ORCID Profile
0000-0003-2333-8437
Current Organisation
University of New South Wales
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Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology | Behavioural neuroscience | Central Nervous System | Biological psychology | Central nervous system | Learning motivation and emotion
Expanding Knowledge in Psychology and Cognitive Sciences | Mental Health |
Publisher: Elsevier BV
Date: 09-2023
Publisher: Oxford University Press (OUP)
Date: 20-10-2016
Abstract: Extinction and latent inhibition each refer to a reduction in conditioned responding: the former occurs when pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) are followed by repeated presentations of the CS alone the latter occurs when CS alone presentations precede its pairings with the US. The present experiments used fear conditioning to test the hypothesis that both phenomena involve a similar form of inhibitory learning that recruits common neuronal substrates. We found that the initial inhibitory memory established by extinction is reactivated in the infralimbic (IL) cortex during additional extinction. Remarkably, this reactivation also occurs when the initial inhibitory memory had been established by latent inhibition. In both cases, the inhibitory memory was strengthened by pharmacological stimulation of the IL. Moreover, NMDA receptor blockade in the IL disrupted the weakening in conditioned responding produced by either latent inhibition or extinction. These findings, therefore, indicate that latent inhibition and extinction produce a similar inhibitory memory that is retrieved from the IL. They also demonstrate that the IL plays a wide role in fear regulation by promoting the retrieval of inhibitory memories generated by CS alone presentations either before or after this CS has been rendered dangerous.
Publisher: Cold Spring Harbor Laboratory
Date: 26-08-2008
DOI: 10.1101/LM.1080108
Abstract: We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but post-extinction infusion spared retention. Pre-extinction infusion of the GABA A agonist, muscimol, depressed freezing and impaired retention as did post-extinction infusion. In Experiment 2, pre-extinction mPFC infusion of ifenprodil spared the development of inhibition whereas muscimol depressed freezing. Both impaired retention when infused pre- or post-extinction. Thus, the development of inhibition involves NMDAr activation in the BLA, whereas its consolidation involves both NMDAr activation in the mPFC and NMDAr-independent mechanisms in the BLA. In Experiment 3, BLA infusion of ifenprodil impaired relearning and retention of inhibition when infused before but did not impair retention when infused after re-extinction. BLA infusion of muscimol depressed freezing but did not impair retention when infused before or after re-extinction. In Experiment 4, mPFC infusion of ifenprodil impaired relearning when infused before re-extinction, whereas muscimol depressed responses. Both drugs impaired retention when infused into the mPFC before or after re-extinction. Thus, relearning to inhibit fear responses involves NMDAr activation in both the BLA and mPFC and consolidation of the inhibitory memory involves NMDAr activation in the mPFC. However, relearning and consolidation occur in the absence of neuronal activity within the BLA. We propose that NMDAr in the mPFC supports relearning inhibition when the BLA is inactivated.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2018
DOI: 10.1007/S00213-018-4957-X
Abstract: The basolateral amygdala complex (BLA) and infralimbic region of the prefrontal cortex (IL) play distinct roles in the extinction of Pavlovian conditioned fear in laboratory rodents. In the past decade, research in our laboratory has examined the roles of these brain regions in the re-extinction of conditioned fear: i.e., extinction of fear that is restored through re-conditioning of the conditioned stimulus (CS) or changes in the physical and temporal context of extinction training (i.e., extinction of renewed or spontaneously recovered fear). This paper reviews this research. It has revealed two major findings. First, in contrast to the acquisition of fear extinction, which usually requires neuronal activity in the BLA but not IL, the acquisition of fear re-extinction requires neuronal activity in the IL but can occur independently of neuronal activity in the BLA. Second, the role of the IL in fear extinction is determined by the training history of the CS: i.e., if the CS was novel prior to its fear conditioning (i.e., it had not been trained), the acquisition of fear extinction does not require the IL if, however, the prior training of the CS included a series of CS-alone exposures (e.g., if the CS had been pre-exposed), the acquisition of fear extinction was facilitated by pharmacological stimulation of the IL. Together, these results were taken to imply that a memory of CS-alone exposures is stored in the IL, survives fear conditioning of the CS, and can be retrieved and strengthened during extinction or re-extinction of that CS (regardless of whether the extinction is first- or second-learned). Hence, under these circumstances, the initial extinction of fear to the CS can be facilitated by pharmacological stimulation of the IL, and re-extinction of fear to the CS can occur in the absence of a functioning BLA.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.NLM.2021.107483
