Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 12, 2019
Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. Th... more Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression.
Addiction is a complex disorder, and one characterised by the acquisition of maladaptive instrume... more Addiction is a complex disorder, and one characterised by the acquisition of maladaptive instrumental (drug-seeking and drug-taking) and pavlovian (cue-drug associations) memories. These memories markedly contribute to the long-term risk of relapse, so reduction of the impact of these memories on behaviour could potentially be an important addition to current therapies for addiction. Memory reconsolidation may provide such a target for disrupting well-consolidated pavlovian cue-drug memories following an extensive drug history. Reconsolidation can be disrupted either by administering amnestic drugs in conjunction with a memory reactivation session, or by updating the memory adaptively through the induction of 'superextinction'. More work is needed before these therapies are ready for translation to the clinic, but if found clinically effective memory manipulation promises a radical new way of treating addiction.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 12, 2019
Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is asso... more Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT −/−) have increased baseline anxiety behaviors, SERT +/− rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT +/− model. Here we sought to determine if SERT +/− or SERT −/− , compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT −/− rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT +/− (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT +/− rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT −/− and SERT +/− rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.
Extinction-defined as the gradual disappearance of a l e a r n e d r e s p o n s e f o l l o w i ... more Extinction-defined as the gradual disappearance of a l e a r n e d r e s p o n s e f o l l o w i n g t h e w i t h d r a w a l o f reinforcement-was first described by Pavlov (1927), and has been a subject of great psychological and neurobiological interest for a number of decades. Extinction is a fundamental learning process that has also formed the basis of prolonged exposure treatments for mental health disorders, including post-traumatic stress disorder and phobia, but potentially also for addictions. However, prolonged exposure therapy is not effective for all patients. Advances in understanding the psychopharmacology of extinction, at the whole-organism and circuit levels, are directing us to novel ways for optimising therapy-based around extinction. It is increasingly providing us with novel insights into the basic process itself. Preclinical research is also helping to address the underlying mechanisms and clinical feasibility of interventions such as exploiting memory updating mechanisms by extinguishing a memory within a critical window of reconsolidation. This special issue on 'The Psychopharmacology of Extinction' aims to provide a comprehensive set of reviews and empirical papers that address these questions and others from many of the leading scientist currently working in this area. The issue developed out of a symposium held at the 2017 biennial European Behavioural Pharmacology Society meeting in Crete. This symposium, like the current collection of articles, highlighted some of the exciting developments in understanding the extinction of both appetitive and aversive memories that have emerged in the 90 years since Pavlov published his foundational ideas. We hope you find the collection of interest and value to your own work as we look ahead to the next era of extinction research.
Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. ... more Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. However, maladaptive expression of fear can lead to debilitating stressor-related and anxiety disorders such as post-traumatic stress disorder. Although the neural basis of fear has been extensively researched for several decades, recent technological advances in pharmacogenetics and optogenetics have allowed greater resolution in understanding the neural circuits that underlie fear. Alongside conceptual advances in the understanding of fear memory, this increased knowledge has clarified mechanisms for some currently available therapies for post-traumatic stress disorder and has identified new potential treatment targets.
Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms... more Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analysed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate CS exposure events. We show that an intermediate re-exposure (4 CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signalling pathway in conjunction with 4 CS presentations had no effect on fear expression, and the NMDA receptor partial agonist D-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (7 CSs), had no behavioural or molecular effect when given in association with 4 CS presentations. These molecular and behavioural data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CSdependent molecular events in the BLA may arrest reconsolidation intracellular signalling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease.
The amygdala has traditionally been associated with fear, mediating the impact of negative emotio... more The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food) or aversive (e.g. electric shock). We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala's mediation of both appetitive and fearful behavior through diverse psychological processes.
