RESUMO
Exposure to stressful conditions induces long-lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. Moreover, the interaction of a stressful experience and the retrieval of an established fear memory trace enhance both fear expression and fear retention. Related to this, the stimulation of the dorsolateral part of the mesencephalic periaqueductal gray matter (dlPAG) prior to retrieval potentiates a fear memory trace previously acquired. Therefore, the question that arises is whether the dlPAG mediates the increased fear expression and fear retention after retrieval. Rats were subjected to a contextual fear conditioning paradigm using a single footshock, and 1 day later, rats were subjected to a stressful situation. As previously reported, there was an increase of freezing response only in those rodents that were re-exposed to the associated context at 1 and 5 days after stress exposure. Muscimol intra-dlPAG prior to the restraint event prevented such increase. Conversely, Muscimol intra-dlPAG infusion immediately after the stress experience had no effect on the resulting fear memory. When the neuroendocrine response to stress was explored, intra-dlPAG infusion of muscimol prior to stress decreased Fos expression in the paraventricular nucleus and serum corticosterone levels. Moreover, this treatment prevented the enhancement of the density of hippocampal "mature" spines associated with fear memory. In conclusion, the present results suggest that the dlPAG is a key neural site for the negative valence instruction necessary to modulate the promoting influence of stress on fear memory.
Assuntos
Medo/fisiologia , Rememoração Mental/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Condicionamento Clássico , Espinhas Dendríticas/fisiologia , Hipocampo/fisiologia , Masculino , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos WistarRESUMO
Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction.
Assuntos
Medo/efeitos dos fármacos , Medo/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Testes Psicológicos , Animais , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Masculino , Midazolam/farmacologia , Psicotrópicos/farmacologia , Distribuição Aleatória , Ratos WistarRESUMO
It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear memory in rats during the reactivation-induced destabilization phase. Our findings show that exposure to an appetitive experience following reactivation can diminish fear retention. This effect persisted after 1 wk. Importantly, it was achieved only under conditions that induced fear memory destabilization. This result could not be explained as a potentiated extinction, because sucrose was unable to promote extinction. Since GluN2B-containing NMDA receptors in the basolateral amygdala complex (BLA) have been implicated in triggering fear memory destabilization, we decided to block pharmacologically these receptors to explore the neurobiological bases of the observed effect. Intra-BLA infusion with ifenprodil, a GluN2B-NMDA antagonist, prevented the fear reduction caused by the appetitive experience. In sum, these results suggest that the expression of a fear memory can be dampened by an unrelated appetitive experience, as long as memory destabilization is achieved during reactivation. Possible mechanisms behind this effect and its clinical implications are discussed.
Assuntos
Comportamento Apetitivo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Medo , Consolidação da Memória/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Retenção Psicológica/fisiologia , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Piperidinas/administração & dosagem , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
The retrosplenial cortex (RSC) is one of the largest cortical areas in rodents, and is subdivided in two main regions, A29 and A30, according to their cytoarchitectural organization and connectivities. However, very little is known about the functional activity of each RSC subdivision during the execution of complex cognitive tasks. Here, we used a well-established fear learning protocol that induced long-lasting contextual fear memory and showed that during evocation of the fear memory, the expression of early growth response gene 1 was up-regulated in A30, and in other brain areas implicated in fear and spatial memory, however, was down-regulated in A29, including layers IV and V. To search for the participation of A29 on fear memory, we triggered selective degeneration of neurons within cortical layers IV and V of A29 by using a non-invasive protocol that takes advantage of the vulnerability that these neurons have MK801-toxicity and the modulation of this neurodegeneration by testosterone. Application of 5 mg/kg MK801 in intact males induced negligible neuronal degeneration of A29 neurons and had no impact on fear memory retrieval. However, in orchiectomized rats, 5 mg/kg MK801 induced overt degeneration of layers IV-V neurons of A29, significantly impairing fear memory recall. Degeneration of A29 neurons did not affect exploratory or anxiety-related behavior nor altered unconditioned freezing. Importantly, protecting A29 neurons from MK801-toxicity by testosterone preserved fear memory recall in orchiectomized rats. Thus, neurons within cortical layers IV-V of A29 are critically required for efficient retrieval of contextual fear memory.