Abstract: The present experiments examined whether extinction of a stimulus predicting food affects the ability of that stimulus to energize instrumental performance to obtain food. We first used a general Pavlovian instrumental transfer (PIT) paradigm in which rats were first given Pavlovian conditioning with a stimulus predicting one type of food outcome and were then trained to lever press for a different food outcome. We found that the Pavlovian stimulus enhanced performance of the lever press response and that this enhancement was preserved after extinction of that stimulus (Experiment 1) even when the context was manipulated to favor the expression of extinction (Experiment 2). Next, we assessed whether extinction influenced the excitatory effect of a stimulus when it was trained as a discriminative stimulus. Extinction of this stimulus alone had no effect on its ability to control instrumental performance however, when extinguished with its associated lever press response, discriminative control was lost (Experiments 3 and 4). Finally, after instrumental and Pavlovian training, we extinguished a Pavlovian stimulus predicting one food outcome with a lever press response that delivered a different outcome. In a general PIT test, we found this extinction abolished the ability of the Pavlovian stimulus to elevate responding on a lever trained with a different outcome, revealing for the first time that extinction can abolish the general PIT effect. We conclude that extinction can produce an inhibitory association between the stimulus and the general response type, whether Pavlovian or instrumental, performed during the extinction training.
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: Cold Spring Harbor Laboratory
Date: 02-2010
DOI: 10.1101/LM.1655010
Abstract: Four experiments used rats to study the role of the basolateral amygdala (BLA) in the reinstatement and extinction of fear responses (freezing) to a previously extinguished conditioned stimulus (CS). In Experiment 1, BLA inactivation before pairing the extinguished CS with the shock unconditioned stimulus (US) or before US-alone exposure impaired the restoration and the reinstatement of fear responses to the extinguished CS. In Experiment 2, BLA inactivation before extinction impaired long-term inhibition of fear responses, but its inactivation before extinction of fear responses restored by CS–US pairing did not impair long-term inhibition. In Experiment 3, BLA inactivation before extinction of fear responses or before the extinction of fear responses reinstated by US-alone exposure impaired long-term inhibition. In Experiment 4, BLA inactivation did not impair long-term inhibition of fear responses reinstated by US-alone exposure if the context where the US-alone exposure occurred had been previously extinguished. These results confirm that the BLA is critical for both learning fear and fear inhibition, but not for relearning this inhibition. The results are consistent with the view that reinstatement is due to the extinguished CS being tested in a dangerous context and are discussed in terms of a contemporary neural model of fear inhibition.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.NLM.2017.01.005
Abstract: It is well established that extinguished fears are restored with the passage of time or a change in physical context. These fear restoration phenomena are believed to mimic the conditions under which relapse occurs in patients that have been treated for anxiety disorders by means of cue-exposure therapy. Here, we used a rodent model to extinguish relapsed fear and assess whether this new extinction prevents further relapse. We found that activity in the basolateral amygdala (BLA) is required to initially extinguish conditioned fear, but this activity was not necessary to subsequently extinguish relapsed fear. That is, extinction of spontaneously recovered or renewed fear was spared by BLA inactivation. Yet, this BLA-independent learning of extinction did not protect against further relapse: extinction of relapsed fear conducted without BLA activity was still likely to return after the passage of time or a shift in physical context. These findings have important clinical implications. They indicate that pharmacological agents with anxiolytic properties may disrupt initial cue-exposure therapy but may be useful when therapy is again needed due to relapse. However, they also suggest that these agents will not protect against further relapse, implying the need for developing drugs that target other brain regions involved in fear inhibition.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.NLM.2021.107485
Abstract: Second-order fear conditioning has been demonstrated in protocols using discrete and simple stimuli, and much is now known about its behavioral and neural characteristics. In contrast, the mechanisms of second-order conditioning to more complex stimuli, such as contexts, are unknown. To address this gap in our knowledge, we conducted a series of experiments to investigate the neural and behavioral characteristics of second-order context fear conditioning in rats. We found that rats acquire fear to a context in which a first-order conditioned stimulus is presented (Experiment 1) neuronal activity in the basolateral amygdala (BLA) is required for the acquisition (Experiment 2) and extinction (Experiment 3) of second-order context fear second-order context fear can be reduced by extinction of its first-order conditioned stimulus associate (Experiment 4) and that second-order fear reduced in this way is restored when fear of the first-order conditioned stimulus spontaneously recovers or is reconditioned (Experiment 5). Thus, second-order context fear requires neuronal activity in the BLA, and once established, tracks the level of fear to its first-order conditioned stimulus-associate. These results are discussed with respect to the substrates of second-order fear conditioning in other protocols, and the role of the amygdala in different forms of conditioning.