Memory reconsolidation is the process by which memories, destabilised at retrieval, require resta... more Memory reconsolidation is the process by which memories, destabilised at retrieval, require restabilisation to persist in the brain. It has been demonstrated that even old, well‐established memories require reconsolidation following retrieval; therefore, memory reconsolidation could potentially be exploited to disrupt, or even erase, aberrant memories that underlie psychiatric disorders, thereby providing a novel therapeutic target. Drug addiction is one such disorder; it is both chronic and relapsing, and one prominent risk factor for a relapse episode is the presentation of environmental cues that have previously been associated with drugs of abuse. This ‘cue‐induced relapse’ can be accounted for in psychological terms by reinforcing memories of the pavlovian association between the cue and the drug, which can thus influence behaviour through at least three psychologically and neurobiologically dissociable mechanisms: conditioned reinforcement, conditioned approach and conditioned motivation. As each of these psychological processes could contribute to the resumption of drug‐seeking following abstinence, it is important to develop treatments that can reduce drug‐seeking re‐established via influences on each or all of these pavlovian processes, in order to minimise the risk of a subsequent relapse. Investigation of the memory reconsolidation mechanisms of the memories underlying conditioned reinforcement, conditioned approach and conditioned motivation indicate that they depend upon different neurochemical systems, including the glutamatergic and adrenergic systems within limbic corticostriatal circuitry. We also discuss here the subsequent translation to the clinic of this preclinical work.
Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challeng... more Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challenge to the treatment of drug addiction. Here we show that blockade of drug memory reconsolidation, through infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala shortly before reexposure to a cocaine-associated stimulus but not simply to the training context, severely impaired subsequently cue-maintained cocaine seeking under a second-order schedule of reinforcement and abolished cue-induced reinstatement of and relapse to cocaine seeking. This reduction in relapse after disrupted memory reconsolidation was not only seen after several hundred pairings of the stimulus with self-administered cocaine, but older, as well as recent, memories were also disrupted. Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction.
NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NM... more NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NMDA receptor antagonists impair these memory processes, whereas the partial agonist D-cycloserine (DCS) potentiates both learning and extinction. Here, we used DCS and the noncompetitive NMDA receptor antagonist (ϩ)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) to investigate the effects of enhancing and blocking NMDA receptor-mediated glutamatergic transmission on the reconsolidation and extinction of a conditioned fear memory. Either long extinction training or short memory reactivation sessions were used to preferentially engage extinction and reconsolidation processes, respectively. MK-801 blocked extinction to maintain high levels of conditioned freezing, and DCS potentiated extinction to reduce freezing, when they were administered before a long extinction training session. However, the opposite behavioral outcome was observed when the brief memory reactivation session was used: MK-801 administration impaired, whereas DCS increased, freezing, likely reflecting impairment and enhancement of reconsolidation, respectively. Finally, by using localized intracerebral infusions, we showed that the basolateral amygdala is a primary locus of action of systemically administered DCS. Thus, intrabasolateral amygdala DCS potentiated both the extinction and the reconsolidation of fear conditioning, depending on the length of the extinction/memory reactivation session. Therefore, memory reconsolidation can be both disrupted and enhanced, and extinction can be both potentiated and impaired, either to reduce or increase conditioned fear. These results have important implications for the use of reconsolidation blockade and potentiation of extinction as treatment strategies for maladaptive memory disorders.
The prospect of exploiting memory reconsolidation to treat mental health disorders has received g... more The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though,
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 12, 2019
Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associati... more Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associating conditioned stimuli with aversive events. Hebbian plasticity within these networks requires additional reinforcement to store particularly salient experiences into long-term memory. Here, we have identified a circuit reciprocally connecting the ventral periaqueductal grey (vPAG)/ dorsal raphe (DR) region and the central amygdala (CE) that gates fear learning. We found that vPAG/DR dopaminergic (vPdRD) neurons encode a positive prediction error in response to unpredicted shocks, and may reshape intra-amygdala connectivity via a dopamine-dependent form of long-term potentiation (LTP). Negative feedback from the CE to vPdRD neurons might limit reinforcement to events that have not been predicted. These findings add a new module to the midbrain DA circuit architecture underlying associative reinforcement learning and identify vPdRD neurons as critical component of Pavlovian fear conditioning. We propose that dysregulation of vPdRD neuronal activity may contribute to fear-related psychiatric disorders. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms * To whom correspondence should be addressed. Author Contributions: F.G. conceived, designed, performed and analyzed most of the experiments and wrote the manuscript. T.M. and S.M. performed whole-cell patch clamp and LFP recordings for LTP experiments. J.K. and P.P. performed and analyzed Ca 2+ imaging experiments. J.G. performed mouse surgeries. D.K performed anatomical tracings and designed and tested AAVs for optogenetics, DREADDs and GCaMP6m.A.R. designed, performed and analyzed microdialysis experiments. S.B. and K.K. performed and analyzed SCH injections, fear conditioning, acute anxiety assays and pain tests. J. Z. designed RNAi viral vectors and supervised knock down experiments. V.L. co-supervised experiments and wrote the manuscript. W.H. initiated and conceived the project, designed, analyzed and supervised experiments and wrote the manuscript. All authors contributed to the experimental design and interpretation and commented on the manuscript.
