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1.
Learn Mem ; 27(5): 190-200, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32295839

RESUMO

In obsessive-compulsive disorder (OCD), functional behaviors such as checking that a door is locked become dysfunctional, maladaptive, and debilitating. However, it is currently unknown how aversive and appetitive motivations interact to produce functional and dysfunctional behavior in OCD. Here we show a double dissociation in the effects of anxiogenic cues and sensitivity to rewarding stimuli on the propensity to develop functional and dysfunctional checking behavior in a rodent analog of OCD, the observing response task (ORT). While anxiogenic manipulations of perceived threat (presentation of threat-associated contextual cues) and actual threat (punishment of incorrect responding on the ORT) enhanced functional checking, dysfunctional checking was unaffected. In contrast, rats that had previously been identified as "sign-trackers" on an autoshaping task-and therefore were highly sensitive to the incentive salience of appetitive environmental cues-selectively showed elevated levels of dysfunctional checking under a range of conditions, but particularly so under conditions of uncertainty. These data indicate that functional and dysfunctional checking are dissociable and supported by aversive and appetitive motivational processes, respectively. While functional checking is modulated by perceived and actual threat, dysfunctional checking recruits appetitive motivational processes, possibly akin to the "incentive habits" that contribute to drug-seeking in addiction.

2.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31824654

RESUMO

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.


Assuntos
Medo , Transtornos de Estresse Pós-Traumáticos , Humanos , Memória
3.
Neuropsychopharmacology ; 44(10): 1762-1768, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30659275

RESUMO

Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This 'retrieval-extinction' procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the 'retrieval-extinction' effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.

4.
Psychopharmacology (Berl) ; 236(1): 111-132, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30656364

RESUMO

Extinction within the reconsolidation window, or 'retrieval-extinction', has received much research interest as a possible technique for targeting the reconsolidation of maladaptive memories with a behavioural intervention. However, it remains to be determined whether the retrieval-extinction effect-a long-term reduction in fear behaviour, which appears resistant to spontaneous recovery, renewal and reinstatement-depends specifically on destabilisation of the original memory (the 'reconsolidation-update' account) or represents facilitation of an extinction memory (the 'extinction-facilitation' account). We propose that comparing the neurotransmitter systems, receptors and intracellular signalling pathways recruited by reconsolidation, extinction and retrieval-extinction will provide a way of distinguishing between these accounts.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Medo/psicologia , Memória/fisiologia , Animais , Humanos , Receptores Dopaminérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Learn Motiv ; 64: 1-8, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30532341

RESUMO

The higher response rates observed on ratio than on matched interval reward schedules has been attributed to the differential reinforcement of longer inter-response times (IRTs) on the interval contingency. Some data, however, seem to contradict this hypothesis, showing that the difference is still observed when the role of IRT reinforcement is neutralized by using a regulated-probability interval schedule (RPI). Given the mixed evidence for these predictions, we re-examined this hypothesis by training three groups of rats to lever press under ratio, interval and RPI schedules across two phases while matching reward rates within triads. At the end of the first phase, the master ratio and RPI groups responded at similar rates. In the second phase, an interval group yoked to the same master ratio group of the first phase responded at a lower rate than the RPI group. Post-hoc analysis showed comparable reward rates for master and yoked schedules. The experienced response-outcome rate correlations were likewise similar and approached zero as training progressed. We discuss these results in terms of a contemporary dual-system model of instrumental conditioning.

7.
Learn Mem ; 25(9): 492-500, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30115771

RESUMO

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.


Assuntos
Condicionamento Clássico , Condicionamento Operante , Consolidação da Memória , Prevenção Secundária , Transtornos Relacionados ao Uso de Substâncias/terapia , Animais , Humanos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
8.
J Neurosci ; 38(13): 3199-3207, 2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29476015

RESUMO

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 analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re-exposure (four 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 signaling pathway in conjunction with four 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 (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling 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.SIGNIFICANCE STATEMENT Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state.


Assuntos
Tonsila do Cerebelo/fisiologia , Memória , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Extinção Psicológica , Sistema de Sinalização das MAP Quinases , Masculino , Inibidores de Proteínas Quinases/farmacologia , Ratos
9.
Psychopharmacology (Berl) ; 235(4): 1069-1082, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29411070

