RESUMO
Repeated presentations of a previously conditioned stimulus lead to a new form of learning known as extinction, which temporarily alters the response to the original stimulus. Previous studies have shown that the consolidation of extinction memory requires de novo protein synthesis. However, the role of specific nodes of translational control in extinction is unknown. Using auditory threat conditioning in mice, we investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and its effector p70 S6 kinase 1 (S6K1) in the extinction of auditory threat conditioning. We found that rapamycin attenuated the consolidation of extinction memory. In contrast, genetic deletion and pharmacological inhibition of S6K1, a downstream effector of mTORC1, blocked within-session extinction, indicating a role for S6K1 independent of protein synthesis. Indeed, the activation of S6K1 during extinction required extracellular signal-regulated kinase (ERK) activation in the basolateral nucleus of the amygdala (BLA) and was necessary for increased phosphorylation of the GluA1 (Thr840) subunit of the AMPA receptor following extinction training. Mice exposed to brief uncontrollable stress showed impaired within-session extinction as well as a downregulation of ERK and S6K1 signaling in the amygdala. Finally, using fiber photometry we were able to record calcium signals in vivo, and we found that inhibition of S6K1 reduces extinction-induced changes in neuronal activity of the BLA. These results implicate a novel ERK-S6K1-GluA1 signaling cascade critically involved in extinction.
Assuntos
Extinção Psicológica/fisiologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Condicionamento Clássico/fisiologia , Condicionamento Operante , Medo/fisiologia , Aprendizagem , Sistema de Sinalização das MAP Quinases , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Receptores de AMPA/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Sirolimo/farmacologiaRESUMO
Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work.
Assuntos
Aprendizagem da Esquiva/fisiologia , Animais , Ansiedade/psicologia , Ansiedade/terapia , Condicionamento Clássico , Condicionamento Operante/fisiologia , Condicionamento Psicológico , Medo/psicologia , Humanos , Reforço PsicológicoRESUMO
Local cerebral blood flow was measured in rats by the 14C-labeled iodoantipyrine technique with quantitative autoradiography during the processing of environmental stimuli. Presentation of a tone increased blood flow in the auditory but not the visual pathway. When the animal had previously been conditioned to fear the tone, blood flow additionally increased in the hypothalamus and amygdala. Local cerebral blood flow can thus be used to detect patterns of cerebral excitation associated with transient (30- to 40-second) mental events in experimental animals.
Assuntos
Encéfalo/irrigação sanguínea , Emoções/fisiologia , Audição/fisiologia , Estimulação Acústica , Tonsila do Cerebelo/irrigação sanguínea , Animais , Autorradiografia , Encéfalo/fisiologia , Estado de Consciência/fisiologia , Hipotálamo/irrigação sanguínea , Masculino , Ratos , Ratos EndogâmicosRESUMO
Transmission of auditory information from the medial geniculate body to the lateral nucleus of the amygdala is believed to be involved in the conditioning of fear responses to acoustic stimuli. This pathway exhibits LTP of electrically evoked field potentials after high frequency stimulation of the medial geniculate body. High frequency stimulation of the medial geniculate body also results in a long-lasting potentiation of a field potential in the lateral amygdala elicited by a naturally transduced acoustic stimulus. This demonstrates that natural information processing can make use of the physiological mechanisms set in motion by LTP induction.
Assuntos
Potenciais Evocados Auditivos/fisiologia , Medo/fisiologia , Potenciação de Longa Duração/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Vias Auditivas/fisiologia , Comportamento Animal/fisiologia , Condutividade Elétrica , Corpos Geniculados/fisiologia , Masculino , Potenciais da Membrana/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Single neurons were recorded in freely behaving rats during fear conditioning from areas of auditory cortex that project to the lateral nucleus of the amygdala (LA). The latency and rate of conditioning and extinction were analyzed, and the results were compared to previous recordings from LA itself. Auditory cortex neurons took more trials to learn, and they responded more slowly than LA neurons within trials. Short-latency plasticity in LA, therefore, reflects inputs from the auditory thalamus rather than the auditory cortex. Unlike LA cells, some auditory cortex cells showed late conditioned responses that seemed to anticipate the unconditioned stimulus, while others showed extinction-resistant memory storage. Thus, rapid conditioning of fear responses to potentially dangerous stimuli depends on plasticity in the amygdala, while cortical areas may be particularly involved in higher cognitive (mnemonic and attentional) processing of fear experiences.
