without impairing the ability of rats to discriminate either the instrumental actions performed or the identity of the earned outcomes. Taken together, these results suggest that the posterior region of the DMS is a crucial neural substrate for the acquisition and expression of action-outcome associations in instrumental conditioning.
Publisher: Cold Spring Harbor Laboratory
Date: 31-10-2022
DOI: 10.1101/2022.10.06.22280808
Abstract: OCD has been characterized by recent data as a disorder of cognition. Recent data also show pathology in prefrontal-subcortical networks. We leveraged cross-species prefrontal-subcortical cytoarchitectonic homologies in order to parse anatomical abnormalities in people with OCD into higher resolution areas and neuronal networks. We established that the anatomical abnormalities associated with OCD predominantly reside in a neuronal network associated with emotional processing. We further provide evidence that current tests do not accurately dissociate emotion from cognition and so relying on them risks mis-stating the role of prefrontal-subcortical networks. Taken together, these findings reveal the neglect of the role of emotion in the pathophysiology of OCD. Recent advances in the cytoarchitectonic parcellation of the human brain have significant implications for major psychiatric conditions such as obsessive-compulsive disorder (OCD). Brodmann’s areas have remained in use as the histological map of the human brain, framing its functional correlates in health and disease. However, cytological research has continued to refine these isions in some cases substantially. For instance, the 16 areas in Brodmann’s prefrontal cortex have expanded to 63, delivering a four-fold increase in granular resolution. These contemporary cytoarchitectonic areas have been parcellated into distinct prefrontal-striatal networks responsible for (i) the control of emotions and visceral organs, (ii) mental representation and classification of external objects, and (iii) the control of visual attention. Interacting pathology across prefrontal-striatal circuits makes OCD a paradigmatic condition upon which to apply these advances. The enhanced granular and network resolution this provides could transform human brain imaging from the original isions of 1909 to higher resolution delineations, for ex le, providing precise mediolateral partitioning of the orbitofrontal cortex, thereby distilling the substrates of obsessions and compulsions. Here we provide a meta-review of existing reports of thousands of people with OCD to reveal impairments spanning sensory integration, affective arousal, cognitive control, and motor action selection. Behavioral data previously interpreted as implicating only cognitive abnormalities have failed to detect cognitive impairment in children and adolescents with OCD casting doubt on the sensitivity of conventional tests and the temporal relationship between apparent pathology in adults and OCD symptoms. Therefore, by relying on that behavioral evidence alone we risk mis-characterizing OCD solely as a disorder of cognition. Moreover, the presence of sensorimotor and neuroimaging abnormalities in young people with OCD indicate the chronological primacy of undifferentiated abnormalities in neuronal structure and function. Neuronal correlates of OCD symptoms were found to map evenly into emotional-visceral and object assessment networks within the visual attention network only the premotor cortex had substantive abnormality. Tasks reported as measuring cognition also distributed equally across networks further calling into question the physiological fidelity of these tasks. In contrast, tasks reported as measuring emotion mapped faithfully onto the emotional-visceral network. Volumetric changes in people with OCD also implicated the emotional-visceral network, in which the number of abnormalities were double those in the object assessment network. Although conventional behavioral tasks characterize OCD as a cognitive disorder, associated anatomical abnormalities are, in fact, distributed across two distinct neuronal networks responsible for (i) the control of emotions and visceral organs and (ii) the representation of external objects. The predominance of abnormalities in an emotional-visceral neuronal network contrasts with the paucity of research on emotional processing in OCD relative to tasks reported to test cognition, showing an inflated attribution of cognitive relative to emotional dysfunction in the pathophysiology of OCD. The histologically derived orbital and medial prefrontal cortex subregions, shown here as selectively affected in people with OCD, provide higher resolution candidate treatment targets for neurostimulation and other therapeutics. Extending our current work to other conditions could identify transdiagnostic neural signatures of psychiatric symptoms. Structural brain changes in people with OCD reside predominantly in a neuronal network responsible for emotional control. Neuronal networks derived from cross-species studies of cell structure, projections, and function transform the granular resolution of human brain imaging analysis to reveal the role of an emotional-visceral network in the pathophysiology of OCD.
Publisher: Elsevier BV
Date: 02-2014
Publisher: Public Library of Science (PLoS)
Date: 10-12-2015
Publisher: Society for Neuroscience
Date: 08-2007
Publisher: Society for Neuroscience
Date: 22-04-2015
DOI: 10.1523/JNEUROSCI.4153-14.2015
Abstract: The anterior insular cortex (IC) and the nucleus accumbens (NAc) core have been separately implicated in the selection and performance of actions based on the incentive value of the instrumental outcome. Here, we examined the role of connections between the IC and the NAc core in the performance of goal-directed actions. Rats were trained on two actions for distinct outcomes, after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed the projection from the IC to the NAc core and then disconnected these structures via asymmetrical excitotoxic lesions before training. Contralateral, but not ipsilateral, disconnection of the IC and NAc core disrupted outcome devaluation. We hypothesized that communication between the IC and NAc core is necessary for the retrieval of incentive value at test. To test this, we infused the GABA A agonist muscimol into the IC and the μ-opioid receptor antagonist CTAP into the contralateral NAc before the choice extinction test. As expected, inactivation of the IC in one hemisphere and blocking μ-opioid receptors in the contralateral NAc core abolished outcome-selective devaluation. These results suggest that the IC and NAc core form part of a circuit mediating the retrieval of outcome values and the subsequent choice between goal-directed actions based on those values.
Publisher: Springer Science and Business Media LLC
Date: 19-10-2021
Publisher: Springer Science and Business Media LLC
Date: 08-03-2021
DOI: 10.1038/S41598-021-84359-7
Abstract: Research in the field of multisensory perception shows that what we hear can influence what we see in a wide range of perceptual tasks. It is however unknown whether this extends to the visual perception of risk, despite the importance of the question in many applied domains where properly assessing risk is crucial, starting with financial trading. To fill this knowledge gap, we ran interviews with professional traders and conducted three laboratory studies using judgments of financial asset risk as a testbed. We provide evidence that the presence of ambient sound impacts risk perception, possibly due to the combination of facilitatory and synesthetic effects of general relevance to the perception of risk in many species as well as humans. We discuss the implications of our findings for various applied domains (e.g., financial, medical, and military decision-making), and raise new questions for future research.
Publisher: Wiley
Date: 30-06-2015
DOI: 10.1111/EJN.12971
Abstract: In instrumental conditioning, newly acquired actions are generally goal-directed and are mediated by the relationship between the action and its consequences or outcome. With continued training, however, the performance of such actions can become automatic, reflexive or habitual and under the control of antecedent stimuli rather than their consequences. Recent evidence suggests that habit learning is mediated by plasticity in the dorsolateral striatum (DLS). To date, however, no direct evidence of learning-related plasticity associated with overtraining has been reported in this region, nor is it known whether, or which, specific cell types are involved in this learning process. The striatum is primarily composed of two classes of spiny projection neurons, the striatonigral and striatopallidal spiny projection neurons, which express dopamine D1 and D2 receptors, and control direct and indirect pathways, respectively. Here we found evidence of a post-synaptic depression in DLS striatopallidal projecting neurons in the indirect pathway during habit learning in mice. Moreover, this training-induced depression occluded post-synaptic depression induced by co-activation of D2 receptors and transient receptor potential vanilloid 1 (TRPV1) channels, implying that this pathway is involved in habit learning. This hypothesis was further tested by disrupting this signal pathway by knocking out TRPV1 channels, resulting in compromised habit learning. Our findings suggest that post-synaptic plasticity at D2 neurons in the DLS mediates habit learning and, by implicating an interaction between the D2 receptor and TRPV1 channel activity, provide a potential drug target for influencing habitual action control.
Publisher: Society for Neuroscience
Date: 26-01-2005
DOI: 10.1523/JNEUROSCI.4716-04.2005
Abstract: Incentive learning is the process via which animals update changes in the value of rewards. Current evidence suggests that, for food rewards in rats, this learning process involves the amygdala. However, it remains unclear whether this learning undergoes protein synthesis-dependent consolidation and “reconsolidation” processes in the lateral and basal nuclei of amygdala. Accordingly, we examined this hypothesis by local infusion of protein-synthesis inhibitor after devaluation of a food reward induced by a shift from a food-deprived to a food-sated state in an instrumental conditioning paradigm. Our results show that intra-amygdala infusions of anisomycin, whether given after the initial devaluation or after a second devaluation session, abolished the changes in the value of the food reward produced by incentive learning. This study provides direct evidence that instrumental incentive learning depends on protein synthesis within the amygdala for both consolidation and reconsolidation and extends the demonstrations of protein synthesis-dependent reconsolidation to reward-related memories.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JNEUMETH.2017.11.010
Abstract: High resolution neuronal information is extraordinarily useful in understanding the brain's functionality. The development of the Golgi-Cox stain allowed observation of the neuron in its entirety with unrivalled detail. Tissue clearing techniques, e.g., CLARITY and CUBIC, provide the potential to observe entire neuronal circuits intact within tissue and without previous restrictions with regard to section thickness. Here we describe an improved Golgi-Cox stain method, optimised for use with CLARITY and CUBIC that can be used in both fresh and fixed tissue. Using this method, we were able to observe neurons in their entirety within a fraction of the time traditionally taken to clear tissue (48h). We were also able to show for the first-time that Golgi stained tissue is fluorescent when visualized using a multi-photon microscope, allowing us to image synaptic spines with a detail previously unachievable. These novel methods provide cheap and easy to use techniques to investigate the morphology of cellular processes in the brain at a new-found depth, speed, utility and detail, without previous restrictions of time, tissue type and section thickness. This is the first application of a Golgi-Cox stain to cleared brain tissue, it is investigated and discussed in detail, describing different methodologies that may be used, a comparison between the different clearing techniques and lastly the novel interaction of these techniques with this ultra-rapid stain.
Publisher: MDPI AG
Date: 21-03-2017
Publisher: Springer Science and Business Media LLC
Date: 03-1994
DOI: 10.3758/BF03199951
Publisher: Frontiers Media SA
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NCOMMS5390
Publisher: Public Library of Science (PLoS)
Date: 05-12-2013
Publisher: Springer Science and Business Media LLC
Date: 03-1998
DOI: 10.3758/BF03199161
Publisher: American Psychological Association (APA)
Date: 1992
Publisher: Elsevier BV
Date: 06-1989
DOI: 10.1016/0006-8993(89)90261-8
Abstract: The effects of stress on self-stimulation were investigated by exposing rats to either controllable, uncontrollable or no footshock. Both controllable and uncontrollable footshock increased medial prefrontal cortex self-stimulation rates immediately as well as 24 h following treatment. Controllable footshock produced a greater enhancement than uncontrollable footshock. In contrast, self-stimulation of the lateral hypothalamus was unaffected by either footshock treatment. These results are interpreted with reference to the neurochemical response of the mesocortical dopaminergic system to acute stress.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.CUB.2016.09.021
Abstract: Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL) inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippoc us (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations.
Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2011
DOI: 10.1101/LM.2229311
Abstract: Here we attempted to clarify the role of dopamine signaling in reward seeking. In Experiment 1, we assessed the effects of the dopamine D 1 /D 2 receptor antagonist flupenthixol (0.5 mg/kg i.p.) on Pavlovian incentive motivation and found that flupenthixol blocked the ability of a conditioned stimulus to enhance both goal approach and instrumental performance (Pavlovian-to-instrumental transfer). In Experiment 2 we assessed the effects of flupenthixol on reward palatability during post-training noncontingent re-exposure to the sucrose reward in either a control 3-h or novel 23-h food-deprived state. Flupenthixol, although effective in blocking the Pavlovian goal approach, was without effect on palatability or the increase in reward palatability induced by the upshift in motivational state. This noncontingent re-exposure provided an opportunity for instrumental incentive learning, the process by which rats encode the value of a reward for use in updating reward-seeking actions. Flupenthixol administered prior to the instrumental incentive learning opportunity did not affect the increase in subsequent off-drug reward-seeking actions induced by that experience. These data suggest that although dopamine signaling is necessary for Pavlovian incentive motivation, it is not necessary for changes in reward experience, or for the instrumental incentive learning process that translates this experience into the incentive value used to drive reward-seeking actions, and provide further evidence that Pavlovian and instrumental incentive learning processes are dissociable.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.NLM.2005.12.001
Abstract: In two experiments we investigated the effects of elevated dopaminergic tone on instrumental learning and performance using dopamine transporter knockdown (DAT KD) mice. In Experiment 1, we showed that both DAT KD mice and wild-type controls were similarly sensitive to outcome devaluation induced by sensory specific satiety, indicating normal action-outcome learning in both groups. In Experiment 2, we used a Pavlovian-to-instrumental transfer procedure to assess the potentiation of instrumental responding by Pavlovian conditional stimuli (CS). Although during the Pavlovian training phase the DAT KD mice entered the food magazine more frequently in the absence of the CS, when tested later both groups showed outcome-selective PIT. These results suggest that the elevated dopaminergic tone reduced the selectivity of stimulus control over conditioned behavior, but did not affect instrumental learning.