Publisher: Public Library of Science (PLoS)
Date: 28-12-2012
Publisher: Springer Science and Business Media LLC
Date: 02-09-2022
DOI: 10.1038/S41386-022-01427-W
Abstract: The basolateral amygdala (BLA) complex receives dense cholinergic projections from the nucleus basalis of Meynert (NBM) and the horizontal limb of the diagonal band of Broca (HDB). The present experiments examined whether these projections regulate the formation, extinction, and renewal of fear memories. This was achieved by employing a Pavlovian fear conditioning protocol and optogenetics in transgenic rats. Silencing NBM projections during fear conditioning weakened the fear memory produced by that conditioning and abolished its renewal after extinction. By contrast, silencing HDB projections during fear conditioning had no effect. Silencing NBM or HDB projections during extinction enhanced the loss of fear produced by extinction, but only HDB silencing prevented renewal. Next, we found that systemic blockade of nicotinic acetylcholine receptors during fear conditioning mimicked the effects produced by silencing NBM projections during fear conditioning. However, this blockade had no effect when given during extinction. These findings indicate that basal forebrain cholinergic signaling in the BLA plays a critical role in fear regulation by promoting strength and durability of fear memories. We concluded that cholinergic compounds may improve treatments for post-traumatic stress disorder by durably stripping fear memories from their fear-eliciting capacity.
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: American Psychological Association (APA)
Date: 2007
DOI: 10.1037/0097-7403.33.3.299
Abstract: A series of experiments studied reacquisition of fear reactions to a completely extinguished context. Reacquisition was rapid when reconditioning occurred as soon as the fear reactions were completely extinguished, showing that the original conditioning was intact. However, when reconditioning occurred after massive extinction training, fear reactions were depressed but then recovered across a long retention interval. This recovery was due to reconditioning and was similar to that produced by conditioning a massively preexposed context. These results show that massive extinction converts a potentially dangerous context into one that is merely familiar.
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: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2004
DOI: 10.1097/00008877-200403000-00006
Abstract: Schizophrenic patients show deficits in their ability to shift attention to new stimuli during attentional set-shifting tasks. An equivalent task has been developed in rodents. This task was used to assess effects of phencyclidine (PCP), a drug widely used to model schizophrenia, in mice. Mice were administered PCP (0.63 or 1.3 mg/kg) daily, beginning 5 days prior to training and continuing throughout the test period. Mice were trained to discriminate stimuli to find a food reward in a series of discriminations. PCP increased the number of trials required to reach the criterion during simple and reversal discriminations, but not when the discriminations were repeated with a new set of stimuli (i.e. during the intradimensional shift and its reversal), suggesting an interaction between PCP effects and novelty. The 1.3 mg/kg of PCP also impaired performance of mice during the extradimensional shift. Similar results have been reported in schizophrenic patients. Although, in control mice, performance of the extradimensional shift was not impaired relative to the intradimensional shift, suggesting that the mouse may not be a suitable species for assessment in this model, specific discriminations within this task were sensitive to impairment by PCP, implying, therefore, that it may have some utility in modelling discrete aspects of schizophrenia in humans.