Assuntos
Tonsila do Cerebelo/citologia , Córtex Auditivo/citologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Estimulação Acústica , Potenciais de Ação/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Aprendizagem por Associação/fisiologia , Córtex Auditivo/fisiologia , Extinção Psicológica/fisiologia , Masculino , Memória/fisiologia , Vias Neurais , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Fatores de TempoRESUMO
The lateral nucleus of the amygdala (LA) is the first site in the amygdala where the plasticity underlying fear conditioning could occur. We simultaneously recorded from multiple LA neurons in freely moving rats during fear conditioning trials in which tones were paired with foot shocks. Conditioning significantly increased the magnitude of tone-elicited responses (often within the first several trials), converted unresponsive cells into tone-responsive ones, and altered functional couplings between LA neurons. The effects of conditioning were greatest on the shortest latency (less than 15 ms) components of the tone-elicited responses, consistent with the hypothesis that direct projections from the auditory thalamus to LA are an important link in the circuitry through which rapid behavioral responses are controlled in the presence of conditioned fear stimuli.
Assuntos
Tonsila do Cerebelo/fisiologia , Comportamento Animal/fisiologia , Condicionamento Psicológico , Medo , Neurônios/fisiologia , Estimulação Acústica , Animais , Eletrofisiologia , Masculino , Plasticidade Neuronal , Ratos , Ratos Sprague-Dawley , Tálamo/fisiologiaRESUMO
Echoplanar functional magnetic resonance imaging (fMRI) was used in normal human subjects to investigate the role of the amygdala in conditioned fear acquisition and extinction. A simple discrimination procedure was employed in which activation to a visual cue predicting shock (CS+) was compared with activation to another cue presented alone (CS-). CS+ and CS- trial types were intermixed in a pseudorandom order. Functional images were acquired with an asymmetric spin echo pulse sequence from three coronal slices centered on the amygdala. Activation of the amygdala/periamygdaloid cortex was observed during conditioned fear acquisition and extinction. The extent of activation during acquisition was significantly correlated with autonomic indices of conditioning in individual subjects. Consistent with a recent electrophysiological recording study in the rat (Quirk et al., 1997), the profile of the amygdala response was temporally graded, although this dynamic was only statistically reliable during extinction. These results provide further evidence for the conservation of amygdala function across species and implicate an amygdalar contribution to both acquisition and extinction processes during associative emotional learning tasks.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Medo , Adolescente , Adulto , Aprendizagem por Associação/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Análise de RegressãoRESUMO
The lateral nucleus of the amygdala (LA) is a site of convergence for auditory (conditioned stimulus) and foot-shock (unconditioned stimulus) inputs during fear conditioning. The auditory pathways to LA are well characterized, but less is known about the pathways through which foot shock is transmitted. Anatomical tracing and physiological recording studies suggest that the posterior intralaminar thalamic nucleus, which projects to LA, receives both auditory and somatosensory inputs. In the present study we examined the expression of the immediate-early gene c-fos in the LA in rats in response to foot-shock stimulation. We then determined the effects of posterior intralaminar thalamic lesions on foot-shock-induced c-Fos expression in the LA. Foot-shock stimulation led to an increase in the density of c-Fos-positive cells in all LA subnuclei in comparison to controls exposed to the conditioning box but not shocked. However, some differences among the dorsolateral, ventrolateral and ventromedial subnuclei were observed. The ventrolateral subnucleus showed a homogeneous activation throughout its antero-posterior extension. In contrast, only the rostral aspect of the ventromedial subnucleus and the central aspect of the dorsolateral subnucleus showed a significant increment in c-Fos expression. The density of c-Fos-labeled cells in all LA subnuclei was also increased in animals placed in the box in comparison to untreated animals. Unilateral electrolytic lesions of the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body reduced foot-shock-induced c-Fos activation in the LA ipsilateral to the lesion. The number of c-Fos labeled cells on the lesioned side was reduced to the levels observed in the animals exposed only to the box. These results indicate that the LA is involved in processing information about the foot-shock unconditioned stimulus and receives this kind of somatosensory information from the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body.