Publisher: Wiley
Date: 09-11-2016
DOI: 10.1111/JNC.13858
Abstract: Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippoc us, prefrontal cortex and ventromedial striatum regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
Publisher: Cambridge University Press (CUP)
Date: 29-07-2008
DOI: 10.1017/S0140525X08004925
Abstract: A central theme of the unified framework for addiction advanced by Redish et al. is that there exists a common value or incentive process controlling Pavlovian and instrumental conditioning. Here we briefly review evidence from a variety of sources demonstrating that these incentive processes are in fact independent. Clearly the influence of Pavlovian predictors and goal values on choice offer distinct potential targets for pathologies of decision-making.
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 12-2008
Publisher: Nanyang Technol. Univ
Date: 2002
Publisher: SAGE Publications
Date: 02-2008
DOI: 10.1080/17470210601154594
Abstract: In each of two experiments, two groups of rats were exposed to three flavoured solutions: A (citric acid), B (salt), and AX (a compound of citric acid and saccharin). Both experiments used a between-subjects design in which a paired group received presentations of A followed by B, alternating with presentations of AX (i.e., A → B/AX), and an unpaired group received alternating presentations of A, B, and AX (i.e., A/B/AX). This arrangement was expected to establish X as an inhibitor of B in group paired but not in group unpaired. In Experiment 1, after preexposure all subjects received a single presentation of an XB compound, then experienced sodium depletion, and were tested for their consumption of X, which was greater in group unpaired than in group paired. In Experiment 2, after preexposure, all subjects received four presentations of a new flavour, C, in compound with B and subsequently, under sodium depletion, were tested for consumption of XC. Intake of the XC compound was less in group paired than in group unpaired. These results suggest that, in group paired, X acquired an inhibitory relationship with B both retarding the acquisition of an excitatory association with B (retardation test, Experiment 1) and reducing the response to a new stimulus, C, strongly associated to B (summation test, Experiment 2). These results provide direct evidence of inhibition between two neutral stimuli and, therefore, of inhibitory sensory preconditioning.
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2022
DOI: 10.1101/2022.07.25.501480
Abstract: Cognitive-behavioural testing in preclinical models of Alzheimer’s disease has typically been limited to visuo-spatial memory tests and has failed to capture the broad scope of deficits patients also display in goal-directed action control. The current study addresses this gap by providing the first comprehensive investigation of how goal-directed actions are affected in a transgenic mouse model of Alzheimer’s disease. Specifically, we tested outcome devaluation performance – a popular test of goal-directed action – in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press a left and right lever for unique pellet and sucrose outcomes respectively (counterbalanced) over four days. On test, mice were fed one of the two outcomes to reduce its value via sensory specific satiety and subsequently given a choice between levers. Goal-directed action was intact for 36-week-old wildtype mice of both sexes, because they responded more on the lever associated with the still-valued outcome than that associated with the devalued outcome (i.e. Valued Devalued). Goal-directed action was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. Following an additional 4 days of lever press training (i.e., 8 days lever pressing in total), outcome devaluation was intact for all mice regardless of age or genotype. Immunohistochemical analysis revealed that increased microglial expression in the dorsal CA1 region of the hippoc us was associated with poorer outcome devaluation performance on initial tests, but not with tests performed after 8 days of lever pressing. Together, these data demonstrate that goal-directed action is transiently impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 region of the hippoc us.
Publisher: SAGE Publications
Date: 02-2002
DOI: 10.1080/02724990143000199
Abstract: Male and female rats were gonadectomized, implanted in adulthood with capsules containing either testosterone propionate (TP) or cholesterol, and were trained to lever press for access to an oestrous female. When lever press performance was tested in extinction, only the male rats implanted with TP displayed significantly higher levels of responding than controls, demonstrating that lever pressing for oestrous females as a reward is sexually dimorphic. Ejaculation patterns from a separate assessment of these rats’ copulatory ability were significantly correlated with their instrumental performance. In a second experiment, “masculinized” females exposed to TP postnatally and given TP implants responded in extinction at mean levels equivalent to those exhibited by adult males that were either intact or castrated with androgen replacement. These data suggest that organizational steroid exposure perinatally affects the actual reward value assigned to oestrous females inadulthood, in combination withconsummatory sexual experience.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.BRAINRES.2014.12.023
Abstract: A recent focus of addiction research has been on the effect of drug exposure on the neural processes that mediate the acquisition and performance of goal-directed instrumental actions. Deficits in goal-directed control and a consequent dysregulation of habit learning processes have been described as resulting in compulsive drug seeking. Similarly, considerable research has focussed on the motivational and emotional changes that drugs produce and that result in changes in the incentive processes that modulate goal-directed performance. Although these areas have developed independently, we argue that the effects they described are likely not independent. Here we hypothesize that these changes result from a core deficit in the way the learning and performance factors that support goal-directed action are integrated at a neural level to maintain behavioural control. A dorsal basal ganglia stream mediating goal-directed learning and a ventral stream mediating various performance factors find several points of integration in the cortical basal ganglia system, most notably in the thalamocortical network linking basal ganglia output to a variety of cortical control centres. Recent research in humans and other animals is reviewed suggesting that learning and performance factors are integrated in a network centred on the mediodorsal thalamus and that disintegration in this network may provide the basis for a 'switch' from recreational to dysregulated drug seeking resulting in the well documented changes associated with addiction.
Publisher: Wiley
Date: 04-07-2017
DOI: 10.1111/PSYP.12913
Abstract: In order to improve our understanding of the components that reflect functionally important processes during reward anticipation and consumption, we used principle components analyses (PCA) to separate and quantify averaged ERP data obtained from each stage of a modified monetary incentive delay (MID) task. Although a small number of recent ERP studies have reported that reward and loss cues potentiate ERPs during anticipation, action preparation, and consummatory stages of reward processing, these findings are inconsistent due to temporal and spatial overlap between the relevant electrophysiological components. Our results show three components following cue presentation are sensitive to incentive cues (N1, P3a, P3b). In contrast to previous research, reward-related enhancement occurred only in the P3b, with earlier components more sensitive to break-even and loss cues. During feedback anticipation, we observed a lateralized centroparietal negativity that was sensitive to response hand but not cue type. We also show that use of PCA on ERPs reflecting reward consumption successfully separates the reward positivity from the independently modulated feedback-P3. Last, we observe for the first time a new reward consumption component: a late negativity distributed over the left frontal pole. This component appears to be sensitive to response hand, especially in the context of monetary gain. These results illustrate that the time course and sensitivities of electrophysiological activity that follows incentive cues do not follow a simple heuristic in which reward incentive cues produce enhanced activity at all stages and substages.
Publisher: Springer Science and Business Media LLC
Date: 06-1995
DOI: 10.3758/BF03199935
Publisher: Elsevier BV
Date: 10-2009
Publisher: Society for Neuroscience
Date: 10-05-2006
DOI: 10.1523/JNEUROSCI.5175-05.2006
Abstract: The capacity for goal-directed behavior requires not only the encoding of the response-outcome relationship but also the ability to resolve conflict induced by competing responses. Recent neuroimaging studies have identified the prefrontal cortex as critical for resolving conflict between competing responses. At present, however, much of this evidence is indirect, and the necessity of dorsomedial prefrontal cortex (dmPFC) function for the resolution of conflict in goal-directed behavior has not been assessed. Here, we develop a rodent paradigm to investigate response conflict caused by the concurrent activation of a correct and incorrect response. In this paradigm, the outcome of one response also acts as a discriminative stimulus signaling that the other response is correct. Whereas rats with a functional dmPFC are able to resolve this conflict, inactivation of dmPFC using an infusion of muscimol produced a deficit by selectively interfering with their ability to inhibit the incorrect, competing response.
Publisher: eLife Sciences Publications, Ltd
Date: 06-07-2020
Publisher: Wiley
Date: 05-2007
Abstract: Contrary to classic stimulus-response (S-R) theory, recent evidence suggests that, in instrumental conditioning, rats encode the relationship between their actions and the specific consequences that these actions produce. It has remained unclear, however, how encoding this relationship acts to control instrumental performance. Although S-R theories were able to give a clear account of how learning translates into performance, the argument that instrumental learning constitutes the acquisition of information of the form "response R leads to outcome O" does not directly imply a particular performance rule or policy this information can be used both to perform R and to avoid performing R. Recognition of this problem has forced the development of accounts that allow the O and stimuli that predict the O (i.e., S-O) to play a role in the initiation of specific Rs. In recent experiments, we have used a variety of behavioral procedures in an attempt to isolate the processes that contribute to instrumental performance, including outcome devaluation, reinstatement, and Pavlovian-instrumental transfer. Our results, particularly from experiments assessing outcome-selective reinstatement, suggest that both "feed-forward" (O-R) and "feed-back" (R-O) associations are critical and that although the former appear to be important to response selection, the latter-together with processes that determine outcome value-mediate response initiation. We discuss a conceptual model that integrates these processes and its neural implementation.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2020
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 12-2007
Abstract: A number of recent findings suggest that the orbitofrontal cortex (OFC) influences action selection by providing information about the incentive value of behavioral goals or outcomes. However, much of this evidence has been derived from experiments using Pavlovian conditioning preparations of one form or another, making it difficult to determine whether the OFC is selectively involved in stimulus-outcome learning or whether it plays a more general role in processing reward value. Although many theorists have argued that these are fundamentally similar processes (i.e., that stimulus-reward learning provides the basis for choosing between actions based on anticipated reward value), several behavioral findings indicate that they are, in fact, dissociable. We have recently investigated the role of the OFC in the control of free operant lever pressing using tests that independently target the effect of stimulus-outcome learning and outcome devaluation on performance. We found that OFC lesions disrupted the tendency of Pavlovian cues to facilitate instrumental performance but left intact the suppressive effects of outcome devaluation. Rather than processing goal value, therefore, we hypothesize that the contribution of the OFC to goal-directed action is limited to encoding predictive stimulus-outcome relationships that can bias instrumental response selection.
Publisher: Elsevier BV
Date: 05-1989
DOI: 10.1016/0741-8329(89)90016-5
Abstract: The mechanisms of ethanol's hyperglycemic and hypothermic effects were investigated by comparing the effects of ethanol with those of tertiary butanol. Tertiary butanol is an intoxicant like ethanol, but unlike ethanol it is only minimally metabolized. Consequently, tertiary butanol does not produce appreciable amounts of active metabolites or energy. Tertiary butanol exerts its neural effects primarily by directly altering the physico-chemical properties of nerve cell membranes. It was found that ethanol and tertiary butanol produce hyperglycemic and hypothermic effects whose magnitude and time course are nearly identical. These data suggest that the hyperglycemic and hypothermic effects of ethanol represent a primary physico-chemical effect on nerve cell membranes and are not secondary to its energy content or metabolites.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.NLM.2018.09.008
Abstract: Although studies examining orbitofrontal cortex (OFC) often treat it as though it were functionally homogeneous, recent evidence has questioned this assumption. Not only are the various subregions of OFC (lateral, ventral, and medial) hetereogeneous, but there is further evidence of heterogeneity within those subregions. For ex le, several studies in both humans and monkeys have revealed a functional sub ision along the anterior-posterior gradient of the medial OFC (mOFC). Given our previous findings suggesting that, in rats, the mOFC is responsible for inferring the likelihood of unobservable action outcomes (Bradfield, Dezfouli, van Holstein, Chieng, & Balleine, 2015), and given the anterior nature of the placements of our prior manipulations, we decided to assess whether the rat mOFC also differs in connection and function along its anteroposterior axis. We first used retrograde tracing to compare the density of efferents from mOFC to several structures known to contribute to goal-directed action: the mediodorsal thalamus, basolateral amygdala, posterior dorsomedial striatum, nucleus accumbens core and ventral tegmental area. We then compared the functional effects of anterior versus posterior mOFC excitotoxic lesions on tests of Pavlovian-instrumental transfer, instrumental outcome devaluation and outcome-specific reinstatement. We found evidence that the anterior mOFC had greater connectivity with the accumbens core and greater functional involvement in goal-directed action than the posterior mOFC. Consistent with previous findings across species, therefore, these results suggest that the anterior and posterior mOFC of the rat are indeed functionally distinct, and that it is the anterior mOFC that is particularly critical for inferring unobservable action outcomes.
Publisher: American Psychological Association (APA)
Date: 04-1995
Publisher: American Psychological Association (APA)
Date: 2005
DOI: 10.1037/0097-7403.31.3.334
Abstract: Two experiments examined the motivational specificity of the associations that support 2nd-order conditioning. In the 1st phase of each experiment rats were exposed to 2 visual conditioned stimuli (CSs) paired with either a saline or food pellet unconditioned stimulus (US) prior to exposure to 2nd-order conditioning using 2 auditory CSs, 1 paired with each visual CS. Rats' motivational state was then shifted prior to a test such that if and only if specific motivational features of the 1st-order training US played a role in the 2nd-order associative structure would responding to the 2nd-order cues shift appropriately with the state change. Even when the US was irrelevant to the training motivational state, shifts in state revealed that it was encoded within the associative structure supporting 2nd-order responding.