Link to publication on Research at Birmingham portal General rights Unless a licence is specified... more Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. • Users may freely distribute the URL that is used to identify this publication. • Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. • User may use extracts from the document in line with the concept of 'fair dealing' under the Copyright, Designs and Patents Act 1988 (?) • Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Addiction is a chronic, relapsing disorder. The progression to pathological drug-seeking is thoug... more Addiction is a chronic, relapsing disorder. The progression to pathological drug-seeking is thought to be driven by maladaptive learning processes which store and maintain associative memory, linking drug highs with cues and actions in the environment. These memories can encode Pavlovian associations which link predictive stimuli (e.g., people, places, and paraphernalia) with a hedonic drug high, as well as instrumental learning about the actions required to obtain drug-associated incentives. Learned memories are not permanent however, and much recent interest has been generated in exploiting the process of reconsolidation to erase or significantly weaken maladaptive memories to treat several mental health disorders, including addictions. Normally reconsolidation serves to update and maintain the adaptive relevance of memories, however administration of amnestic agents within the critical "reconsolidation window" can weaken or even erase maladaptive memories. Here we discuss recent advances in the field, including ongoing efforts to translate preclinical reconsolidation research in animal models into clinical practice.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 12, 2019
Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. Th... more Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression.
Addiction is a complex disorder, and one characterised by the acquisition of maladaptive instrume... more Addiction is a complex disorder, and one characterised by the acquisition of maladaptive instrumental (drug-seeking and drug-taking) and pavlovian (cue-drug associations) memories. These memories markedly contribute to the long-term risk of relapse, so reduction of the impact of these memories on behaviour could potentially be an important addition to current therapies for addiction. Memory reconsolidation may provide such a target for disrupting well-consolidated pavlovian cue-drug memories following an extensive drug history. Reconsolidation can be disrupted either by administering amnestic drugs in conjunction with a memory reactivation session, or by updating the memory adaptively through the induction of 'superextinction'. More work is needed before these therapies are ready for translation to the clinic, but if found clinically effective memory manipulation promises a radical new way of treating addiction.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 12, 2019
Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is asso... more Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT −/−) have increased baseline anxiety behaviors, SERT +/− rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT +/− model. Here we sought to determine if SERT +/− or SERT −/− , compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT −/− rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT +/− (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT +/− rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT −/− and SERT +/− rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.
Extinction-defined as the gradual disappearance of a l e a r n e d r e s p o n s e f o l l o w i ... more Extinction-defined as the gradual disappearance of a l e a r n e d r e s p o n s e f o l l o w i n g t h e w i t h d r a w a l o f reinforcement-was first described by Pavlov (1927), and has been a subject of great psychological and neurobiological interest for a number of decades. Extinction is a fundamental learning process that has also formed the basis of prolonged exposure treatments for mental health disorders, including post-traumatic stress disorder and phobia, but potentially also for addictions. However, prolonged exposure therapy is not effective for all patients. Advances in understanding the psychopharmacology of extinction, at the whole-organism and circuit levels, are directing us to novel ways for optimising therapy-based around extinction. It is increasingly providing us with novel insights into the basic process itself. Preclinical research is also helping to address the underlying mechanisms and clinical feasibility of interventions such as exploiting memory updating mechanisms by extinguishing a memory within a critical window of reconsolidation. This special issue on 'The Psychopharmacology of Extinction' aims to provide a comprehensive set of reviews and empirical papers that address these questions and others from many of the leading scientist currently working in this area. The issue developed out of a symposium held at the 2017 biennial European Behavioural Pharmacology Society meeting in Crete. This symposium, like the current collection of articles, highlighted some of the exciting developments in understanding the extinction of both appetitive and aversive memories that have emerged in the 90 years since Pavlov published his foundational ideas. We hope you find the collection of interest and value to your own work as we look ahead to the next era of extinction research.
Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. ... more Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. However, maladaptive expression of fear can lead to debilitating stressor-related and anxiety disorders such as post-traumatic stress disorder. Although the neural basis of fear has been extensively researched for several decades, recent technological advances in pharmacogenetics and optogenetics have allowed greater resolution in understanding the neural circuits that underlie fear. Alongside conceptual advances in the understanding of fear memory, this increased knowledge has clarified mechanisms for some currently available therapies for post-traumatic stress disorder and has identified new potential treatment targets.
Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms... more Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analysed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate CS exposure events. We show that an intermediate re-exposure (4 CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signalling pathway in conjunction with 4 CS presentations had no effect on fear expression, and the NMDA receptor partial agonist D-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (7 CSs), had no behavioural or molecular effect when given in association with 4 CS presentations. These molecular and behavioural data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CSdependent molecular events in the BLA may arrest reconsolidation intracellular signalling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease.
The amygdala has traditionally been associated with fear, mediating the impact of negative emotio... more The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food) or aversive (e.g. electric shock). We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala's mediation of both appetitive and fearful behavior through diverse psychological processes.
Memory reconsolidation is the process by which memories, destabilised at retrieval, require resta... more Memory reconsolidation is the process by which memories, destabilised at retrieval, require restabilisation to persist in the brain. It has been demonstrated that even old, well‐established memories require reconsolidation following retrieval; therefore, memory reconsolidation could potentially be exploited to disrupt, or even erase, aberrant memories that underlie psychiatric disorders, thereby providing a novel therapeutic target. Drug addiction is one such disorder; it is both chronic and relapsing, and one prominent risk factor for a relapse episode is the presentation of environmental cues that have previously been associated with drugs of abuse. This ‘cue‐induced relapse’ can be accounted for in psychological terms by reinforcing memories of the pavlovian association between the cue and the drug, which can thus influence behaviour through at least three psychologically and neurobiologically dissociable mechanisms: conditioned reinforcement, conditioned approach and conditioned motivation. As each of these psychological processes could contribute to the resumption of drug‐seeking following abstinence, it is important to develop treatments that can reduce drug‐seeking re‐established via influences on each or all of these pavlovian processes, in order to minimise the risk of a subsequent relapse. Investigation of the memory reconsolidation mechanisms of the memories underlying conditioned reinforcement, conditioned approach and conditioned motivation indicate that they depend upon different neurochemical systems, including the glutamatergic and adrenergic systems within limbic corticostriatal circuitry. We also discuss here the subsequent translation to the clinic of this preclinical work.
Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challeng... more Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challenge to the treatment of drug addiction. Here we show that blockade of drug memory reconsolidation, through infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala shortly before reexposure to a cocaine-associated stimulus but not simply to the training context, severely impaired subsequently cue-maintained cocaine seeking under a second-order schedule of reinforcement and abolished cue-induced reinstatement of and relapse to cocaine seeking. This reduction in relapse after disrupted memory reconsolidation was not only seen after several hundred pairings of the stimulus with self-administered cocaine, but older, as well as recent, memories were also disrupted. Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction.
NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NM... more NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NMDA receptor antagonists impair these memory processes, whereas the partial agonist D-cycloserine (DCS) potentiates both learning and extinction. Here, we used DCS and the noncompetitive NMDA receptor antagonist (ϩ)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) to investigate the effects of enhancing and blocking NMDA receptor-mediated glutamatergic transmission on the reconsolidation and extinction of a conditioned fear memory. Either long extinction training or short memory reactivation sessions were used to preferentially engage extinction and reconsolidation processes, respectively. MK-801 blocked extinction to maintain high levels of conditioned freezing, and DCS potentiated extinction to reduce freezing, when they were administered before a long extinction training session. However, the opposite behavioral outcome was observed when the brief memory reactivation session was used: MK-801 administration impaired, whereas DCS increased, freezing, likely reflecting impairment and enhancement of reconsolidation, respectively. Finally, by using localized intracerebral infusions, we showed that the basolateral amygdala is a primary locus of action of systemically administered DCS. Thus, intrabasolateral amygdala DCS potentiated both the extinction and the reconsolidation of fear conditioning, depending on the length of the extinction/memory reactivation session. Therefore, memory reconsolidation can be both disrupted and enhanced, and extinction can be both potentiated and impaired, either to reduce or increase conditioned fear. These results have important implications for the use of reconsolidation blockade and potentiation of extinction as treatment strategies for maladaptive memory disorders.