Assuntos
Tonsila do Cerebelo/metabolismo , Condicionamento Psicológico/fisiologia , Eletrochoque , Regulação da Expressão Gênica/efeitos da radiação , Núcleos Posteriores do Tálamo/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Comportamento Animal , Mapeamento Encefálico , Contagem de Células/métodos , Pé/inervação , Lateralidade Funcional , Masculino , Vias Neurais/fisiologia , Núcleos Posteriores do Tálamo/lesões , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-DawleyRESUMO
Fear-arousing stimuli elicit innate reactions and can reinforce acquisition of new responses. We tested whether mechanisms mediating these conditioned stimulus (CS) properties were isomorphic or dissociable within the amygdala. Rats trained on a fear-conditioning task (CS paired with footshock) were then trained on an escape-from-fear task (EFF) in which the CS reinforced a locomotor response terminating the CS. Lateral nucleus (LA) lesions blocked acquisition of both conditioned freezing responses and the CS's reinforcement of a new response in the EFF task. Central nucleus (CE) lesions blocked conditioned freezing but not the EFF, whereas basal nucleus (B) lesions blocked the EFF but not conditioned freezing. Thus, activation of the LA by a CS seems to trigger conditioned reactions via CE and conditioned aversion via B activation, reduction of which reinforces new actions.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Medo/fisiologia , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/cirurgia , Animais , Comportamento Animal/fisiologia , Eletrodos Implantados , Eletrólise , Eletrochoque , Modelos Neurológicos , Ratos , Ratos Sprague-Dawley , Técnicas EstereotáxicasRESUMO
Single-cell activity was recorded in the dorsal subnucleus of the lateral amygdala (LAd) of freely behaving rats during Pavlovian fear conditioning, to determine the relationship between neuronal activity and behavioral learning. Neuronal responses elicited by the conditioned stimulus typically increased before behavioral fear was evident, supporting the hypothesis that neural changes in LAd account for the conditioning of behavior. Furthermore, two types of these rapidly modified cells were found. Some, located in the dorsal tip of LAd, exhibited short-latency responses (<20 ms) that were only transiently changed. A second class of cells, most commonly found in ventral regions of LAd, had longer latency responses, but maintained enhanced responding throughout training and even through extinction. These anatomically distinct cells in LAd may be differentially involved in the initiation of learning and long-term memory storage.
Assuntos
Tonsila do Cerebelo/fisiologia , Memória/fisiologia , Tonsila do Cerebelo/citologia , Animais , Condicionamento Clássico/fisiologia , Medo/fisiologia , Masculino , Plasticidade Neuronal , Ratos , Ratos Sprague-DawleyRESUMO
Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans.
Assuntos
Mapeamento Encefálico , Medo/psicologia , Córtex Motor/fisiologia , Vias Neurais/fisiologia , Adulto , Tonsila do Cerebelo/irrigação sanguínea , Tonsila do Cerebelo/fisiologia , Gânglios da Base/irrigação sanguínea , Gânglios da Base/fisiologia , Feminino , Resposta Galvânica da Pele/fisiologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Córtex Motor/irrigação sanguínea , Vias Neurais/irrigação sanguínea , Oxigênio/sangue , Estimulação Luminosa/métodosRESUMO
The amygdala is located in the medial aspects of the temporal lobe. In spite of the fact that the amygdala has been implicated in a variety of functions, ranging from attention to memory to emotion, it has not attracted neuroscientists to the same extent as its laminated neighbours, in particular the hippocampus and surrounding cortex. However, recently, principles of information processing within the amygdala, particularly in the rat, have begun to emerge from anatomical, physiological and behavioral studies. These findings suggest that after the stimulus enters the amygdala, the highly organized intra-amygdaloid circuitries provide a pathway by which the representation of a stimulus becomes distributed in parallel to various amygdaloid nuclei. As a consequence, the stimulus representation may become modulated by different functional systems, such as those mediating memories from past experience or knowledge about ongoing homeostatic states. The amygdaloid output nuclei, especially the central nucleus, receive convergent information from several other amygdaloid regions and generate behavioral responses that presumably reflect the sum of neuronal activity produced by different amygdaloid nuclei.
Assuntos
Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/citologia , Animais , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiologia , RatosRESUMO
Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. Although considerable progress has been made in understanding the neural substrates of fear conditioning at the systems level, until recently little has been learned about the underlying cellular and molecular mechanisms. The success of systems-level work aimed at defining the neuroanatomical pathways underlying fear conditioning, combined with the knowledge accumulated by studies of long-term potentiation (LTP), has recently given way to new insights into the cellular and molecular mechanisms that underlie acquisition and consolidation of fear memories. Collectively, these findings suggest that fear memory consolidation in the amygdala shares essential biochemical features with LTP, and hold promise for understanding the relationship between memory consolidation and synaptic plasticity in the mammalian brain.