Publisher: Public Library of Science (PLoS)
Date: 11-04-2014
Publisher: Society for Neuroscience
Date: 17-01-2023
DOI: 10.1523/ENEURO.0363-22.2023
Abstract: Cognitive-behavioral testing in preclinical models of Alzheimer’s disease has failed to capture deficits in goal-directed action control. Here, we provide the first comprehensive investigation of goal-directed action in a transgenic mouse model of Alzheimer’s disease. Specifically, we tested outcome devaluation performance in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press left and right levers for pellet and sucrose outcomes, respectively (counterbalanced), over 4 d. On test, mice were prefed one of the outcomes to satiety and given a choice between levers. Devaluation performance was intact for 36-week-old wild-types of both sexes, who responded more on the valued relative to the devalued lever (Valued Devalued). By contrast, devaluation was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. After additional lever press training (i.e., 8-d lever pressing in total), devaluation was intact for all mice, demonstrating that the initial deficits were not a result of a nonspecific impairment in reward processing, depression, or locomotor activity in J20 or aging mice. Follow-up analyses revealed that microglial expression in the dorsal CA1 region of the hippoc us was associated with poorer outcome devaluation performance on initial, but not later tests. Together, these data demonstrate that goal-directed action is initially impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 hippoc al region.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0091-3057(02)00957-7
Abstract: We assessed the effect of nimodipine, an L-type calcium channel blocker, on the escape deficit induced by prior exposure to inescapable shock in rats in four experiments. In Experiment 1, we injected rats at each of three time points (i.e., before shock exposure, after shock exposure, and before shuttle escape testing) with one of four doses of nimodipine (0, 0.5, 2.5, 5.0 mg/kg). The 5.0-mg/kg dose was most effective, acting to reduce shuttle escape latencies of inescapably shocked rats to a level comparable with nonshocked controls. No benefit occurred in Experiment 2, however, when nimodipine was administered at only one of the three time points used in the first experiment. Moreover, escape performance did not improve when rats received injections of nimodipine on the 2 days prior the experiment, and then one additional injection at one of the three time points identified above in Experiment 3. Finally, administration of nimodipine at two of the three time points did improve escape responding, but only when injected immediately prior both to shock exposure and the shuttle escape test.
Publisher: Elsevier BV
Date: 15-12-2005
DOI: 10.1016/J.PHYSBEH.2005.08.061
Abstract: Recent studies suggest that there are multiple 'reward' or 'reward-like' systems that control food seeking evidence points to two distinct learning processes and four modulatory processes that contribute to the performance of food-related instrumental actions. The learning processes subserve the acquisition of goal-directed and habitual actions and involve the dorsomedial and dorsolateral striatum, respectively. Access to food can function both to reinforce habits and as a reward or goal for actions. Encoding and retrieving the value of a goal appears to be mediated by distinct processes that, contrary to the somatic marker hypothesis, do not appear to depend on a common mechanism but on emotional and more abstract evaluative processes, respectively. The anticipation of reward on the basis of environmental events exerts a further modulatory influence on food seeking that can be dissociated from that of reward itself earning a reward and anticipating a reward appear to be distinct processes and have been doubly dissociated at the level of the nucleus accumbens. Furthermore, the excitatory influence of reward-related cues can be both quite specific, based on the identity of the reward anticipated, or more general based on its motivational significance. The influence of these two processes on instrumental actions has also been doubly dissociated at the level of the amygdala. Although the complexity of food seeking provides a hurdle for the treatment of eating disorders, the suggestion that these apparently disparate determinants are functionally integrated within larger neural systems may provide novel approaches to these problems.
Publisher: Elsevier
Date: 2009
Publisher: Springer Science and Business Media LLC
Date: 05-1996
DOI: 10.1007/BF02247396
Abstract: Vascular access is the lifeline for hemodialysis patients and the single most important component of the hemodialysis procedure. Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients, but nearly 60% of AVFs created fail to successfully mature due to early intimal hyperplasia development and poor outward remodeling. There are currently no therapies available to prevent AVF maturation failure. First, we showed the important regulatory role of nitric oxide (NO) on AVF development by demonstrating that intimal hyperplasia development was reduced in an overexpressed endothelial nitric oxide synthase (NOS3) mouse AVF model. This supported the rationale for the potential application of NO to the AVF. Thus, we developed a self-assembled NO releasing nanomatrix gel and applied it perivascularly at the arteriovenous anastomosis immediately following rat AVF creation to investigate its therapeutic effect on AVF development. We demonstrated that the NO releasing nanomatrix gel inhibited intimal hyperplasia formation (more than 70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress approaching the preoperative level and less vorticity). Therefore, direct application of the NO releasing nanomatrix gel to the AVF anastomosis immediately following AVF creation may enhance AVF development, thereby providing long-term and durable vascular access for hemodialysis.
Publisher: Wiley
Date: 31-07-2019
DOI: 10.1111/EJN.13964
Abstract: Considerable evidence suggests that the learning and performance of instrumental actions depend on activity in basal ganglia circuitry however, these two functions have generally been considered independently. Whereas research investigating the associative mechanisms underlying instrumental conditioning has identified critical cortical and limbic input pathways to the dorsal striatum, the performance of instrumental actions has largely been attributed to activity in the dorsal striatal output pathways, with direct and indirect pathway projection neurons mediating action initiation, perseveration and cessation. Here, we discuss evidence that the dorsal striatal input and basal ganglia output pathways mediate the learning and performance of instrumental actions, respectively, with the dorsal striatum functioning as a transition point. From this perspective, the issue of how multiple striatal inputs are integrated at the level of the dorsal striatum and converted into relatively restricted outputs becomes one of critical significance for understanding how learning is translated into action. So too does the question of how learning signals are modulated by recent experience. We propose that this occurs through recurrent corticostriatothalamic feedback circuits that serve to integrate performance signals by updating ongoing action-related learning.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PSYNEUEN.2012.04.018
Abstract: The mammalian neuropeptide oxytocin has well-characterized effects in facilitating prosocial and affiliative behavior. Additionally, oxytocin decreases physiological and behavioral responses to social stress. In the present study we investigated the effects of oxytocin on cognitive appraisals after a naturalistic social stress task in healthy male students. In a randomized, double-blind, placebo-controlled trial, 48 participants self-administered either an oxytocin or placebo nasal spray and, following a wait period, completed an impromptu speech task. Eye gaze to a pre-recorded video of an audience displayed during the task was simultaneously collected. After the speech, participants completed questionnaires assessing negative cognitive beliefs about speech performance. Whilst there was no overall effect of oxytocin compared to placebo on either eye gaze or questionnaire measures, there were significant positive correlations between trait levels of anxiety and negative self-appraisals following the speech. Exploratory analyses revealed that whilst higher trait anxiety was associated with increasingly poorer perceptions of speech performance in the placebo group, this relationship was not found in participants administered oxytocin. These results provide preliminary evidence to suggest that oxytocin may reduce negative cognitive self-appraisals in high trait anxious males. It adds to a growing body of evidence that oxytocin seems to attenuate negative cognitive responses to stress in anxious in iduals.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-06-2023
Abstract: The loss of neurons in parafascicular thalamus (Pf) and their inputs to dorsomedial striatum (DMS) in Lewy body disease (LBD) and Parkinson’s disease dementia (PDD) have been linked to the effects of neuroinflammation. We found that, in rats, these inputs were necessary for both the function of striatal cholinergic interneurons (CINs) and the flexible encoding of the action-outcome (AO) associations necessary for goal-directed action, producing a burst-pause pattern of CIN firing but only during the remapping elicited by a shift in AO contingency. Neuroinflammation in the Pf abolished these changes in CIN activity and goal-directed control after the shift in contingency. However, both effects were rescued by either the peripheral or the intra-DMS administration of selegiline, a monoamine oxidase B inhibitor that we found also enhances adenosine triphosphatase activity in CINs. These findings suggest a potential treatment for the cognitive deficits associated with neuroinflammation affecting the function of the Pf and related structures.
Publisher: Springer Science and Business Media LLC
Date: 08-2017
DOI: 10.1007/S11136-017-1666-6
Abstract: Multi-attribute utility instruments (MAUIs) are widely used to measure utility weights. This study sought to compare utility weights of two popular MAUIs, the EQ-5D-3L and the SF-6D, and inform researchers in the selection of generic MAUI for use with cardiovascular (CVD) patients. Data were collected in the Young@Heart study, a randomised controlled trial of a nurse-led multidisciplinary home-based intervention compared to standard usual care. Participants (n = 598) completed the EQ-5D-3L and the SF-12v2, from which the SF-6D can be constructed, at baseline and at 24-month follow-up. This study examined discrimination, responsiveness, correlation and differences across the two instruments. Both MAUIs were able to discriminate between the NYHA severity classes and recorded similar changes between the two time points although only SF-6D differences were significant. Correlations between the dimensions of the two MAUIs were low. There were significant differences between the two instruments in mild conditions but they were similar in severe conditions. Substantial ceiling and floor effects were observed. Our findings indicate that the EQ-5D and the SF-6D cover different spaces in health due to their classification systems. Both measures were capable of discriminating between severity groups and responsive to quality of life changes in the follow-up. It is recommended to use the EQ-5D-3L in severe and the SF-6D in mild CVD conditions.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Cold Spring Harbor Laboratory
Date: 27-09-2019
DOI: 10.1101/783308
Abstract: Rats use spatiotemporal features of the environment to navigate to a goal, but whether representations of ‘action space’ are necessary for non-navigational goal-directed actions is unknown. We addressed this question by assessing goal-directed action control across contexts and under hippoc al inactivation and found that such actions do indeed rely on a representation of action space but only immediately after initial acquisition. Goal-directed actions depend on a hippoc al representation of action space immediately after initial encoding but not after a delay.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2016
DOI: 10.1007/S10198-014-0651-Z
Abstract: To determine if taxation policies that increase the price of alcohol differentially reduce alcohol consumption for heavy drinkers in Australia. A two-part demand model for alcohol consumption is used to determine the price elasticity of alcohol. Quantile regression is used to determine the price elasticity estimates for various levels of consumption. The study uses Australian data collected by the National Drug Strategy Household Survey for the years 2001, 2004 and 2007. Measures of in idual annual alcohol consumption were derived from three waves of the National Drug Strategy Household Survey alcohol prices were taken from market research reports. For the overall population of drinkers, a 1% increase in the price of alcohol was associated with a 0.96% (95% CI -0.35%, -1.57%) reduction in alcohol consumption. For those in the highest 10% of drinkers by average amount consumed, a 1% increase in the price of alcohol was associated with a 1.26% (95% CI 0.82%, 1.70%) reduction in consumption. Within Australia, policies that increase the price of alcohol are about equally effective in relative terms for reducing alcohol consumption both for the general population and among those who drink heavily.
Publisher: Springer Science and Business Media LLC
Date: 07-2007
DOI: 10.1038/NN0707-807
Publisher: Wiley
Date: 12-2011
DOI: 10.1111/J.1749-6632.2011.06270.X
Abstract: Considerable evidence suggests that choice between goal-directed actions depends on two incentive processes encoding the reward value of the goal or outcome and the predicted value of an action based on outcome-related stimuli. Although incentive theories generally assume that these processes are mediated by a common associative mechanism, a number of recent findings suggest that they are dissociable the reward value of an action is derived from consummatory experience with the outcome itself, whereas the predicted value of an action is based on the presence of outcome-associated stimuli from which estimates of the likelihood of an outcome are derived. Importantly, the orbitofrontal cortex (OFC) in rodents appears to mediate the effect of outcome-related stimuli on choice OFC lesions disrupt the influence of Pavlovian stimuli on choice in tests of outcome-specific Pavlovian-instrumental transfer. However, the influence of outcome-related stimuli on choice involves a larger circuit including the OFC, the ventral striatum, and the amygdala. How these structures interact, however, is not yet fully understood and is an important question for future research.
Publisher: Society for Neuroscience
Date: 06-11-2013
DOI: 10.1523/JNEUROSCI.3271-13.2013
Abstract: The posterior dorsomedial striatum (pDMS) is essential for the acquisition and expression of the specific response–outcome (R–O) associations that underlie goal-directed action. Here we examined the role of a pathway linking the basolateral amygdala (BLA) and pDMS in such goal-directed learning. In Experiment 1, rats received unilateral lesions of the BLA and were implanted with cannula targeting the pDMS in either the ipsilateral (control) or contralateral (disconnection) hemisphere. After initial training, rats received infusions of muscimol to inactivate the pDMS immediately before sessions in which novel R–O associations were introduced. Sensitivity to devaluation by specific satiety was then assessed. Whereas rats in the ipsilateral group used the recently acquired associations to direct performance following devaluation, those in the contralateral group could not, indicating that BLA–pDMS disconnection prevented the acquisition of the new R–O associations. Indeed, evidence suggested that these rats relied instead on learning acquired during prior training to direct performance following devaluation. In Experiment 2, rats underwent similar surgery and training except they received muscimol infusions immediately before devaluation testing. Those in the ipsilateral group showed a selective devaluation effect, again based on the most recently introduced R–O associations. In contrast, rats in the contralateral group showed nonselective performance after devaluation indicating that the BLA–DMS pathway is also required for the expression of selective R–O associations. Together these results suggest that input from the BLA is essential for specific R–O learning by the pDMS.
