ORCID Profile
0000-0003-3921-0745
Current Organisation
University of Technology Sydney
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Central Nervous System | Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology | Decision Making
Nervous System and Disorders | Mental Health | Expanding Knowledge in Psychology and Cognitive Sciences |
Publisher: Center for Open Science
Date: 05-06-2019
Abstract: The orbitofrontal cortex (OFC) has recently been proposed to function as a cognitive map oftask space: a mental model of the various steps involved in a task. This idea has proven popularbecause it provides a cohesive explanation for a number of disparate findings regarding the OFC’srole in a broad array of tasks. Concurrently, mounting evidence has begun to reveal the functional heterogeneity of OFC subregions, particularly the medial and lateral OFC. How these subregions might uniquely contribute to the OFC’s role as a cognitive map of task space, however, has not been explored. Here we propose that the lateral OFC represents the agent’s initial position within that task map (i.e. initial state), determining which actions are available as a consequence of that position, whereas the medial OFC represents the agent’s desired future position within the task map(i.e. terminal state), influencing which actions are selected to achieve that position. We argue thatthese processes are achieved somewhat independently and somewhat interdependently, and are achieved through similar but non-identical circuitry.
Publisher: Frontiers Media SA
Date: 19-03-2021
DOI: 10.3389/FNBEH.2021.655029
Abstract: Several lines of evidence accrued over the last 5–10 years have converged to suggest that the parafascicular nucleus of the thalamus and the lateral orbitofrontal cortex each represent or contribute to internal state/context representations that guide action selection in partially observable task situations. In rodents, inactivations of each structure have been found to selectively impair performance in paradigms testing goal-directed action selection, but only when that action selection relies on state representations. Electrophysiological evidence has suggested that each structure achieves this function via inputs onto cholinergic interneurons (CINs) in the dorsomedial striatum. Here, we briefly review these studies, then point to anatomical evidence regarding the afferents of each structure and what they suggest about the specific features that each contribute to internal state representations. Finally, we speculate as to whether this role might be achieved interdependently through direct PF→OFC projections, or through the convergence of independent direct orbitofrontal cortex (OFC) and parafascicular nucleus of the thalamus (PF) inputs onto striatal targets.
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2021
DOI: 10.1101/2021.07.28.454246
Abstract: Research from human and animal studies has found that responding that has been successfully reduced following treatment can return upon exposure to certain contexts. An in idual in recovery from alcohol use disorder, for ex le, might relapse to drinking upon visiting their favourite bar. However, most of these data have been derived from experiments involving a single (active) response, and the context-dependence of returned responding in situations involving choice between multiple actions and outcomes is less well-understood. We thus investigated how outcome-selective reinstatement – a procedure involving choice between multiple actions – was affected by altering the physical context in rats. In Experiment 1, rats were trained over 6 days to press a left lever for one food outcome (pellets or sucrose) and a right lever for the other outcome. Then, rats received an extinction session in either the same context (A) as lever press training, or in a different context (B). Rats were tested immediately (5 minutes) after extinction in Context A or B such that there were four groups in total: AAA, ABB, ABA, and AAB. Reinstatement testing consisted of one food outcome being delivered ‘freely’ (i.e. unearned by lever pressing and unsignalled by cues) to the food magazine every 4 minutes in the following order: Sucrose, Pellet, Pellet, Sucrose. Selective reinstatement was considered intact if pellet delivery increased pressing selectively on the pellet lever, and sucrose delivery selectively increased pressing on the sucrose lever. This result (Reinstated Nonreinstated) was observed for rats in group AAA and ABB, but not rats in groups ABA and AAB. Experiment 2 was conducted identically, except that rats received two extinction sessions over two days and tested one day later. This time, all groups demonstrated intact outcome-selective reinstatement regardless of context. Analysis of c-Fos expression in several brain regions revealed that only c-Fos expression in the posterior dorsomedial striatum (pDMS) was related to intact reinstatement performance. Overall, these results suggest that outcome-selective reinstatement is predominantly context-independent, and that intact reinstatement is related to neuronal activity in the pDMS. Outcome-selective reinstatement is predominantly context-independent Outcome-selective reinstatement is entirely context-independent after multiple extinction sessions Outcome-selective reinstatement increases c-Fos expression in dorsomedial striatum c-Fos expression in orbitofrontal cortex and dorsal hippoc us is unaffected by selective reinstatement.