The prospect of exploiting memory reconsolidation to treat mental health disorders has received g... more The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though,
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 12, 2019
Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associati... more Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associating conditioned stimuli with aversive events. Hebbian plasticity within these networks requires additional reinforcement to store particularly salient experiences into long-term memory. Here, we have identified a circuit reciprocally connecting the ventral periaqueductal grey (vPAG)/ dorsal raphe (DR) region and the central amygdala (CE) that gates fear learning. We found that vPAG/DR dopaminergic (vPdRD) neurons encode a positive prediction error in response to unpredicted shocks, and may reshape intra-amygdala connectivity via a dopamine-dependent form of long-term potentiation (LTP). Negative feedback from the CE to vPdRD neurons might limit reinforcement to events that have not been predicted. These findings add a new module to the midbrain DA circuit architecture underlying associative reinforcement learning and identify vPdRD neurons as critical component of Pavlovian fear conditioning. We propose that dysregulation of vPdRD neuronal activity may contribute to fear-related psychiatric disorders. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms * To whom correspondence should be addressed. Author Contributions: F.G. conceived, designed, performed and analyzed most of the experiments and wrote the manuscript. T.M. and S.M. performed whole-cell patch clamp and LFP recordings for LTP experiments. J.K. and P.P. performed and analyzed Ca 2+ imaging experiments. J.G. performed mouse surgeries. D.K performed anatomical tracings and designed and tested AAVs for optogenetics, DREADDs and GCaMP6m.A.R. designed, performed and analyzed microdialysis experiments. S.B. and K.K. performed and analyzed SCH injections, fear conditioning, acute anxiety assays and pain tests. J. Z. designed RNAi viral vectors and supervised knock down experiments. V.L. co-supervised experiments and wrote the manuscript. W.H. initiated and conceived the project, designed, analyzed and supervised experiments and wrote the manuscript. All authors contributed to the experimental design and interpretation and commented on the manuscript.
Link to publication on Research at Birmingham portal General rights Unless a licence is specified... more Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. • Users may freely distribute the URL that is used to identify this publication. • Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. • User may use extracts from the document in line with the concept of 'fair dealing' under the Copyright, Designs and Patents Act 1988 (?) • Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Addiction is a chronic, relapsing disorder. The progression to pathological drug-seeking is thoug... more Addiction is a chronic, relapsing disorder. The progression to pathological drug-seeking is thought to be driven by maladaptive learning processes which store and maintain associative memory, linking drug highs with cues and actions in the environment. These memories can encode Pavlovian associations which link predictive stimuli (e.g., people, places, and paraphernalia) with a hedonic drug high, as well as instrumental learning about the actions required to obtain drug-associated incentives. Learned memories are not permanent however, and much recent interest has been generated in exploiting the process of reconsolidation to erase or significantly weaken maladaptive memories to treat several mental health disorders, including addictions. Normally reconsolidation serves to update and maintain the adaptive relevance of memories, however administration of amnestic agents within the critical "reconsolidation window" can weaken or even erase maladaptive memories. Here we discuss recent advances in the field, including ongoing efforts to translate preclinical reconsolidation research in animal models into clinical practice.
Memory of a traumatic event becomes consolidated within hours. Intrusive memories can then flash ... more Memory of a traumatic event becomes consolidated within hours. Intrusive memories can then flash back repeatedly into the mind’s eye and cause distress. We investigated whether reconsolidation—the process during which memories become malleable when recalled—can be blocked using a cognitive task and whether such an approach can reduce these unbidden intrusions. We predicted that reconsolidation of a reactivated visual memory of experimental trauma could be disrupted by engaging in a visuospatial task that would compete for visual working memory resources. We showed that intrusive memories were virtually abolished by playing the computer game Tetris following a memory-reactivation task 24 hr after initial exposure to experimental trauma. Furthermore, both memory reactivation and playing Tetris were required to reduce subsequent intrusions (Experiment 2), consistent with reconsolidation-update mechanisms. A simple, noninvasive cognitive-task procedure administered after emotional memory has already consolidated (i.e., > 24 hours after exposure to experimental trauma) may prevent the recurrence of intrusive memories of those emotional events.
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