Publisher: Wiley
Date: 16-11-2007
DOI: 10.1111/J.1460-9568.2007.05934.X
Abstract: This study compared the contribution of the general activating and specific cueing properties of Pavlovian stimuli to Pavlovian-instrumental transfer (PIT) and the role of the ventral tegmental area (VTA) in mediating these effects. In Experiment 1, hungry rats initially received Pavlovian training, in which three distinct auditory stimuli predicted the delivery of three different food outcomes. Next, the rats were trained to perform two instrumental actions, each earning a unique outcome selected from the three used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Presentation of a stimulus that had been paired with the same outcome as an action increased its performance relative to the other action, demonstrating that PIT effects can be outcome selective. In contrast, presentation of the stimulus that predicted the outcome that was not earned during instrumental training facilitated the performance of both actions indiscriminately. This effect, but not the outcome-selective effect, was abolished by a shift from a hungry to a relatively sated state. Experiment 2 examined the effects of inactivation of the VTA on these two forms of PIT. VTA inactivation was found to attenuate PIT but, unlike satiety, did not appear to differentially affect the general or the outcome-selective forms of PIT. The VTA appears therefore to play an important but general role in the initiation of instrumental actions, enabling cues to influence performance whether they enhance responding by changes in arousal or by retrieving particular actions based on their consequences.
Publisher: Society for Neuroscience
Date: 02-04-2014
DOI: 10.1523/JNEUROSCI.3707-13.2014
Abstract: Access to highly palatable and calorically dense foods contributes to increasing rates of obesity worldwide. Some have made the controversial argument that consumption of such foods can lead to “food addiction,” yet little is known about how long-term access to highly palatable foods might alter goal-directed learning and decision making. In the following experiments, rats were given 5 weeks of continuous or restricted daily access to sweetened condensed milk (SCM) before instrumental training for food reward. Subsequently we examined whether goal-directed performance was impaired in these groups using the outcome-devaluation task. Control rats reduced responding following devaluation of the earned outcome as did those with previous continuous access to SCM. Of interest, rats with previous restricted access to SCM responded similarly under the devalued and nondevalued conditions, indicating loss of goal-directed control of responding. To identify whether the loss of goal-directed control was accompanied by differences in neuronal activity, we used c-Fos immunohistochemistry to examine the patterns of activation during devaluation testing. We observed greater c-Fos immunoreactivity in the dorsolateral striatum (DLS) and associated cortical regions in the group that received previous restricted access to SCM and demonstrated a lack of sensitivity to outcome devaluation. Infusion of the AMPA-receptor antagonist CNQX or dopamine D1-receptor antagonist SCH-23390 into the DLS before testing restored goal-directed performance in the restricted SCM group, confirming that this region is essential for habit-based performance. These results indicate that previous diet can alter subsequent learning and activity in the neural circuits that support performance.
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.BBR.2003.09.023
Abstract: Numerous studies have implicated human and primate prefrontal cortex in the ability to hold and manipulate goal or outcome-related information in working memory to guide the performance of forthcoming actions. Here we report that cell-body lesions of prelimbic cortex impair the ability of rats to select an action based on previously encoded action-outcome associations. Rats were food deprived and trained to press two levers, one delivering food pellets and the other a sucrose solution. All rats acquired the lever-press response although the initial acquisition in the prelimbic rats was significantly slower than in sham controls. Furthermore, whereas in sham-lesioned rats, post-training devaluation of one of the two outcomes using a specific satiety procedure produced a selective reduction in performance on the lever that in training delivered the prefed outcome, prelimbic rats failed to show a selective devaluation effect and appeared to reduce performance on both levers non-selectively. Importantly, this impairment only emerged in extinction in subsequent experiments it was found that, when a specific action-outcome association was cued either by presentation of the outcome itself or by presenting a stimulus previously paired with the outcome, rats demonstrated an ability to select the associated action. These results suggest that action-outcome encoding may be intact in prelimbic rats and that the lesion impaired their ability to retain this learning in working memory in order to establish a course of action. Alternatively, the lesion may have altered the relative contribution of action-outcome and outcome-action associations to instrumental performance. On this account, prelimbic lesions affect action-outcome encoding but leave outcome-action associations intact providing the basis for outcome-mediated initiation of an action sufficient, perhaps, to support acquisition and performance in the lesioned rats.
Publisher: Society for Neuroscience
Date: 09-10-2013
DOI: 10.1523/JNEUROSCI.1927-13.2013
Abstract: The ability of animals to extract predictive information from the environment to inform their future actions is a critical component of decision-making. This phenomenon is studied in the laboratory using the pavlovian–instrumental transfer protocol in which a stimulus predicting a specific pavlovian outcome biases choice toward those actions earning the predicted outcome. It is well established that this transfer effect is mediated by corticolimbic afferents on the nucleus accumbens shell (NAc-S), and recent evidence suggests that δ-opioid receptors (DORs) play an essential role in this effect. In DOR-eGFP knock-in mice, we show a persistent, learning-related plasticity in the translocation of DORs to the somatic plasma membrane of cholinergic interneurons (CINs) in the NAc-S during the encoding of the specific stimulus–outcome associations essential for pavlovian–instrumental transfer. We found that increased membrane DOR expression reflected both stimulus-based predictions of reward and the degree to which these stimuli biased choice during the pavlovian–instrumental transfer test. Furthermore, this plasticity altered the firing pattern of CINs increasing the variance of action potential activity, an effect that was exaggerated by DOR stimulation. The relationship between the induction of membrane DOR expression in CINs and both pavlovian conditioning and pavlovian–instrumental transfer provides a highly specific function for DOR-related modulation in the NAc-S, and it is consistent with an emerging role for striatal CIN activity in the processing of predictive information. Therefore, our results reveal evidence of a long-term, experience-dependent plasticity in opioid receptor expression on striatal modulatory interneurons critical for the cognitive control of action.
Publisher: Center for Open Science
Date: 17-12-2020
Abstract: Abnormal orbitofrontal cortex (OFC) activity is one of the most common findings from neuroimaging studies of in iduals with compulsive disorders such as substance use disorder and obsessive-compulsive disorder. The nature of this abnormality is complex however, with some studies reporting the OFC to be over-active in compulsive in iduals relative to controls, whereas other studies report it being under-active, and a further set of studies reporting OFC abnormality in both directions within the same in iduals. The OFC has been implicated in a broad range of cognitive processes such as decision-making and goal-directed action. OFC dysfunction could impair these processes leading to the kinds of cognitive/behavioural deficits observed in in iduals with compulsive disorders. One such deficit that could arise as a result of OFC dysfunction is an altered sensitivity to punishment, which is one of the core characteristics displayed by in iduals across multiple types of compulsive disorders. It is, therefore, the aim of the current review to assess the evidence implicating the OFC in adaptation to punishment and to attempt to identify the critical factors determining this relationship. We distil from this analysis some guidelines for future studies attempting to determine the precise role of the OFC in punishment.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2009
DOI: 10.1038/NPP.2009.131
Publisher: Elsevier BV
Date: 05-1991
DOI: 10.1016/S0166-4328(05)80067-1
Abstract: The effect of acute stress on the acquisition of an instrumental action reinforced by electrical stimulation of the medial prefrontal cortex (MPC) was investigated by exposing rats to either escapable, inescapable or no footshock prior to daily self-stimulation training sessions. Treatment with inescapable footshock did not affect the number of sessions required for acquisition of MPC self-stimulation but did increase the rate of responding over acquisition sessions compared with the no-shock group. When the treatment footshock was escapable, however, both a facilitation in acquisition, as indexed by a reduction in the number of sessions to criterion, and an increase in the rate of MPC self-stimulation was found. These data were interpreted as offering evidence for the operation of a dopaminergic mechanism in the acquisition of MPC self-stimulation. Further, they indicate, contrary to the reported effects of footshock on self-stimulation of other brain areas, that exposure to acute stress has a facilitatory effect on the rate of self stimulation of the MPC.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.NEUROIMAGE.2018.11.051
Abstract: A comprehensive understanding of how the brain responds to a changing environment requires techniques capable of recording functional outputs at the whole-brain level in response to external stimuli. Positron emission tomography (PET) is an exquisitely sensitive technique for imaging brain function but the need for anaesthesia to avoid motion artefacts precludes concurrent behavioural response studies. Here, we report a technique that combines motion-compensated PET with a robotically-controlled animal enclosure to enable simultaneous brain imaging and behavioural recordings in unrestrained small animals. The technique was used to measure in vivo displacement of [
Publisher: Elsevier BV
Date: 08-1989
DOI: 10.1016/0031-9384(89)90262-X
Abstract: Electrical stimulation of the medial prefrontal cortex (MPC) was administered according to the triadic design typically used to demonstrate learned helplessness. Three groups received either controllable, uncontrollable or no stimulation during the pretreatment phase. The effects of this pretreatment on the acquisition of self-stimulation at the same electrode site were investigated in the second phase of the experiment. Relative to unstimulated controls, both controllable and uncontrollable prestimulation facilitated the acquisition of self-stimulation and produced higher self-stimulation rates. In addition, compared with controllable stimulation, pretreatment with uncontrollable stimulation produced a greater facilitation in self-stimulation rate. The unambiguous demonstration of a behavioural facilitation produced by pretreatment with uncontrollable stimulation is, effectively, the inverse of the typical learned helplessness finding. It was also found, in the second phase of the experiment, that 6 of the 7 rats previously exposed to uncontrollable stimulation developed full class 5 seizures. No behavioural evidence of kindling was seen in any of the other rats or during the prestimulation procedure. These data are interpreted in terms of kindling and stress effects both proximal and distal to the site of stimulation.
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.2165/11594850-000000000-00000
Abstract: In Australia and elsewhere, fiscal measures such as alcohol taxation are a commonly used intervention and cost-effective strategy to reduce alcohol consumption and associated harm. However, alcohol taxation policies distort the market for alcohol, specifically increasing the marginal cost of alcohol. It is proposed that a volumetric tax, which taxes alcohol equally across all beverage types, is less distortive of consumer preferences and more efficient at reducing alcohol consumption than the current Australian tax model, where taxes are charged at varying amounts per litre of pure alcohol, depending on the beverage type. This paper quantifies the effect of four different alcohol taxation systems, relative to the current Australian system: two different types of volumetric taxation (deadweight loss neutral and tax revenue neutral) the recent strategy trialled in Australia of increasing the tax only on ready-to-drink alcoholic beverages (i.e. premixed spirits) and a tiered tax system, which may be more politically acceptable. A partial equilibrium approach was used to measure taxation revenue, consumer welfare and consumption in alcohol markets. Estimates of taxation revenue, consumer welfare and consumption were first calculated for 2008 and then compared with the four scenarios considered. Relative to the previous alcohol taxation scheme in Australia, the taxation strategy that increased the tax solely on ready-to-drink alcoholic beverages increased taxation revenue by 479 million Australian dollars ($A), reduced pure alcohol consumption by 754 000 litres and increased the net deadweight loss of taxation by $A62 million. For a tax-neutral approach, for the same level of taxation revenue as is currently generated, a volumetric tax could substantially reduce the cost of taxation (as described by the net loss in consumer welfare) by $A177 million and reduce pure alcohol consumption by 4 68 000 litres. Under a deadweight loss-neutral scenario, for the same amount of deadweight loss generated from the previous taxation scenario, taxation revenue could be increased by $A1153 million, in addition to reducing pure alcohol consumption by 4 316 000 litres. A tiered taxation regime, as modelled here, could decrease pure alcohol consumption by 2 616 000 litres whilst increasing taxation revenue by $A1101 million. However, this scenario would also increase the deadweight loss of taxation by $A113 million. From these scenarios, it can be shown that, for the same tax revenue, consumer welfare can be reduced or, for the same level of loss to consumer welfare, taxation revenue can be increased. Both these scenarios result in a reduction of pure alcohol consumption.
Publisher: American Psychological Association (APA)
Date: 2009
DOI: 10.1037/A0014793
Abstract: According to O-R theory of instrumental learning, incongruent biconditional discriminations should be impossible to solve in a goal-directed manner because the event acting as the outcome of one response also acts as a discriminative stimulus for an opposite response. Each event should therefore be associated with two competing responses. However, Dickinson and de Wit (2003) have presented evidence that rats can learn incongruent discriminations. The present study investigated whether rats were able to engage additional processes to solve incongruent discriminations in a goal-directed manner. Experiment 1 provides evidence that rats resolve the response conflict that arises in the incongruent discrimination by differentially encoding events in their roles as discriminative stimulus and as outcome. Furthermore, Experiment 2 shows that once goal-directed control has been established the dorsomedial prefrontal cortex is not directly involved in its maintenance but rather plays a central role in conflict resolution processes.