Assuntos
Condicionamento Psicológico/fisiologia , Medo/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Animais , HumanosRESUMO
The amygdala appears to play an essential role in many aspects of emotional information processing and behavior. Studies over the past year have begun to clarify the anatomical organization of the amygdala and the contribution of its individual subregions to emotional functions, especially emotional learning and memory. Researchers can now point to plausible circuits involved in the transmission of sensory inputs into the amygdala, between amygdaloid subregions, and to efferent targets in cortical and subcortical regions, for specific emotional learning and memory processes.
Assuntos
Tonsila do Cerebelo/fisiologia , Encéfalo/fisiologia , Emoções/fisiologia , Aprendizagem/fisiologia , HumanosRESUMO
Learning and memory depend on signaling molecules that affect synaptic efficacy. The cytoskeleton has been implicated in regulating synaptic transmission but its role in learning and memory is poorly understood. Fear learning depends on plasticity in the lateral nucleus of the amygdala. We therefore examined whether the cytoskeletal-regulatory protein, myosin light chain kinase, might contribute to fear learning in the rat lateral amygdala. Microinjection of ML-7, a specific inhibitor of myosin light chain kinase, into the lateral nucleus of the amygdala before fear conditioning, but not immediately afterward, enhanced both short-term memory and long-term memory, suggesting that myosin light chain kinase is involved specifically in memory acquisition rather than in posttraining consolidation of memory. Myosin light chain kinase inhibitor had no effect on memory retrieval. Furthermore, ML-7 had no effect on behavior when the training stimuli were presented in a non-associative manner. Anatomical studies showed that myosin light chain kinase is present in cells throughout lateral nucleus of the amygdala and is localized to dendritic shafts and spines that are postsynaptic to the projections from the auditory thalamus to lateral nucleus of the amygdala, a pathway specifically implicated in fear learning. Inhibition of myosin light chain kinase enhanced long-term potentiation, a physiological model of learning, in the auditory thalamic pathway to the lateral nucleus of the amygdala. When ML-7 was applied without associative tetanic stimulation it had no effect on synaptic responses in lateral nucleus of the amygdala. Thus, myosin light chain kinase activity in lateral nucleus of the amygdala appears to normally suppress synaptic plasticity in the circuits underlying fear learning, suggesting that myosin light chain kinase may help prevent the acquisition of irrelevant fears. Impairment of this mechanism could contribute to pathological fear learning.
Assuntos
Tonsila do Cerebelo/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Plasticidade Neuronal/fisiologia , Sinapses/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Azepinas/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Inibidores Enzimáticos/administração & dosagem , Medo/fisiologia , Injeções Intraventriculares , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Microinjeções , Naftalenos/administração & dosagem , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacosRESUMO
Neurons in the lateral amygdala (LA) receive glutamatergic sensory input from the auditory thalamus and auditory cortex, and these inputs can be modulated by serotonin (5-HT). In the present study, we examined whether serotonergic inhibition of glutamatatergic excitation in the LA occurs via activation of GABAergic interneurons. Single-unit extracellular activity in the LA was recorded in response to iontophoretically applied glutamate. Concurrent application of 5-HT reduced the number of glutamate-evoked action potentials in the majority of neurons tested. GABA antagonists were then iontophoresed with both glutamate and 5-HT. Of the neurons that were inhibited by 5-HT, concurrent application of the GABA antagonists significantly reversed this effect. Application of the GABA antagonists alone had little or no effect on basal neuronal activity. We conclude that the 5-HT-induced inhibition of glutamatergic activity occurs in part through activation of serotonergic receptors on GABAergic interneurons.