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: 02-2010
DOI: 10.1101/LM.1668310
Abstract: Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In Experiment 2, rats extinguished under an intracerebroventricular (ICV) infusion of haloperidol suppressed fear responses across extinction but froze more on a subsequent drug-free retention test than control rats. In Experiment 3, rats extinguished under an infusion of haloperidol in the nucleus accumbens were impaired in suppressing fear responses across extinction and froze more on subsequent drug-free retention test than control rats. These results show that learning to inhibit fear responses in extinction requires dopamine activity in the nucleus accumbens. They were interpreted to mean that dopaminergic activity in the nucleus accumbens regulates the prediction error required for learning to inhibit fear responses in extinction.
Publisher: Wiley
Date: 07-2014
DOI: 10.1111/BPH.12731
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: 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: Oxford University Press (OUP)
Date: 06-05-2022
Abstract: How do animals process experiences that provide contradictory information? The present study addressed this question using second-order fear conditioning in rats. In second-order conditioning, rats are conditioned to fear a stimulus, S1, through its pairings with foot-shock (stage 1) and some days later, a second stimulus, S2, through its pairings with the already-conditioned S1 (stage 2). However, as foot-shock is never presented during conditioning to S2, we hypothesized that S2 simultaneously encodes 2 contradictory associations: one that drives fear to S2 (S2-danger) and another that reflects the absence of the expected unconditioned stimulus and partially masks that fear (e.g. S2-safety). We tested this hypothesis by manipulating the substrates of danger and safety learning in the brain (using a chemogenetic approach) and assessing the consequences for second-order fear to S2. Critically, silencing activity in the basolateral amygdala (important for danger learning) reduced fear to S2, whereas silencing activity in the infralimbic cortex (important for safety learning) enhanced fear to S2. These bidirectional changes are consistent with our hypothesis that second-order fear conditioning involves the formation of competing S2-danger and S2-safety associations. More generally, they show that a single set of experiences can produce contradictory associations and that the brain resolves the contradiction by encoding these associations in distinct brain regions.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.NLM.2018.03.001
Abstract: Evidence indicates that the infralimbic cortex (IL) encodes and retrieves the inhibitory memory produced by fear extinction. Recently, we have shown that the IL is also involved in the inhibitory memory generated by stimulus pre-exposure that causes latent inhibition. These results are surprising because a stimulus undergoing fear extinction carries aversive motivational value, whereas a pre-exposed stimulus is neutral. The present experiments tested the hypothesis that the IL encodes inhibition irrespective of the motivational information about the stimulus. Using rats, we first confirmed that IL activity during stimulus pre-exposure is required for latent inhibition. Then, we found that pharmacological stimulation of the IL facilitated aversive extinction to a stimulus that had been trained and extinguished as an appetitive stimulus. This facilitation was stimulus specific and required appetitive extinction. The same facilitation was found when appetitive extinction was replaced with random presentations of the stimulus and an appetitive outcome. Together, these findings indicate that non-reinforced stimulus presentations establish an inhibitory memory that is reactivated and strengthened in the IL during subsequent aversive extinction. This is consistent with the view that the IL encodes inhibition irrespective of motivational value, suggesting that this brain region plays a general role in inhibitory learning.
Publisher: Wiley
Date: 23-12-2014
DOI: 10.1111/BPH.12818
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: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.NLM.2018.10.009
Abstract: People and animals sometimes associate events that never occurred together. These false memories can have disastrous consequences, yet little is known about the conditions under which they form. In four experiments, we investigated how rats learn to fear a context in which they have never experienced danger (i.e., how they form a false context fear memory). In each experiment, rats were pre-exposed to a context on day 1, shocked in a similar-but-different context on day 2, and tested in the pre-exposed or explicitly-conditioned context on day 3. The results revealed that: (1) the true memory of the explicitly-conditioned context and false memory of the pre-exposed context develop simultaneously and independently and (2) the conditions of pre-exposure on day 1 and time of shock exposure on day 2 interact to determine the strength of the false memory. These findings are anticipated by a recent computational model, the Bayesian Context Fear Algorithm/Automaton (BACON Krasne, Cushman, & Fanselow, 2015). They are discussed in relation to this model and more general theories of context learning.