Publisher: BMJ
Date: 04-2016
Publisher: Elsevier
Date: 2008
Publisher: Society for Neuroscience
Date: 08-2007
DOI: 10.1523/JNEUROSCI.1554-07.2007
Abstract: Although the involvement in the striatum in the refinement and control of motor movement has long been recognized, recent description of discrete frontal corticobasal ganglia networks in a range of species has focused attention on the role particularly of the dorsal striatum in executive functions. Current evidence suggests that the dorsal striatum contributes directly to decision-making, especially to action selection and initiation, through the integration of sensorimotor, cognitive, and motivational/emotional information within specific corticostriatal circuits involving discrete regions of striatum. We review key evidence from recent studies in rodent, nonhuman primate, and human subjects.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2018
DOI: 10.3758/S13423-018-1500-3
Abstract: Within a rational framework, a decision-maker selects actions based on the reward-maximization principle, which stipulates that they acquire outcomes with the highest value at the lowest cost. Action selection can be ided into two dimensions: selecting an action from various alternatives, and choosing its vigor, i.e., how fast the selected action should be executed. Both of these dimensions depend on the values of outcomes, which are often affected as more outcomes are consumed together with their associated actions. Despite this, previous research has only addressed the computational substrate of optimal actions in the specific condition that the values of outcomes are constant. It is not known what actions are optimal when the values of outcomes are non-stationary. Here, based on an optimal control framework, we derive a computational model for optimal actions when outcome values are non-stationary. The results imply that, even when the values of outcomes are changing, the optimal response rate is constant rather than decreasing. This finding shows that, in contrast to previous theories, commonly observed changes in action rate cannot be attributed solely to changes in outcome value. We then prove that this observation can be explained based on uncertainty about temporal horizons e.g., the session duration. We further show that, when multiple outcomes are available, the model explains probability matching as well as maximization strategies. The model therefore provides a quantitative analysis of optimal action and explicit predictions for future testing.
Publisher: Springer Science and Business Media LLC
Date: 14-10-2007
DOI: 10.1038/NN1987
Abstract: Instrumental conditioning allows animals to learn about the consequences of their own actions, but the underpinning molecular mechanisms remain elusive. Here we show that the sphingosine-1-phosphate (S1P) receptor Gpr6 is selectively expressed in the striatopallidal neurons in the striatum. Gpr6-deficient mice showed reduced striatal cyclic AMP production in vitro and selective alterations in instrumental conditioning in vivo. Thus, Gpr6 is the first striatopallidal neuron-specific genetic regulator of instrumental conditioning in a mammal.
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Psychological Association (APA)
Date: 2006
DOI: 10.1037/0097-7403.32.4.481
Abstract: The effect of conditioning or extinguishing the more salient element of a previously reinforced compound on responding to the less salient element of that compound was assessed in rats. Experiment 1 established that the 2 elements making up an audiovisual compound differed significantly in salience. In Experiment 2A, compound conditioning was followed by either reinforcement or extinction of either the less or more salient element. On test, evidence of retrospective revaluation of the less salient element was found but not of the more salient element. In Experiment 2B, extinction of the more salient element was found to be more effective than its reinforcement in producing retrospective revaluation of the less salient element. The implications of these results are discussed.
Publisher: Wiley
Date: 14-11-2018
DOI: 10.1111/EJN.13750
Abstract: It has been recently demonstrated that predictive learning induces a persistent accumulation of delta-opioid receptors (DOPrs) at the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (Nac-S). This accumulation is required for predictive learning to influence subsequent choice between goal-directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub-territories induced DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro-APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co-administration of both agonists again generated DOPr translocation, suggesting the effect of the D1 agonist alone was due to receptor internalisation. In support of this, local administration of cocaine was found to increase DOPr translocation as was chloro-APB when co-administered with the DOPr antagonist naltrindole. These studies provide the first evidence of delta-opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism - involving an interaction between dopamine and SP signalling via NK1R - regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated that may be particularly relevant to learning-induced DOPr trafficking.
Publisher: Elsevier
Date: 2017
Publisher: American Psychological Association (APA)
Date: 2003
DOI: 10.1037/0097-7403.29.2.99
Abstract: Two experiments compared the effects of Pavlovian stimuli and incentive learning on the performance of a heterogeneous chain of instrumental actions. Using a Pavlovian-instrumental transfer design, the authors found that only a stimulus paired with the same outcome as that earned by performance of the chain produced positive transfer, an effect that was restricted to the action in the chain most proximal to reward delivery. In contrast, after a shift to a nondeprived state, only animals that had previously consumed the instrumental outcome when they were nondeprived decreased instrumental performance. Furthermore, this effect of the incentive learning treatment was limited to performance of the distal action. Together these data suggest that Pavlovian and instrumental incentive manipulations have dissociable effects on instrumental performance.
Publisher: Society for Neuroscience
Date: 24-02-2010
DOI: 10.1523/JNEUROSCI.1778-09.2010
Abstract: The performance of goal-directed actions relies on an animal's previous knowledge of the outcomes or consequences that result from its actions. Additionally, a sensorimotor learning process linking environmental stimuli with actions influences instrumental performance by selecting actions for additional evaluation. These distinct decision-making processes in rodents depend on separate subregions of the dorsal striatum. Whereas the posterior dorsomedial striatum (pDMS) is required for the encoding of actions with their outcomes or consequences, the dorsolateral striatum (DLS) mediates action selection based on sensorimotor learning. However, the molecular mechanisms within these brain regions that support learning and performance of goal-directed behavior are not known. Here we show that activation of extracellular signal-regulated kinase (ERK) in the dorsal striatum has a critical role in learning and performance of instrumental goal-directed behavior in rodents. We observed an increase in p42 ERK (ERK2) activation in both the pDMS and DLS during both the acquisition and performance of recently acquired instrumental goal-directed actions. Furthermore, disruption of ERK activation in the pDMS prevented both the acquisition of action–outcome associations, as well as the performance of goal-directed actions guided by previously acquired associations, whereas disruption of ERK activation in the DLS disrupted instrumental performance but left instrumental action–outcome learning intact. These results provide evidence of a critical, region-specific role for ERK signaling in the dorsal striatum during the acquisition of instrumental learning and suggest that processes sensitive to ERK signaling within these striatal subregions interact to control instrumental performance after initial acquisition.
Publisher: Society for Neuroscience
Date: 16-02-2011
DOI: 10.1523/JNEUROSCI.3354-10.2011
Abstract: Contingency theories of goal-directed action propose that experienced disjunctions between an action and its specific consequences, as well as conjunctions between these events, contribute to encoding the action–outcome association. Although considerable behavioral research in rats and humans has provided evidence for this proposal, relatively little is known about the neural processes that contribute to the two components of the contingency calculation. Specifically, while recent findings suggest that the influence of action–outcome conjunctions on goal-directed learning is mediated by a circuit involving ventromedial prefrontal, medial orbitofrontal cortex, and dorsomedial striatum, the neural processes that mediate the influence of experienced disjunctions between these events are unknown. Here we show differential responses to probabilities of conjunctive and disjunctive reward deliveries in the ventromedial prefrontal cortex, the dorsomedial striatum, and the inferior frontal gyrus. Importantly, activity in the inferior parietal lobule and the left middle frontal gyrus varied with a formal integration of the two reward probabilities, Δ P , as did response rates and explicit judgments of the causal efficacy of the action.
Publisher: Informa UK Limited
Date: 12-2017
DOI: 10.1080/13696998.2016.1261031
Abstract: The cost-effectiveness of a heart failure management intervention can be further informed by incorporating the expected benefits and costs of future survival. This study compared the long-term costs per quality-adjusted life year (QALY) gained from home-based (HBI) vs specialist clinic-based intervention (CBI) among elderly patients (mean age = 71 years) with heart failure discharged home (mean intervention duration = 12 months). Cost-utility analysis was conducted from a government-funded health system perspective. A Markov cohort model was used to simulate disease progression over 15 years based on initial data from a randomized clinical trial (the WHICH? study). Time-dependent hazard functions were modeled using the Weibull function, and this was compared against an alternative model where the hazard was assumed to be constant over time. Deterministic and probabilistic sensitivity analyses were conducted to identify the key drivers of cost-effectiveness and quantify uncertainty in the results. During the trial, mortality was the highest within 30 days of discharge and decreased thereafter in both groups, although the declining rate of mortality was slower in CBI than HBI. At 15 years (extrapolated), HBI was associated with slightly better health outcomes (mean of 0.59 QALYs gained) and mean additional costs of AU$13,876 per patient. The incremental cost-utility ratio and the incremental net monetary benefit (vs CBI) were AU$23,352 per QALY gained and AU$15,835, respectively. The uncertainty was driven by variability in the costs and probabilities of readmissions. Probabilistic sensitivity analysis showed HBI had a 68% probability of being cost-effective at a willingness-to-pay threshold of AU$50,000 per QALY. Compared with CBI (outpatient specialized HF clinic-based intervention), HBI (home-based predominantly, but not exclusively) could potentially be cost-effective over the long-term in elderly patients with heart failure at a willingness-to-pay threshold of AU$50,000/QALY, albeit with large uncertainty.
Publisher: Informa UK Limited
Date: 2021
Publisher: American Psychological Association (APA)
Date: 2005
DOI: 10.1037/0097-7403.31.3.341
Abstract: Forward and backward blocking of taste preference learning was compared in rats. In the forward condition, thirsty rats were exposed to a flavor (A) in sucrose solution (+) or in water (-), after which they were exposed to A in compound with another flavor (B) in sucrose solution (i.e., AB+). In the backward condition, these phases were reversed. Consumption of B alone was assessed when rats were food deprived. In the forward condition, rats given A+ consumed less B than rats given A-, providing evidence of forward blocking, whereas in the backward condition, rats given A+ drank more of B than those given A-. Subsequent experiments found that alternating but not blocked preexposure to A and B, when given prior to training, produced blocking of B whether A+ was given before or after AB+, suggesting that prior failures to observe backward blocking reflect failures of discrimination.
Publisher: The Royal Society
Date: 05-11-2014
Abstract: Goal-directed action involves making high-level choices that are implemented using previously acquired action sequences to attain desired goals. Such a hierarchical schema is necessary for goal-directed actions to be scalable to real-life situations, but results in decision-making that is less flexible than when action sequences are unfolded and the decision-maker deliberates step-by-step over the outcome of each in idual action. In particular, from this perspective, the offline revaluation of any outcomes that fall within action sequence boundaries will be invisible to the high-level planner resulting in decisions that are insensitive to such changes. Here, within the context of a two-stage decision-making task, we demonstrate that this property can explain the emergence of habits. Next, we show how this hierarchical account explains the insensitivity of over-trained actions to changes in outcome value. Finally, we provide new data that show that, under extended extinction conditions, habitual behaviour can revert to goal-directed control, presumably as a consequence of decomposing action sequences into single actions. This hierarchical view suggests that the development of action sequences and the insensitivity of actions to changes in outcome value are essentially two sides of the same coin, explaining why these two aspects of automatic behaviour involve a shared neural structure.
Publisher: Portland Press Ltd.
Date: 14-11-2022
DOI: 10.1042/ETLS20220007
Abstract: Although the hey-day of motivation as an area of study is long past, the issues with which motivational theorists grappled have not grown less important: i.e. the development of deterministic explanations for the particular tuning of the nervous system to specific changes in the internal and external environment and the organisation of adaptive behavioural responses to those changes. Here, we briefly elaborate these issues in describing the structure and function of the ‘positive valence system’. We describe the origins of adaptive behaviour in an ascending arousal system, sensitive to peripheral regulatory changes, that modulates and activates various central motivational states. Associations between these motivational states and sensory inputs underlie evaluative conditioning and generate the representation of the ‘unconditioned’ stimuli fundamental to Pavlovian conditioning. As a consequence, associations with these stimuli can generate Pavlovian conditioned responses through the motivational control of stimulus event associations with sensory and affective components of the valence system to elicit conditioned orienting, consummatory and preparatory responses, particularly the affective responses reflecting Pavlovian excitation and inhibition, arousal and reinforcement, the latter used to control the formation of habits. These affective processes also provoke emotional responses, allowing the externalisation of positive valence in hedonic experience to generate the goal or reward values that mediate goal-directed action. Together these processes form the positive valence system, ensure the maintenance of adaptive behaviour and, through the association of sensory events and emotional responses through consummatory experience, provide the origins of reward.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.IJCARD.2015.08.066
Abstract: To assess the long-term cost-effectiveness of two multidisciplinary management programs for elderly patients hospitalized with chronic heart failure (CHF) and how it is influenced by patient characteristics. A trial-based analysis was conducted alongside a randomized controlled trial of 280 elderly patients with CHF discharged to home from three Australian tertiary hospitals. Two interventions were compared: home-based intervention (HBI) that involved home visiting with community-based care versus specialized clinic-based intervention (CBI). Bootstrapped incremental cost-utility ratios were computed based on quality-adjusted life-years (QALYs) and total healthcare costs. Cost-effectiveness acceptability curves were constructed based on incremental net monetary benefit (NMB). We performed multiple linear regression to explore which patient characteristics may impact patient-level NMB. During median follow-up of 3.2 years, HBI was associated with slightly higher QALYs (+0.26 years per person p=0.078) and lower total healthcare costs (AU$ -13,100 per person p=0.025) mainly driven by significantly reduced duration of all-cause hospital stay (-10 days p=0.006). At a willingness-to-pay threshold of AU$ 50,000 per additional QALY, the probability of HBI being better-valued was 96% and the incremental NMB of HBI was AU$ 24,342 (discounted, 5%). The variables associated with increased NMB were HBI (vs. CBI), lower Charlson Comorbidity Index, no hyponatremia, fewer months of HF, fewer prior HF admissions <1 year and a higher patient's self-care confidence. HBI's net benefit further increased in those with fewer comorbidities, a lower self-care confidence or no hyponatremia. Compared with CBI, HBI is likely to be cost-effective in elderly CHF patients with significant comorbidity.