Publisher: eLife Sciences Publications, Ltd
Date: 20-11-2019
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: eLife Sciences Publications, Ltd
Date: 07-03-2023
Publisher: Springer Science and Business Media LLC
Date: 10-08-2020
Publisher: American Psychological Association (APA)
Date: 04-2021
DOI: 10.1037/BNE0000443
Publisher: American Psychological Association (APA)
Date: 2013
DOI: 10.1037/A0030941
Publisher: Frontiers Media SA
Date: 2013
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: 10-2021
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: Elsevier BV
Date: 2020
Publisher: eLife Sciences Publications, Ltd
Date: 26-11-2019
DOI: 10.7554/ELIFE.52765
Abstract: Our behaviour is shaped by its consequences – we seek rewards and avoid harm. It has been reported that in iduals vary markedly in their avoidance of detrimental consequences, that is in their sensitivity to punishment. The underpinnings of this variability are poorly understood they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48 18 female) trained in a conditioned punishment task that permitted concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.
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: MDPI AG
Date: 16-06-2023
DOI: 10.3390/MOLECULES28124808
Abstract: L-Azetidine-2-carboxylic acid (AZE) is a non-protein amino acid that shares structural similarities with its proteogenic L-proline amino acid counterpart. For this reason, AZE can be misincorporated in place of L-proline, contributing to AZE toxicity. In previous work, we have shown that AZE induces both polarization and apoptosis in BV2 microglial cells. However, it is still unknown if these detrimental effects involve endoplasmic reticulum (ER) stress and whether L-proline co-administration prevents AZE-induced damage to microglia. Here, we investigated the gene expression of ER stress markers in BV2 microglial cells treated with AZE alone (1000 µM), or co-treated with L-proline (50 µM), for 6 or 24 h. AZE reduced cell viability, nitric oxide (NO) secretion and caused a robust activation of the unfolded protein response (UPR) genes (ATF4, ATF6, ERN1, PERK, XBP1, DDIT3, GADD34). These results were confirmed by immunofluorescence in BV2 and primary microglial cultures. AZE also altered the expression of microglial M1 phenotypic markers (increased IL-6, decreased CD206 and TREM2 expression). These effects were almost completely prevented upon L-proline co-administration. Finally, triple/quadrupole mass spectrometry demonstrated a robust increase in AZE-bound proteins after AZE treatment, which was reduced by 84% upon L-proline co-supplementation. This study identified ER stress as a pathogenic mechanism for AZE-induced microglial activation and death, which is reversed by co-administration of L-proline.
Publisher: Center for Open Science
Date: 23-06-2022
Abstract: Habits are the subject of intense international research. Under the associative dual-process model the outcome devaluation paradigm has been used extensively to classify behaviours as being either goal-directed (sensitive to shifts in the value of associated outcomes) or habitual (triggered by stimuli without anticipation of consequences). This has proven to be a useful framework for studying the neurobiology of habit and relevance of habits in clinical psychopathology. However, in recent years issues have been raised about this rather narrow definition of habits in comparison to habitual behaviour experienced in the real world. Specifically, defining habits as the absence of goal-directed control, the very specific set-ups required to demonstrate habit experimentally and the lack of direct evidence for habits as stimulus-response behaviours are viewed as problematic. In this review paper we address key critiques that have been raised about habit research within the framework of the associative dual-process model. We then highlight novel research approaches studying different features of habits with methods that expand beyond traditional paradigms.
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2010
DOI: 10.1101/LM.1798810
Abstract: We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.
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: 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: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.NEUBIOREV.2019.11.009
Abstract: The orbitofrontal cortex (OFC) has been proposed to function as a cognitive map of task space: a mental model of the steps involved in a task. This idea has proven popular because it provides a cohesive explanation for a number of disparate findings regarding the OFC's role in a broad array of tasks. Concurrently, evidence has begun to reveal the functional heterogeneity of OFC subregions, particularly the medial and lateral OFC. How these subregions uniquely contribute to the OFC's role as a cognitive map of task space, however, has not been explored. Here we propose that, in rodents, the lateral OFC represents the agent's initial position within that task map (i.e. initial state), determining which actions are available as a consequence of that position, whereas the medial OFC represents the agent's future position within the task map (i.e. terminal state), influencing which actions are selected to achieve that position. We argue that these processes are achieved somewhat independently and somewhat interdependently, and are achieved through similar but non-identical circuitry.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier
Date: 2017
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: Elsevier BV
Date: 07-2013
Publisher: Elsevier BV
Date: 12-2021
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: Oxford University Press (OUP)
Date: 2020
Abstract: Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsive disorders and related behaviors. 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 rats from learning to avoid a lever that was punished with a stimulus that coterminated with footshock. Our second experiment demonstrated that retrieval of punishment learning is also somewhat mOFC-dependent, as lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent rats from reacquiring the ability to avoid a punished lever when it was learned prior to lesions being administered. In both experiments, Pavlovian fear conditioning to the stimulus was intact for all animals. Together, these results reveal that the mOFC regulates punishment learning and retrieval in a manner that is separate from any role in Pavlovian fear conditioning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.