RESUMO

RATIONALE: Animal models of alcohol-seeking are useful for understanding alcohol addiction and for treatment development, but throughput in these models is limited by the extensive pretraining required to overcome the aversive taste of ethanol. Work by Augier et al. (Psychopharmacology 231: 4561-4568, 2014) indicates that Wistar rats will self-administer alcohol without water deprivation, exposure to sweetened ethanol solutions or intermittent access to ethanol. OBJECTIVES AND METHODS: We sought to replicate and extend the work of Augier et al. by comparing the acquisition of instrumental self-administration of ethanol in Lister-Hooded rats that had been previously saccharin faded (SF group) or not (NSF group). We also aimed to determine whether NMDA receptor antagonism with MK-801, given at memory reactivation, reduced subsequent ethanol-seeking behaviour in both groups of animals. Finally, we assessed the ethanol preference of SF and NSF rats using the two-bottle choice procedure. RESULTS: Both SF and NSF groups acquired instrumental self-administration of ethanol, though SF rats consumed fewer of the earned reinforcers. MK-801, given at memory reactivation, had different effects on NSF and SF rats: impairing the capacity of an ethanol-paired conditioned stimulus (CS) to support reinstatement in NSF rats, and enhancing it in SF rats. Finally, neither SF nor NSF rats showed a preference for ethanol. CONCLUSIONS: Our data support those of Augier et al. (Psychopharmacology 231: 4561-4568, 2014) that pretraining is unnecessary for rats to acquire instrumental self-administration of ethanol. Indeed, saccharin fading may produce a weaker memory that extinguishes more readily, thus accounting for the different effects of MK-801 on SF and NSF rats.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Sinais (Psicologia) , Etanol/administração & dosagem , Memória/efeitos dos fármacos , Sacarina/administração & dosagem , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Maleato de Dizocilpina/farmacologia , Masculino , Memória/fisiologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Autoadministração
10.
Artigo em Inglês | MEDLINE | ID: mdl-29352022

RESUMO

The science of mental life is critical for understanding both how we function, and impairments in our functioning. However, understanding the causal mechanisms underlying mental health disorders and developing new treatments are challenges too great to be solved by any individual approach. There is a growing awareness that translational research-from laboratory to patient and back again to animal models-will be critical for the improved understanding and treatment of mental health disorders. The motivation and intention to pursue translational approaches is therefore strong in mental health research, but critically, opportunities for interaction between basic scientists and clinicians are relatively limited, and vary depending on the institution in which researchers are working. This has promoted the development of a 'culture gap' between basic and clinical scientists that limits interaction and sharing of knowledge. Here, we provide 14 examples of contemporary translational research and call for an increased collaborative approach to mental health research that spans clinical diagnoses, levels of analysis and bridges between basic to clinical mental health sciences, including, but not limited to, psychology and neuroscience. What is needed is an inclusive and integrated approach, bringing together scientists working at all levels of enquiry with clinicians providing insights on what works (and what does not). To stimulate the much-needed innovation in therapeutic techniques, an analysis of component parts is critical. Our approach suggests simplifying complex behaviours into distinct psychological components. Asking collaboratively driven scientific questions about dysfunction will also benefit our fundamental understanding of mental life.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.


Assuntos
Transtornos Mentais/terapia , Saúde Mental , Camundongos/psicologia , Pesquisa Médica Translacional , Animais
11.
Neuroscience ; 370: 112-120, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28736133

RESUMO

Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like 'response' memory, but not an instrumental goal-directed 'place' memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories.


Assuntos
Corpo Estriado/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Recompensa , Animais , Condicionamento Clássico/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Técnicas de Silenciamento de Genes , Hábitos , Masculino , Distribuição Aleatória , Ratos
12.
Neuropsychopharmacology ; 41(4): 1103-11, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26279079

RESUMO

Alcohol addiction is a problem of great societal concern, for which there is scope to improve current treatments. One potential new treatment for alcohol addiction is based on disrupting the reconsolidation of the maladaptive Pavlovian memories that can precipitate relapse to drug-seeking behavior. In alcohol self-administering rats, we investigated the effects of bidirectionally modulating adrenergic signaling on the strength of a Pavlovian cue-alcohol memory, using a behavioral procedure that isolates the specific contribution of one maladaptive Pavlovian memory to relapse, the acquisition of a new alcohol-seeking response for an alcohol-associated conditioned reinforcer. The ß-adrenergic receptor antagonist propranolol, administered in conjunction with memory reactivation, persistently disrupted the memory that underlies the capacity of a previously alcohol-associated cue to act as a conditioned reinforcer. By contrast, enhancement of adrenergic signaling by administration of the adrenergic prodrug dipivefrin at reactivation increased the strength of the cue-alcohol memory and potentiated alcohol seeking. These data demonstrate the importance of adrenergic signaling in alcohol-associated memory reconsolidation, and suggest a pharmacological target for treatments aiming to prevent relapse through the disruption of maladaptive memories.