Publisher: Cold Spring Harbor Laboratory
Date: 26-09-2019
DOI: 10.1101/780346
Abstract: Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits mediating goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of striatal projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN trans-modulation across the dorsal striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.
Publisher: Elsevier BV
Date: 09-2002
Abstract: A three-phase experiment manipulated sexual experience and hormone exposure (perinatally and in adulthood) in female rats housed in idually from weaning so as to limit peripubertal social and sexual experience. Noncontact partner preference for a male or estrous female rat was measured both before and after sexual experience, first while rats were under the influence of circulating testosterone propionate (TP) and later after priming them with ovarian hormones (estradiol benzoate and progesterone EB & P). When implanted with TP capsules and tested while sexually naive, all groups of female rats preferred females to males without differing statistically. However, following three sexual experience sessions with estrous females, differences emerged between the masculinized and control groups in the magnitude of their female-directed preference, with masculinized females demonstrating a significantly greater preference for estrous females. Sexual experience with male rats under EB & P did not result in a significant shift in preference in any group. Histological assessment indicated that the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) was increased by exposure to TP postnatally, and SDN-POA volume correlated positively with partner preference scores but only when rats were both sexually experienced and exposed to circulating TP in adulthood. These results suggest that sexual experience interacts with steroid exposure to shape partner preference.
Publisher: Oxford University Press (OUP)
Date: 11-05-2018
DOI: 10.1093/BRAIN/AWY123
Abstract: Behavioural-variant frontotemporal dementia is characterized by a number of ostensibly disparate clinical features, which have largely been considered independently. This update proposes an integrated conceptual framework for these symptoms, by bringing together findings from animal studies, functional neuroimaging and behavioural neurology. The combined evidence indicates that many of the clinical symptoms--such as altered eating behaviour overspending and susceptibility to scams reduced empathy and socially inappropriate behaviour apathy and stereotyped/ritualistic behaviour--can be conceptualized as a common underlying deficiency in goal-directed behaviour and the concomitant emergence of habits. This view is supported by similarities between the characteristic patterns of frontostriatal and insular atrophy in behavioural-variant frontotemporal dementia and the circuitry of homologous brain regions responsible for goal-directed and habitual behaviour in animals. Appreciating the impact of disturbance in goal-directed behaviour provides a new, integrated understanding of the common mechanisms underpinning prototypical clinical symptoms in behavioural-variant frontotemporal dementia. Furthermore, by drawing parallels between animal and clinical research, this translational approach has important implications for the development and evaluation of novel therapeutic treatments, from animal models through to behavioural interventions and clinical trials in humans.10.1093/brain/awy123_video1awy123media15796485557001.
Publisher: Society for Neuroscience
Date: 02-05-2007
DOI: 10.1523/JNEUROSCI.5443-06.2007
Abstract: Previous studies have implicated the orbitofrontal cortex (OFC) in outcome encoding. However, it remains unknown whether the OFC is selectively involved in pavlovian stimulus–outcome learning or whether it also contributes to instrumental action–outcome learning. In experiment 1, we investigated this issue by assessing the effects of bilateral lesions of the OFC on the sensitivity of instrumental lever press performance to a reduction in the incentive value of the training outcome (a test of action–outcome encoding) and to outcome-specific pavlovian-instrumental transfer (a test of stimulus–outcome encoding). We found that post-training lesions of the OFC did not affect instrumental outcome devaluation, but abolished the transfer effect. Interestingly, lesions made before training had no effect on either task. In experiment 2, we explored the involvement of the OFC in updating stimulus–outcome associations after the underlying contingency, or predictive relationship, between these two events has been degraded. Shams displayed clear contingency learning, withholding conditioned responding to a stimulus that no longer reliably predicted its outcome while continuing to respond to a control stimulus that remained a good predictor of a different outcome. In contrast, OFC-lesioned rats stopped responding to both stimuli, regardless of their predictive status. Together, these findings suggest that the OFC supports outcome encoding in pavlovian, but not instrumental conditioning.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2020
DOI: 10.1101/2020.05.12.092205
Abstract: Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsion and compulsive disorders. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented instrumental conditioned punishment learning in a manner that could not be attributed to differences in Pavlovian conditioned fear. We then showed that increasing the frequency of punishing outcomes allowed mOFC-lesioned animals to overcome their initial deficit. Our second experiment demonstrated that the retrieval of instrumental punishment is also mOFC-dependent, as mOFC lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent the re-acquisition of conditioned punishment that was learned prior to lesions being administered. Together, these results reveal that the mOFC does indeed regulate punishment learning and retrieval in a manner that is disassociated from any role in Pavlovian fear learning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2020
DOI: 10.1038/S41598-020-61892-5
Abstract: Deficits in instrumental, goal-directed control, combined with the influence of drug-associated Pavlovian-conditioned stimuli, are thought to influence the development and maintenance of addiction. However, direct evidence has mainly come from animal studies. We sought to establish whether alcohol use disorder (AUD) is characterized by behavioral or neurobiological deficits in (i) the integration of Pavlovian and instrumental values and (ii) goal-directed control and (iii) whether duration or severity of AUD is associated with such deficits. The influence of cues predicting food rewards on instrumental action was assessed in a Pavlovian-to-instrumental transfer (PIT) test, measuring both specific and general PIT, and goal-directed behavior in an outcome-devaluation test. Brain activity was measured using functional MRI in 38 abstinent in iduals with AUD and 22 matched healthy control in iduals (HCs). We found significant specific and general PIT and outcome-devaluation effects across groups indicating goal-directed control, mediated by distinct corticostriatal signals, but no significant differences between in iduals with AUD and healthy controls. Bayesian analyses provided substantial-to-strong evidence for the absence of group differences for these effects, or any relationship with duration or severity of AUD. These results suggest intact ability to integrate action-outcome associations on specific and general PIT and goal-directed learning in AUD during abstinence.
Publisher: Society for Neuroscience
Date: 28-05-2008
DOI: 10.1523/JNEUROSCI.0897-08.2008
Abstract: In outcome-specific transfer, pavlovian cues that are predictive of specific outcomes bias action choice toward actions associated with those outcomes. This transfer occurs despite no explicit training of the instrumental actions in the presence of pavlovian cues. The neural substrates of this effect in humans are unknown. To address this, we scanned 23 human subjects with functional magnetic resonance imaging while they made choices between different liquid food rewards in the presence of pavlovian cues previously associated with one of these outcomes. We found behavioral evidence of outcome-specific transfer effects in our subjects, as well as differential blood oxygenation level-dependent activity in a region of ventrolateral putamen when subjects chose, respectively, actions consistent and inconsistent with the pavlovian-predicted outcome. Our results suggest that choosing an action incompatible with a pavlovian-predicted outcome might require the inhibition of feasible but nonselected action–outcome associations. The results of this study are relevant for understanding how marketing actions can affect consumer choice behavior as well as for how environmental cues can influence drug-seeking behavior in addiction.
Publisher: Wiley
Date: 10-2008
Publisher: American Psychological Association (APA)
Date: 2013
DOI: 10.1037/A0030941
Publisher: Springer Science and Business Media LLC
Date: 12-1992
DOI: 10.3758/BF03197955
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.NEURON.2016.03.006
Abstract: For goal-directed action to remain adaptive, new strategies are required to accommodate environmental changes, a process for which parafascicular thalamic modulation of cholinergic interneurons in the striatum (PF-to-CIN) appears critical. In the elderly, however, previously acquired experience frequently interferes with new learning, yet the source of this effect has remained unexplored. Here, combining sophisticated behavioral designs, cell-specific manipulation, and extensive neuronal imaging, we investigated the involvement of the PF-to-CIN pathway in this process. We found functional alterations of this circuit in aged mice that were consistent with their incapacity to update initial goal-directed learning, resulting in faulty activation of projection neurons in the striatum. Toxicogenetic ablation of CINs in young mice reproduced these behavioral and neuronal defects, suggesting that age-related deficits in PF-to-CIN function reduce the ability of older in iduals to resolve conflict between actions, likely contributing to impairments in adaptive goal-directed action and executive control in aging. VIDEO ABSTRACT.
Publisher: Frontiers Media SA
Date: 2007
Publisher: Wiley
Date: 17-08-2022
DOI: 10.1111/JEP.13613
Abstract: To identify outcome measures used to evaluate performance of healthcare professional role substitution against usual medical doctor or specialist medical doctor care to facilitate our understanding of the adequacy of these measures in assessing quality of healthcare delivery. Using a systematic approach, we searched Medline, Cochrane Central Register of Controlled Trials, Embase, CINAHL, and Web of Science from database inception until May 2020. Studies that presented original comparative data on at least one outcome measure were included following screening by two authors. Findings were synthesized, and outcome measures classified into six domains which included: effectiveness, safety, appropriateness, access, continuity of care, efficiency, and sustainability which were informed by the Institute of Medicine dimensions of healthcare quality, the Australian health performance framework, and Levesque and Sutherland's integrated performance measurement framework. One thirty five articles met the inclusion criteria, describing 58 separate outcome measures. Safety of role substitution models of care was assessed in 80 studies, effectiveness (n = 60), appropriateness (n = 40), access (n = 36), continuity of care (n = 6), efficiency and productivity (n = 45). Two‐thirds of the studies that assessed productivity and efficiency performed an economic analysis (n = 27). The quality and rigour of evaluations varied substantially across studies, with two‐thirds of all studies measuring and reporting outcomes from only one or two of these domains. There are a growing number of studies measuring the performance of non‐medical healthcare professional substitution roles. Few have been subject to robust evaluations, and there is limited evidence on the scientific rigour and adequacy of outcomes measured. A systematic and coordinated approach is required to support healthcare settings in assessing the value of non‐medical role substitution healthcare delivery models.
Publisher: American Psychological Association (APA)
Date: 10-2017
DOI: 10.1037/XAN0000148
Abstract: Although there has been extensive research in both humans and rodents regarding the influence of excitatory predictions on action selection, the influence of inhibitory reward predictions is less well understood. We used a feature-negative conditioned inhibition procedure to generate Pavlovian excitors and inhibitors, predicting the presence or absence of specific outcomes, and assessed their influence on action selection using a Pavlovian-instrumental transfer test. Inhibitors predicting the absence of a specific outcome reversed the bias in action selection elicited by outcome-specific excitors whereas excitors promoted responding on the action associated with the same outcome as the cue, inhibitors shifted responding away from such actions and toward other actions. Furthermore, the influence of the inhibitors on choice reflected the nature of the inhibitory associations learned by participants those encoding outcome-specific inhibitory associations showed a strong reversal in the bias elicited by the excitors, selectively biasing performance away from the action associated with the to-be-omitted outcome and toward other actions. In contrast, those encoding only general inhibitory associations did not show any bias during the transfer test and instead reduced their performance of both actions. (PsycINFO Database Record
Publisher: Society for Neuroscience
Date: 26-01-2005
DOI: 10.1523/JNEUROSCI.4507-04.2005
Abstract: This series of experiments compared the effects of lesions of the basolateral complex (BLA) and the central nucleus (CN) of the amygdala on a number of tests of instrumental learning and performance and particularly on the contribution of these structures to the specific and general forms of pavlovian-instrumental transfer (PIT). In experiment 1, groups of BLA-, CN-, and sham-lesioned rats were first trained to press two levers, each earning a unique food outcome (pellets or sucrose), after which they were given training in which two auditory stimuli (tone and white noise) were paired with these same outcomes. Tests of specific satiety induced outcome devaluation, and tests of PIT revealed that, although the rats in all of the groups performed similarly during both the instrumental and pavlovian acquisition phases, BLA, but not CN, lesions abolished selective sensitivity to a change in the reward value of the instrumental outcome as well as to the selective excitatory effects of reward-related cues in PIT. In experiment 2, we developed a procedure in which both the general motivational and the specific excitatory effects of pavlovian cues could be assessed in the same animal and found that BLA lesions abolished the outcome-specific but spared the general motivational effects of pavlovian cues. In contrast, lesions of CN abolished the general motivational but spared the specific effects of these cues. Together, these results suggest that the BLA mediates outcome-specific incentive processes, whereas CN is involved in controlling the general motivational influence of reward-related events.