Publisher: Cold Spring Harbor Laboratory
Date: 25-08-2009
DOI: 10.1101/LM.1474609
Abstract: Rats were subjected to one or two cycles of context fear conditioning and extinction to study the roles of the prelimbic cortex (PL) and infralimbic cortex (IL) in learning and relearning to inhibit fear responses. Inactivation of the PL depressed fear responses across the first or second extinction but did not impair learning or relearning fear inhibition (experiment 1). Inactivation of the IL did not affect inhibition across the first extinction but disrupted its long-term retention. Inactivation of the IL impaired inhibition across the second extinction, and inactivation before or after this extinction impaired long-term retention (experiments 2 and 3). Inactivation of the IL before the retention test restored extinguished fear responses (experiment 4). These results show for the first time that neuronal activity in the PL is involved in the expression of fear responses but not in the learning that underlies long-term fear inhibition. They also confirm that the IL is involved in this inhibitory learning: Specifically, they show that the IL is critical for consolidation and retrieval of this inhibitory learning. The role of the IL is discussed in terms of a contemporary neural model of fear extinction.
Publisher: Frontiers Media SA
Date: 15-04-2022
DOI: 10.3389/FNBEH.2022.877720
Abstract: Pavlovian conditioning enables predictive stimuli to control action performance and action selection. The present experiments used sensory-specific satiety to examine the role of outcome value in these two forms of control. Experiment 1 employed a general Pavlovian-instrumental transfer design to show that a stimulus predicting a food outcome energizes the performance of an instrumental action earning another food outcome. This energizing effect was removed when the stimulus-predicted outcome or a novel outcome was devalued by sensory-specific satiety. Experiments 2 and 3 employed a specific Pavlovian-instrumental transfer design to demonstrate that a stimulus predicting a particular food outcome promotes the selection of an instrumental action earning the same, but not a different, food outcome. Remarkably, this effect was maintained when all or just one of the stimulus-predicted outcomes were devalued by sensory-specific satiety. These results indicate that satiety alone removes the expression of general PIT. By contrast, satiety or outcome-specific devaluation does not regulate the expression of specific PIT, which is insensitive to changes in outcome value. This dissociation is consistent with the view that general and specific PIT are two separate phenomena driven by distinct psychological mechanisms.
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: Frontiers Media SA
Date: 24-04-2018
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2023
DOI: 10.1101/2023.03.29.534845
Abstract: Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CIN does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.
Publisher: Frontiers Media SA
Date: 11-03-2022
DOI: 10.3389/FNBEH.2022.801474
Abstract: Evidence suggests that, in Pavlovian conditioning, associations form between conditioned stimuli and multiple components of the unconditioned stimulus (US). It is common, for ex le, to regard USs as composed of sensory and affective components, the latter being either appetitive (e.g., food or water) or aversive (e.g., shock or illness) and, therefore, to suppose different USs of the same affective class activate a common affective system. Furthermore, evidence is growing for the suggestion that, in competitive learning situations, competition between predictive stimuli is primarily for association with the affective system activated by the US. Thus, a conditioned stimulus (CS) previously paired with one US will block conditioning to another CS when both are presented together and paired with a different US of the same affective class, a phenomenon called transreinforcer blocking. Importantly, similar effects have been reported when steps are taken to turn the pretrained CS into a conditioned inhibitor, which activates the opposing affective state to the excitor that it inhibits. Thus, an appetitive inhibitor can block conditioning to a second CS when they are presented together and paired with foot shock. Here we show that the same is true of an aversive inhibitor. In two experiments conducted in rats, we found evidence that an aversive inhibitor blocked conditioning to a second CS when presented in a compound and paired with food. Such findings demonstrate that affective processes and their opponency organize appetitive-aversive interactions and establish the valences on which they are based, consistent with incentive theories of Pavlovian conditioning.
Publisher: Elsevier
Date: 2018
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.
Start Date: 2020
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2022
End Date: 2026
Funder: Australian Research Council
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End Date: 2015
Funder: Australian Research Council
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End Date: 2016
Funder: National Health and Medical Research Council
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End Date: 2019
Funder: Australian Research Council
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: Australian Research Council
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End Date: 12-2026
Amount: $562,000.00
Funder: Australian Research Council
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End Date: 12-2019
Amount: $426,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 02-2013
End Date: 12-2015
Amount: $435,000.00
Funder: Australian Research Council
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End Date: 03-2017
Amount: $389,967.00
Funder: Australian Research Council
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End Date: 12-2026
Amount: $920,868.00
Funder: Australian Research Council
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