Assuntos
Condicionamento Clássico/fisiologia , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Consolidação da Memória/fisiologia , Receptores Adrenérgicos beta/fisiologia , Agonistas Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Condicionamento Clássico/efeitos dos fármacos , Sinais (Psicologia) , Comportamento de Procura de Droga/efeitos dos fármacos , Epinefrina/administração & dosagem , Epinefrina/análogos & derivados , Masculino , Consolidação da Memória/efeitos dos fármacos , Nadolol/administração & dosagem , Propranolol/administração & dosagem , Ratos , Autoadministração
13.
eNeuro ; 2(1)2015.
Artigo em Inglês | MEDLINE | ID: mdl-26464966

RESUMO

Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disorders, but little is known about the neurochemical mechanisms underlying the induction of lability, or destabilization, of a retrieved consolidated memory. Destabilization has been theoretically linked to the violation of expectations during memory retrieval, which, in turn, has been suggested to correlate with prediction error (PE). It is well-established that PE correlates with dopaminergic signaling in limbic forebrain structures that are critical for emotional learning. The basolateral amygdala is a key neural substrate for the reconsolidation of pavlovian reward-related memories, but the involvement of dopaminergic mechanisms in inducing lability of amygdala-dependent memories has not been investigated. Therefore, we tested the hypothesis that dopaminergic signaling within the basolateral amygdala is required for the destabilization of appetitive pavlovian memories by investigating the effects dopaminergic and protein synthesis manipulations on appetitive memory reconsolidation in rats. Intra-amygdala administration of either the D1-selective dopamine receptor antagonist SCH23390 or the D2-selective dopamine receptor antagonist raclopride prevented memory destabilization at retrieval, thereby protecting the memory from the effects of an amnestic agent, the protein synthesis inhibitor anisomycin. These data show that dopaminergic transmission within the basolateral amygdala is required for memory labilization during appetitive memory reconsolidation.

14.
Psychol Sci ; 26(8): 1201-15, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26133572

RESUMO

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.


Assuntos
Emoções , Memória Episódica , Rememoração Mental , Transtornos de Estresse Pós-Traumáticos/psicologia , Jogos de Vídeo , Adolescente , Adulto , Emoções/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Adulto Jovem
15.
Neuropsychopharmacology ; 39(11): 2529-37, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24801769

RESUMO

We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/farmacologia , Medo/efeitos dos fármacos , Memória/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Percepção Auditiva/efeitos dos fármacos , Percepção Auditiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Benzamidas/farmacologia , Bicuculina/farmacologia , Carbamatos/farmacologia , Condicionamento Clássico , Eletrochoque , Inibidores Enzimáticos/farmacologia , Medo/fisiologia , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/fisiologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptores de GABA-A/metabolismo
16.
J Neurosci ; 34(7): 2422-31, 2014 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-24523532

RESUMO

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.


Assuntos
Tonsila do Cerebelo/metabolismo , Comportamento Animal , Calcineurina/metabolismo , Extinção Psicológica/fisiologia , Medo , Memória/fisiologia , Animais , Western Blotting , Masculino , Ratos
17.
Front Behav Neurosci ; 7: 190, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24367307

RESUMO

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.

18.
PLoS One ; 8(6): e65088, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23776445

RESUMO

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.


Assuntos
Aprendizagem por Associação/fisiologia , Delusões/fisiopatologia , Medo/psicologia , Ketamina/farmacologia , Memória/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Adulto , Estudos de Casos e Controles , Condicionamento Clássico , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Memória/fisiologia
19.
J Neurosci ; 33(3): 1109-15, 2013 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-23325248

RESUMO

Signaling at NMDA receptors (NMDARs) is known to be important for memory reconsolidation, but while most studies show that NMDAR antagonists prevent memory restabilization and produce amnesia, others have shown that GluN2B-selective NMDAR antagonists prevent memory destabilization, protecting the memory. These apparently paradoxical, conflicting data provide an opportunity to define more precisely the requirement for different NMDAR subtypes in the mechanisms underlying memory reconsolidation and to further understand the contribution of glutamatergic signaling to this process. Here, using rats with fully consolidated pavlovian auditory fear memories, we demonstrate a double dissociation in the requirement for GluN2B-containing and GluN2A-containing NMDARs within the basolateral amygdala in the memory destabilization and restabilization processes, respectively. We further show a double dissociation in the mechanisms underlying memory retrieval and memory destabilization, since AMPAR antagonism prevented memory retrieval while still allowing the destabilization process to occur. These data demonstrate that glutamatergic signaling mechanisms within the basolateral amygdala differentially and dissociably mediate the retrieval, destabilization, and restabilization of previously consolidated fear memories.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Aprendizagem por Associação/efeitos dos fármacos , Memória/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tonsila do Cerebelo/metabolismo , Animais , Anisomicina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Masculino , Piperidinas/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Quinoxalinas/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo
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