Publisher: American Psychological Association (APA)
Date: 2003
Publisher: Springer Science and Business Media LLC
Date: 21-06-2015
DOI: 10.1007/S11064-015-1638-6
Abstract: The delta opioid receptor (DOPr), whilst not the primary target of clinically used opioids, is involved in development of opioid tolerance and addiction. There is growing evidence that DOPr trafficking is involved in drug addiction, e.g., a range of studies have shown increased plasma membrane DOPr insertion during chronic treatment with opioids. The present study used a transgenic mouse model in which the C-terminal of the DOPr is tagged with enhanced-green fluorescence protein to examine the effects of chronic morphine treatment on surface membrane expression in striatal cholinergic interneurons that are implicated in motivated learning following both chronic morphine and morphine sensitization treatment schedules in male mice. A sex difference was noted throughout the anterior striatum, which was most prominent in the nucleus accumbens core region. Incontrast with previous studies in other neurons, chronic exposure to a high dose of morphine for 6 days had no effect, or slightly decreased (anterior dorsolateral striatum) surface DOPr expression. A morphine sensitization schedule produced similar results with a significant decrease in surface DOPr expression in nucleus accumbens shell. These results suggest that chronic morphine and morphine sensitisation treatment may have effects on instrumental reward-seeking behaviours and learning processes related to drug addiction, via effects on striatal DOPr function.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.IJNURSTU.2022.104191
Abstract: Pressure injuries are a leading hospital adverse event, yet they are mostly preventable. Understanding their financial costs will help to appreciate the burden they place on the health system and assist in better planning and management of health expenditures to prevent pressure injuries. To estimate the cost of pressure injuries in Australian public hospitals in 2020 demonstrating its economic burden in a well-resourced health system. A cost of illness study with a 12-month time horizon was conducted. Resource use for the treatment of pressure injuries and productivity loss due to pressure injuries were derived using a bottom-up approach. Parameters of the cost estimates were obtained from secondary sources and literature syntheses. A simulation with 10,000 draws was used to generate statistical properties of the cost estimates. Based on a prevalence of 12.9%, the total cost of pressure injuries in Australian public hospitals was $9.11 billion [95% confidence intervals: 9.02, 9.21]. The two largest shares of costs were accounted for by the opportunity cost of excess length of stay of $3.60 billion [3.52, 3.68] and treatment costs of $3.59 billion [3.57, 3.60]. Productivity loss associated with pressure injuries amounts to $493 million [482, 504]. Hospital-acquired pressure injuries account for a total of $5.50 billion [5.44, 5.56], whereas pressure injuries present on admissions costed $3.71 billion [3.70, 3.72]. In terms of severity, Stage 2 pressure injuries contributed the most to total treatment costs, total excessive length of stay, and total loss of healthy life years. Australian society is willing to pay $1.43 billion [1.40, 1.45] to save 6,701 [6,595 6,807] healthy life years lost by pressure injury. Reducing preventable pressure injuries and stopping the progression of Stage 1 pressure injuries will likely result in an immense cost-saving for Australia and will likely have similar benefits for other countries with comparable profiles. Australian public hospital study provides comprehensive analysis of the cost of pressure injury, including estimates of direct and indirect medical costs, and indirect non-medical costs - such as productivity and quality of life.
Publisher: Wiley
Date: 30-10-2015
DOI: 10.1111/ADB.12316
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.NLM.2017.11.006
Abstract: Contemporary theories of learning emphasize the role of a prediction error signal in driving learning, but the nature of this signal remains hotly debated. Here, we used Pavlovian conditioning in rats to investigate whether primary motivational and emotional states interact to control prediction error. We initially generated cues that positively or negatively predicted an appetitive food outcome. We then assessed how these cues modulated aversive conditioning when a novel cue was paired with a foot shock. We found that a positive predictor of food enhances, whereas a negative predictor of that same food impairs, aversive conditioning. Critically, we also showed that the enhancement produced by the positive predictor is removed by reducing the value of its associated food. In contrast, the impairment triggered by the negative predictor remains insensitive to devaluation of its associated food. These findings provide compelling evidence that the motivational value attributed to a predicted food outcome can directly control appetitive-aversive interactions and, therefore, that motivational processes can modulate emotional processes to generate the final error term on which subsequent learning is based.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.NEURON.2015.10.044
Abstract: Choice between actions often requires the ability to retrieve action consequences in circumstances where they are only partially observable. This capacity has recently been argued to depend on orbitofrontal cortex however, no direct evidence for this hypothesis has been reported. Here, we examined whether activity in the medial orbitofrontal cortex (mOFC) underlies this critical determinant of decision-making in rats. First, we simulated predictions from this hypothesis for various tests of goal-directed action by removing the assumption that rats could retrieve partially observable outcomes and then tested those predictions experimentally using manipulations of the mOFC. The results closely followed predictions consistent deficits only emerged when action consequences had to be retrieved. Finally, we put action selection based on observable and unobservable outcomes into conflict and found that whereas intact rats selected actions based on the value of retrieved outcomes, mOFC rats relied solely on the value of observable outcomes.
Publisher: Society for Neuroscience
Date: 23-11-2016
DOI: 10.1523/JNEUROSCI.1772-16.2016
Abstract: The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2–3 and 5–6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning. Rats were given either a single session of training to press a lever for a pellet reward or yoked reward deliveries without instrumental training and assessed 5 or 60 min after training for pERK expression. Relative to yoked training, instrumental training produced an increase in pERK expression in all regions of the PL both at 5 and 60 min, and this was accompanied by an increase in nuclear pERK expression in the posterior PL in rats given instrumental training. pDMS-projecting neurons showed a transient increase in pERK expression in posterior layer 5–6 projection neurons after 5 min, and a delayed increase in anterior layer 2–3 neurons after 60 min, suggesting that ERK expression in the PL is necessary for the consolidation of goal-directed learning. Consistent with this claim, we found that rats trained on two lever press actions for distinct outcomes and then infused with the MEK inhibitor PD98059 into the PL immediately after training failed to acquire specific action–outcome associations, suggesting that persistent pERK signaling in the PL is necessary for goal-directed learning. SIGNIFICANCE STATEMENT The prelimbic cortex is implicated in goal-directed learning in rodents however, it is unclear whether it is involved in the consolidation of this learning, and what cellular processes are involved. We used pERK as a marker of activity-related synaptic plasticity to assess learning-induced changes in distinct layers and neuronal populations of the prelimbic prefrontal cortex (PL). Training produced long-lasting upregulation of pERK throughout the PL and specifically within neurons that project to the pDMS, another region critical for goal-directed learning. Next, we demonstrated that pERK signaling in the PL was necessary for the consolidation of goal-directed learning. Together, these results indicate that instrumental training induces ERK signaling in distinct layers and populations in the PL and this signaling underlies the consolidation of goal-directed learning.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 21-03-2022
DOI: 10.1101/2022.03.19.22272645
Abstract: Establishing the motivational influences on human action is essential for understanding choice and decision-making in health and disease. Here we used tests of value-based decision-making, manipulating both predicted and experienced reward values to assess the motivational control of goal-directed action in adolescents and the functional impact of OCD. After instrumental training on a two action-two outcome probabilistic task, participants underwent Pavlovian conditioning using stimuli predicting either the instrumental outcomes, a third outcome or nothing. We then assessed fMRI during choice tests in which we varied predicted value, using specific and general Pavlovian-instrumental transfer (PIT), and experienced value, using outcome devaluation. Both predicted and experienced values influenced the performance of goal-directed actions in healthy adolescent participants, mediated by distinct orbitofrontal (OFC)-striatal circuits involving the lateral-OFC and medial-OFC respectively. To establish their functional significance, we tested a matched cohort of adolescents with obsessive-compulsive disorder (OCD). We found that choice between actions in OCD was insensitive to changes in both predicted and experienced values and that these impairments corresponded to hypoactivity activity in the lateral OFC and hyperactivity in medial OFC during specific PIT and hypoactivity in anterior prefrontal cortex, caudate nucleus and their connectivity in the devaluation test. We found, therefore, that predicted and experienced values exerted a potent influence on the performance of goal-directed actions in adolescents via distinct orbitofrontal- and prefrontal-striatal circuits. The influence of these motivational processes was severely blunted in OCD resulting in dysregulated action control associated with the intrusion of competing actions.
Publisher: SAGE Publications
Date: 04-2017
DOI: 10.1080/17470218.2016.1149198
Abstract: Predictive learning is known to influence instrumental responding for reward. Cues associated with an instrumental outcome can influence performance in two ways: (a) by selectively promoting actions associated with the outcome predicted by the cue (specific transfer), and (b) by increasing motivation and the vigour of instrumental responding (general transfer). To examine these two distinct processes in humans we developed a novel behavioural task in which participants were able to liberate junk-food snacks from a virtual vending machine. Additionally, the relationship between stress and cue-driven reward seeking was examined using participant scores on the Depression Anxiety and Stress Scale (DASS). Reward-paired cues were found to separately bias action selection and influence the rate of responding for rewards. Furthermore, the effects of reward-paired cues on the rate of responding for reward was influenced by increased stress and anxiety. Increased levels of stress and anxiety were associated particularly with changes in cue-driven response vigour whereas high levels of stress and anxiety were associated with elevated responding above baseline in the presence of a cue associated with a non-rewarding outcome, participants with low levels of anxiety and stress showed appropriate suppression of responding during this cue. These differences in performance between high and low anxiety and stress participants provides initial evidence that, as has been demonstrated in rodents, stress affects the influence of cue-driven response vigour in humans.
Publisher: Public Library of Science (PLoS)
Date: 06-09-2019
Publisher: Springer Science and Business Media LLC
Date: 17-02-2014
DOI: 10.1038/NPP.2014.37
Publisher: American Psychological Association (APA)
Date: 2006
DOI: 10.1037/0097-7403.32.1.33
Abstract: Hungry and thirsty rats lever pressed for food pellets in 1 visual stimulus (V1) and for a saline solution in another stimulus (V2). In a 2nd phase, the rats were made either hungry or thirsty and pressed for a starch solution in 2 stimulus compounds, each containing 1 of the visual cues and an auditory cue, that is, V1A1 and V2A2. On test, rats responded less to A1 than to A2 when hungry but less to A2 than to A1 when thirsty. Two further experiments replicated this selective blocking effect when the rats were both hungry and thirsty during Phase 2 and demonstrated that the magnitude of blocking was comparable to that observed when the reinforcer identity was held constant across the 2 phases.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.NEURON.2019.09.024
Abstract: The ability to establish behaviorally what psychological capacity an animal is deploying-to discern accurately what an animal is doing-is key to functional analyses of the brain. Our current understanding of these capacities suggests, however, that this task is complex there is evidence that multiple capacities are engaged simultaneously and contribute independently to the control of behavior. As such, establishing the contribution of a cell, circuit, or neural system to any one function requires careful dissection of that role from its influence on other functions and, therefore, the careful selection and design of behavioral tasks fit for that purpose. Here I describe recent research that has sought to utilize behavioral tools to investigate the neural bases of instrumental conditioning, particularly the circuits and systems supporting the capacity for goal-directed action, as opposed to conditioned reflexes and habits, and how these sources of action control interact to generate adaptive behavior.
Publisher: American Psychological Association (APA)
Date: 1994
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.TINS.2006.03.002
Abstract: The amygdala is a heterogeneous structure that has been implicated in a wide variety of functions, most notably in fear conditioning. From this research, an influential serial model of amygdala processes has emerged in which aversive learning is mediated by the amygdala basolateral nucleus whereas performance, in this case of various defensive reflexes, is mediated by the central nucleus. By contrast, recent evidence from appetitive conditioning studies suggests that the basolateral and central nuclei operate in parallel to mediate distinct incentive processes: the basolateral nucleus encodes emotional events with reference to their particular sensory-specific features, whereas the central nucleus encodes their more general motivational or affective significance. Given that there is little if any direct behavioral evidence for the serial model, we suggest that more attention should be given to the claims of the parallel view.
Publisher: Oxford University Press (OUP)
Date: 16-10-2016
Abstract: The cost-effectiveness of heart failure management programs (HF-MPs) is highly variable. We explored intervention and clinical characteristics likely to influence cost outcomes. A systematic review of economic analyses alongside randomized clinical trials comparing HF-MPs and usual care. Electronic databases were searched for English peer-reviewed articles published between 1990 and 2013. Of 511 articles identified, 34 comprising 35 analyses met the inclusion criteria. Eighteen analyses (51%) reported a HF-MP as more effective and less costly four analyses (11%), and five analyses (14%) also reported they were more effective but with no significant or an increased cost difference, respectively. Alternatively, five analyses (14%) reported no statistically significant difference in effects or costs, and one analysis (3%) reported no statistically significant effect difference but was less costly. Finally, two analyses (6%) reported no statistically significant effect difference but were more costly. Interventions that reduced hospital admissions tended to result in favorable cost outcomes, moderated by increased resource use, intervention cost and/or the durability of the intervention effect. The reporting quality of economic evaluation assessed by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist varied substantially between 5% and 91% (median 45% 34 articles) of the checklist criteria adequately addressed. Overall, none of the study, patient or intervention characteristics appeared to independently influence the cost-effectiveness of a HF-MP. The extent that HF-MPs reduce hospital readmissions appears to be associated with favorable cost outcomes. The current evidence does not provide a sufficient evidence base to explain what intervention or clinical attributes may influence the cost implications.
Publisher: Frontiers Media SA
Date: 26-05-2014
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Publisher: Springer Science and Business Media LLC
Date: 10-02-2004
Publisher: SAGE Publications
Date: 10-1995
Publisher: Oxford University PressNew York
Date: 30-09-2004
DOI: 10.1093/ACPROF:OSO/9780195162851.003.0041
Abstract: This chapter discusses the incentive behavior of rats in the context of evaluative, Pavlovian, and instrumental conditioning procedures. These incentive processes constitute a hierarchy: instrumental incentives involve in part processes engaged by Pavlovian incentives that in part involve processes engaged by evaluative incentives. Whether these incentive processes can in fact be fully dissociated structurally is still a matter of debate, and some current issues are discussed in the final section.