Publisher: Oxford University Press
Date: 10-2017
DOI: 10.1093/MED/9780190228163.003.0031
Abstract: This chapter discusses the considerable research that has identified distinct functional circuits linking frontal cortex with the basal ganglia in the control of goal-directed and habitual actions. OCD is characterized by hyperactivity in a circuit involving some of these regions. Recent accounts of the interaction of goal-directed actions and habits suggest that these control processes interact hierarchically, so one alternative to current theories is that OCD reflects a dysfunction in this interactive process resulting in dysregulated action selection, whether that selection is driven by the outcome itself or by cues predicting the outcome. Importantly, it appears that both sources of action selection depend on the OFC—outcome based retrieval on the medial OFC and cue-related retrieval on the lateral OFC. From this perspective, therefore, hyperactivity of the OFC could produce both elevated outcome retrieval and increased responsiveness to outcomes-related cues, resulting in dysregulated action selection and compulsive action initiation as a consequence.
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: American Psychological Association (APA)
Date: 2008
DOI: 10.1037/0097-7403.34.2.256
Abstract: Six experiments used rats to study blocking and unblocking of fear learning. An excitatory stimulus (A) blocked fear learning to a neutral stimulus (B). Unblocking of B occurred if the AB compound signaled an increase in unconditioned stimulus (US) intensity or number. Assessments of associative change during blocking showed that more was learned about B than A. Such assessments during unblocking revealed that more was learned about B than A following an increase in US intensity but not US number. These US manipulations had no differential effects on single-cue learning. The results show that variations in US intensity or number produce unblocking of fear learning, but for each there is a different profile of associative change and a potentially different mechanism.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.NLM.2021.107556
Abstract: Research from human and animal studies has found that after responding has been successfully reduced following treatment it can return upon exposure to certain contexts. An in idual in recovery from alcohol use disorder, for ex le, might relapse to drinking upon visiting their favourite bar. However, most of these data have been derived from experiments involving a single (active) response, and the context-dependence of returned responding in situations involving choice between multiple actions and outcomes is less well-understood. We thus investigated how outcome-selective reinstatement - a procedure involving choice between two actions and outcomes - was affected by altering the physical context in rats. In Experiment 1, rats were trained over 6 days to press a left lever for one food outcome (pellets or sucrose) and a right lever for the other outcome. Then, rats received an extinction session in either the same context (A) as lever press training, or in a different context (B). Rats were tested immediately (5 min) after extinction in Context A or B such that there were four groups in total: AAA, ABB, ABA, and AAB. Reinstatement testing consisted of one food outcome being delivered 'freely' (i.e. unearned by lever pressing and unsignalled by cues) to the food magazine every 4 min in the following order: Sucrose, Pellet, Pellet, Sucrose. Selective reinstatement was considered intact if pellet delivery increased pressing selectively on the pellet lever, and sucrose delivery selectively increased pressing on the sucrose lever. This result (Reinstated > Nonreinstated) was observed for rats in group AAA and ABB, but not rats in groups ABA and AAB. Experiment 2 was conducted identically, except that rats received two extinction sessions over two days and tested one day later. This time, all groups demonstrated intact outcome-selective reinstatement regardless of context. Analysis of c-Fos expression in several brain regions revealed that only c-Fos expression in the posterior dorsomedial striatum (pDMS) was related to intact reinstatement performance. Overall, these results suggest that outcome-selective reinstatement is predominantly context-independent, and that intact reinstatement is related to neuronal activity in the pDMS.
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2019
DOI: 10.1101/808873
Abstract: Our behaviour is shaped by its consequences – we seek rewards and avoid harm. It has been reported that in iduals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats ( n = 48 18 female) trained in a task permitting concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.
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: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.NEURON.2018.10.041
Abstract: Sequential ordering of motor commands is required for the simplest of our daily activities. In this issue of Neuron, Díaz-Hernández et al. (2018) show that distinct thalamic inputs to different regions of the dorsal striatum critically modulate the initiation and execution of action sequences.
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: 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.
Start Date: 2022
End Date: 2024
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2020
End Date: 2022
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 05-2020
End Date: 07-2023
Amount: $500,929.00
Funder: Australian Research Council
View Funded Activity