Assuntos
Tonsila do Cerebelo/fisiologia , Antagonistas GABAérgicos/farmacologia , Serotonina/fisiologia , Ácido gama-Aminobutírico/fisiologia , Potenciais de Ação , Tonsila do Cerebelo/citologia , Animais , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Antagonistas GABAérgicos/administração & dosagem , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/farmacologia , Interneurônios/fisiologia , Iontoforese , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The lateral nucleus of the amygdala (LA) is an essential component of the neural circuitry underlying Pavlovian fear conditioning. Although blockade of NMDA receptors in LA and adjacent areas before training disrupts the acquisition of fear conditioning, blockade before testing also often disrupts the expression of fear responses. With this pattern of results, it is not possible to distinguish a contribution of NMDA receptors to plasticity from a role in synaptic transmission. In past studies, NMDA blockade has been achieved using the antagonist d,l-2-amino-5-phosphovalerate, which blocks the entire heteromeric receptor complex. The present experiments examined the effects of selective blockade of the NR2B subunit of the NMDA receptor in LA using the selective antagonist ifenprodil. Systemic injections of ifenprodil before training led to a dose-dependent impairment in the acquisition of auditory and contextual fear conditioning, whereas injections before testing had no effect. Intra-amygdala infusions of ifenprodil mirrored these results and, in addition, showed that the effects are attributable to a disruption of fear learning rather than a disruption of memory consolidation. NMDA receptors in LA are thus involved in fear conditioning, and the NR2B subunit appears to make unique contributions to the underlying plasticity.
Assuntos
Tonsila do Cerebelo/metabolismo , Condicionamento Clássico/fisiologia , Medo/fisiologia , Aprendizagem/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Estimulação Acústica , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrochoque , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Injeções Intraperitoneais , Aprendizagem/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Microinjeções , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Retenção Psicológica/efeitos dos fármacosRESUMO
Two competing theories predict different effects on memory consolidation when the amygdala is inactivated after fear conditioning. One theory, based on studies using inhibitory avoidance training, proposes that the amygdala modulates the strength of fear learning, and post-training amygdala manipulations interfere with memory consolidation. The other, based on studies using Pavlovian fear conditioning, hypothesizes that fear learning occurs in the amygdala, and post-training manipulations after acquisition will not affect memory consolidation. We infused the GABAA agonist muscimol (4.4 nmol/side) or vehicle into lateral and basal amygdala (LBA) of rats either before or immediately after tone-foot shock Pavlovian fear conditioning. Pre-training infusions eliminated acquisition, whereas post-training infusions had no effect. These findings indicate that synaptic activity in LBA is necessary during learning, but that amygdala inactivation directly after training does not affect memory consolidation. Results suggest that essential aspects of plasticity underlying auditory fear conditioning take place within LBA during learning.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Memória/fisiologia , Estimulação Acústica , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Eletrofisiologia , Aprendizagem/fisiologia , Masculino , Muscimol/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Although much has been learned about the neurobiological mechanisms underlying Pavlovian fear conditioning at the systems and cellular levels, relatively little is known about the molecular mechanisms underlying fear memory consolidation. The present experiments evaluated the role of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the amygdala during Pavlovian fear conditioning. We first show that ERK/MAPK is transiently activated-phosphorylated in the amygdala, specifically the lateral nucleus (LA), at 60 min, but not 15, 30, or 180 min, after conditioning, and that this activation is attributable to paired presentations of tone and shock rather than to nonassociative auditory stimulation, foot shock sensitization, or unpaired tone-shock presentations. We next show that infusions of U0126, an inhibitor of ERK/MAPK activation, aimed at the LA, dose-dependently impair long-term memory of Pavlovian fear conditioning but leaves short-term memory intact. Finally, we show that bath application of U0126 impairs long-term potentiation in the LA in vitro. Collectively, these results demonstrate that ERK/MAPK activation is necessary for both memory consolidation of Pavlovian fear conditioning and synaptic plasticity in the amygdala.
Assuntos
Tonsila do Cerebelo/enzimologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Memória/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estimulação Acústica , Animais , Associação , Western Blotting , Butadienos/farmacologia , Eletrochoque , Inibidores Enzimáticos/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Imuno-Histoquímica , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Plasticidade Neuronal/fisiologia , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologiaRESUMO
We sought to determine whether contextual fear conditioning, a hippocampal-dependent task, would affect neurogenesis in the dentate gyrus of the hippocampus, and if so, to identify which aspect of the training experience accounts for the change. The immediate shock deficit paradigm was used, together with bromodeoxyuridine immunohistochemistry, to isolate the contribution of different aspects of contextual fear conditioning to neurogenesis. Contextual fear learning caused a 33% decrease in the number of proliferating cells that was anatomically restricted to the dentate gyrus with no change in cell survival or differentiation. This attenuation was not related to exposure to the conditioned stimulus alone, the footshock unconditioned stimulus alone, or the expression of fear to the context after training. Instead, the effect of context conditioning on cell proliferation appears to be specifically due to the formation of an association between the context and shock during training, an amygdala dependent function.