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.APPET.2017.02.009
Abstract: The influence of binge-like feeding schedules on subsequent food-related behavior is not well understood. We investigated the effect of repeated cycles of restriction and refeeding on two food-related behaviors goal-directed responding for a palatable food reward and sensory-specific satiety. Hungry rats were trained to perform two instrumental actions for two distinct food outcomes and were then subjected to repeated cycles of restricted and unrestricted access to their maintenance chow for 30-days or were maintained on food restriction. Goal-directed control was then assessed using specific satiety-induced outcome devaluation. Rats were given 1 h access to one of theoutcomes and were then immediately given a choice between the two actions. Rats maintained on restriction responded more for the valued than the devalued reward but rats with a history of restriction and refeeding failed to show this effect. Importantly, all rats showed sensory-specific satiety when offered a choice between the two foods, indicating that pre-feeding selectively reduced the value of the pre-fed food. By contrast, sensory-specific satiety was not observed in rats with a history of intermittent feeding when the foods were offered sequentially. These results indicate that, similar to calorically dense diets, intermittent feeding patterns can impair the performance of goal-directed actions as well as the ability to reject a pre-fed food when it is offered alone.
Publisher: Elsevier
Date: 2009
Publisher: Wiley
Date: 05-11-2012
DOI: 10.1111/J.1749-6632.2012.06768.X
Abstract: Learning theory proposes that drug seeking is a synthesis of multiple controllers. Whereas goal-directed drug seeking is determined by the anticipated incentive value of the drug, habitual drug seeking is elicited by stimuli that have formed a direct association with the response. Moreover, drug-paired stimuli can transfer control over separately trained drug seeking responses by retrieving an expectation of the drug's identity (specific transfer) or incentive value (general transfer). This review covers outcome devaluation and transfer of stimulus-control procedures in humans and animals, which isolate the differential governance of drug seeking by these four controllers following various degrees of contingent and noncontingent drug exposure. The neural mechanisms underpinning these four controllers are also reviewed. These studies suggest that although initial drug seeking is goal-directed, chronic drug exposure confers a progressive loss of control over action selection by specific outcome representations (impaired outcome devaluation and specific transfer), and a concomitant increase in control over action selection by antecedent stimuli (enhanced habit and general transfer). The prefrontal cortex and mediodorsal thalamus may play a role in this drug-induced transition to behavioral autonomy.
Publisher: Public Library of Science (PLoS)
Date: 30-07-2013
Publisher: Society for Neuroscience
Date: 22-01-2014
DOI: 10.1523/JNEUROSCI.4592-13.2014
Abstract: Decision-making depends on the ability to extract predictive information from the environment to guide future actions. Outcome-specific Pavlovian-instrumental transfer (PIT) provides an animal model of this process in which a stimulus predicting a particular outcome biases choice toward actions earning that outcome. Recent evidence suggests that cellular adaptations of δ-opioid receptors (DORs) on cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) are necessary for PIT. Here we found that modulation of DORs in CINs critically influences D 1 -receptor (D1R)-expressing projection neurons in the NAc-S to promote PIT. First, we assessed PIT-induced changes in signaling processes in dopamine D 1 - and D 2 -receptor-expressing neurons using drd2 -eGFP mice, and found that PIT-related signaling was restricted to non-D2R-eGFP-expressing neurons, suggesting major involvement of D1R-neurons. Next we confirmed the role of D1Rs pharmacologically: the D1R antagonist SCH-23390, but not the D2R antagonist raclopride, infused into the NAc-S abolished PIT in rats, an effect that depended on DOR activity. Moreover, asymmetrical infusion of SCH-23390 and the DOR antagonist naltrindole into the NAc-S also abolished PIT. DOR agonists were found to sensitize the firing responses of CINs in brain slices prepared immediately after the PIT test. We confirmed the opioid-acetylcholinergic influence over D1R-neurons by selectively blocking muscarinic M4 receptors in the NAc-S, which tightly regulate the activity of D1Rs, a treatment that rescued the deficit in PIT induced by naltrindole. We describe a model of NAc-S function in which DORs modulate CINs to influence both D1R-neurons and stimulus-guided choice between goal-directed actions.
Publisher: Society for Neuroscience
Date: 16-03-2022
DOI: 10.1523/JNEUROSCI.1079-21.2022
Abstract: From an associative perspective the acquisition of new goal-directed actions requires the encoding of specific action-outcome (AO) associations and, therefore, sensitivity to the validity of an action as a predictor of a specific outcome relative to other events. Although competitive architectures have been proposed within associative learning theory to achieve this kind of identity-based selection, whether and how these architectures are implemented by the brain is still a matter of conjecture. To investigate this issue, we trained human participants to encode various AO associations while undergoing functional neuroimaging (fMRI). We then degraded one AO contingency by increasing the probability of the outcome in the absence of its associated action while keeping other AO contingencies intact. We found that this treatment selectively reduced performance of the degraded action. Furthermore, when a signal predicted the unpaired outcome, performance of the action was restored, suggesting that the degradation effect reflects competition between the action and the context for prediction of the specific outcome. We used a Kalman filter to model the contribution of different causal variables to AO learning and found that activity in the medial prefrontal cortex (mPFC) and the dorsal anterior cingulate cortex (dACC) tracked changes in the association of the action and context, respectively, with regard to the specific outcome. Furthermore, we found the mPFC participated in a network with the striatum and posterior parietal cortex to segregate the influence of the various competing predictors to establish specific AO associations. SIGNIFICANCE STATEMENT Humans and other animals learn the consequences of their actions, allowing them to control their environment in a goal-directed manner. Nevertheless, it is unknown how we parse environmental causes from the effects of our own actions to establish these specific action-outcome (AO) relationships. Here, we show that the brain learns the causal structure of the environment by segregating the unique influence of actions from other causes in the medial prefrontal and anterior cingulate cortices and, through a network of structures, including the caudate nucleus and posterior parietal cortex, establishes the distinct causal relationships from which specific AO associations are formed.
Publisher: American Psychological Association (APA)
Date: 1994
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.BIOPSYCH.2014.06.005
Abstract: Goal-directed actions depend on our capacity to integrate the anticipated consequences of an action with the value of those consequences, with the latter derived from direct experience or inferred from predictive stimuli. Schizophrenia is associated with poor goal-directed performance, but whether this reflects a deficit in experienced or predicted value or in integrating these values with action-outcome information is unknown, as is the locus of any associated neuropathology. We assessed the contribution of these sources of value to goal-directed actions in people with schizophrenia (SZ) (n = 18) and healthy adults (n = 18). Participants learned to use specific actions to liberate snack foods from a vending machine. They also learned about the reward value of the foods, changes in reward value, and the relationship between various predictive stimuli and food delivery. We then evaluated the ability of subjects to use experienced or predicted value to guide goal-directed actions while undergoing functional magnetic resonance imaging. Acquisition and sensitivity to experienced changes in outcome value did not differ in SZ and healthy adults. The SZ were, however, deficient in their ability to integrate action-outcome learning with outcome values to guide choice, more so when actions were guided by experienced than by predicted values. These effects were differentially associated with reductions in activity in caudate and limbic structures, respectively. This novel assessment of goal-directed learning revealed dysfunction in corticostriatal control associated with a profound deficit in integrating changes in experienced value with the action-outcome association in schizophrenia.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Society for Neuroscience
Date: 25-06-2008
Publisher: Cold Spring Harbor Laboratory
Date: 26-08-2022
DOI: 10.1101/2022.08.25.505358
Abstract: The loss of neurons in parafascicular thalamus (Pf) and of their inputs to dorsomedial striatum (DMS) are associated with Lewy body disease (LBD) and Parkinson’s disease dementia (PDD) and have been linked to the effects of neuroinflammation. In rats, these inputs regulate the function of striatal cholinergic interneurons (CINs) that are necessary for the flexible encoding of the action-outcome (AO) associations for goal-directed action. We found that these inputs modify the encoding, not retrieval, of new AO associations and cause burst-pause firing of CINs in the DMS during AO remapping. These adaptive effects were abolished by neuroinflammation in the Pf, resulting in the loss of goal-directed control when the rats were required to update AO associations after a change in contingency. We found that the neuronal and behavioral deficits induced by inflammation in the Pf were rescued by administration of selegiline, a MAO-B inhibitor that we found also enhances ATPase activity in CINs, suggesting a potential treatment for cognitive deficits associated with inflammation affecting the function of midline thalamic nuclei and related structures.
Publisher: Wiley
Date: 14-07-2017
DOI: 10.1111/ADB.12534
Publisher: American Psychological Association (APA)
Date: 1991
Publisher: Society for Neuroscience
Date: 24-06-2009
Publisher: American Psychological Association (APA)
Date: 1996
Publisher: Frontiers Media SA
Date: 11-12-2019
Publisher: Wiley
Date: 21-03-2016
DOI: 10.1002/AUR.1613
Abstract: Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental conditions associated with persistent, stereotyped or repetitive actions, and patterns of interest that are maintained in spite of possible negative outcomes. The aim of the present study was to investigate whether impairments in the ability to execute flexible goal-directed actions may be an underlying feature in ASD contributing to these symptoms. Young adults diagnosed with ASD were recruited along with controls and adults with social anxiety disorder (SAD). Participants were trained to make keyboard actions for food outcomes and then subsequently allowed to consume one outcome till satiety. As expected, this outcome devaluation procedure reduced subsequent responding for actions predicting the devalued outcome, while maintaining responding on the other still-valued action, in controls. However, both ASD and SAD participants were unable to demonstrate flexible goal-directed actions, and were insensitive to the change in outcome value on subsequent action control. This behavioral deficit was not due to impairments in appropriate contingency awareness, as all groups rated the devalued food outcome as less pleasant after devaluation. A lack of control over actions may underlie persistent and habitual actions in anxiety-inducing contexts typical in both ASD and SAD, such as avoidance and safety behaviors. Using a translational behavioral paradigm, this study demonstrated that in iduals with ASD are unable to use changes in the environment to flexibly update their behavior in the same context. This reduced behavioral control may underlie persistence of intrusive actions and restricted inflexible cognition, representing a specific area for targeted behavioral interventions. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2016, 9: 1285-1293. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Publisher: Society for Neuroscience
Date: 27-02-2017
DOI: 10.1523/JNEUROSCI.3860-16.2017
Abstract: We (Bradfield et al., 2013) have demonstrated previously that parafascicular thalamic nucleus (PF)-controlled neurons in the posterior dorsomedial striatum (pDMS) are critical for interlacing new and existing action–outcome contingencies to control goal-directed action. Based on these findings, it was suggested that animals with a dysfunctional PF–pDMS pathway might suffer a deficit in creating or retrieving internal contexts or “states” on which such information could become conditional. To assess this hypothesis more directly, rats were given a disconnection treatment using contralateral cytotoxic lesions of the PF and pDMS (Group CONTRA) or ipsilateral control lesions (Group IPSI) and trained to press a right and left lever for sucrose and pellet outcomes, after which these contingencies were reversed. The rats were then given an outcome devaluation test (all experiments) and a test of outcome-specific reinstatement (Experiments 1 and 3). We found that devaluation performance was intact for both groups after training of initial contingencies, but impaired for Group CONTRA after reversal. However, performance was restored by additional reversal training. Furthermore, when tested a second time after reversal training, rats in both groups demonstrated responding in accordance with the original contingencies, providing direct evidence of modulation of action selection by state. Finally, we found that external context could substitute for internal state and so could rescue responding in Group CONTRA, but only in the reinstatement test. Together, these findings suggest that animals use internal state information to guide action selection and that this information is modulated by the PF–pDMS pathway. SIGNIFICANCE STATEMENT In iduals with Parkinson's disease dementia often suffer a characteristic deficit in “cognitive flexibility.” It has been suggested that neurodegeneration in the pathway between the centromedian arafascicular thalalmic nucleus (PF) and striatum might underlie such deficits (Smith et al., 2014). In rats, we have similarly observed that a functional disconnection of the PF–posterior dorsomedial striatal pathway produces a specific impairment in the ability to alter goal-directed actions (Bradfield et al., 2013). It was suggested that this impairment could be a result of a deficit in state modulation. Here, we present four experiments that provide evidence for this hypothesis and suggest several ways (e.g., extended practice, providing external cues) in which this state modulation can be rescued.
Publisher: Public Library of Science (PLoS)
Date: 11-06-2019
Publisher: Wiley
Date: 04-2012
Start Date: 2015
End Date: 2019
Funder: National Health and Medical Research Council
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Funder: Australian Research Council
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End Date: 2018
Funder: National Health and Medical Research Council
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End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2019
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 1997
End Date: 2014
Funder: National Institute of Mental Health
View Funded ActivityStart Date: 1997
End Date: 2002
Funder: National Institute of Mental Health
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2014
Funder: Australian Research Council
View Funded ActivityStart Date: 2008
End Date: 2014
Funder: National Institute of Child Health and Human Development
View Funded ActivityStart Date: 2011
End Date: 2013
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 2018
Funder: Australian Research Council
View Funded ActivityStart Date: 2008
End Date: 2014
Funder: National Institute On Alcohol Abuse and Alcoholism
View Funded ActivityStart Date: 2010
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2010
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
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