Assuntos
Medo/fisiologia , Giro do Cíngulo/fisiologia , Rememoração Mental/fisiologia , Neurônios/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Maleato de Dizocilpina/administração & dosagem , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Medo/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Masculino , Rememoração Mental/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Wistar , Testosterona/administração & dosagemRESUMO
Memories can be altered by negative or arousing experiences due to the activation of the stress-responsive sympatho-adrenal-medullary axis (SYM). Here, we used a neutral declarative memory that was acquired during multi-trial training to determine the effect of a threatening event on memory without emotional valence. To this end, participants received a new threatening social protocol before learning pairs of meaningless syllables and were tested either 15 min, 2 days or 8 days after acquisition. We first demonstrated that this threatening social situation activates not only the SYM axis (Experiment 1) and the hypothalamus-pituitary-adrenal axis (HPA; Experiment 2), but also, it improves the acquisition or early consolidation of the syllable pairs (Experiment 3). This improvement is not a transient effect; it can be observed after the memory is consolidated. Furthermore, this modulation increases the persistence of memory (Experiment 4). Thus, it is possible to affect memories with specific events that contain unrelated content and a different valence.
Assuntos
Afeto/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Memória/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Estresse Psicológico , Sistema Nervoso Simpático/fisiologia , Adulto , Pressão Sanguínea , Feminino , Frequência Cardíaca , Humanos , Hidrocortisona/metabolismo , Masculino , Fala , Adulto JovemRESUMO
GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long-term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra-BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress-induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Espinhas Dendríticas/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Moduladores GABAérgicos/farmacologia , Masculino , Midazolam/farmacologia , Plasticidade Neuronal/fisiologia , Distribuição Aleatória , Ratos Wistar , Restrição Física , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologiaRESUMO
The present research investigated the resulting contextual fear memory and structural plasticity changes in the dorsal hippocampus (DH) following stress and fear conditioning. This combination enhanced fear retention and increased the number of total and mature dendritic spines in DH. Intra-basolateral amygdala (BLA) infusion of midazolam prior to stress prevented both the enhancement of fear retention and an increase in the density of total and mature dendritic spines in DH. These findings emphasize the role of the stress-induced attenuation of GABAergic neurotransmission in BLA in the promoting influence of stress on fear memory and on synaptic remodeling in DH. In conclusion, the structural remodeling in DH accompanied the facilitated fear memory following a combination of fear conditioning and stressful stimulation.
Assuntos
Tonsila do Cerebelo/fisiologia , Espinhas Dendríticas/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Estresse Fisiológico , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Condicionamento Clássico , Midazolam/farmacologia , Ratos , Ratos WistarRESUMO
There is growing interest in the neurobiological mechanisms involved in the extinction of aversive memory. This cognitive process usually occurs after repeated or prolonged presentation of a conditioned stimulus that was previously associated with an unconditioned stimulus. If extinction is considered to be a new memory, the role of the γ-aminobutyric acid system (GABAergic system) during extinction memory consolidation should be similar to that described for the original trace. It is also accepted that negative modulation of the GABAergic system before testing can impair extinction memory expression. However, it seems possible to speculate that inhibitory mechanisms may be required in order to acquire a memory that is inhibitory in nature. Using a combination of behavioral protocols, such as weak and robust extinction training procedures, and pharmacological treatments, such as the systemic administration of GABAA agonist (muscimol) and antagonist (bicuculline), we investigated the role of the GABAergic system in the different phases of the extinction memory in the crab Neohelice granulata. We show that the stimulation of the GABAergic system impairs and its inactivation facilitates the extinction memory consolidation. Moreover, fine variations in the GABAergic tone affect its expression at testing. Finally, an active GABAergic system is necessary for the acquisition of the extinction memory. This detailed description may contribute to the understanding of the role of the GABAergic system in diverse aspects of the extinction memory.
Assuntos
Bicuculina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Memória/efeitos dos fármacos , Muscimol/farmacologia , Animais , Braquiúros , Condicionamento ClássicoRESUMO
The present study investigates the fear memory resulting from the interaction of a stressful experience and the retrieval of an established fear memory trace. Such a combination enhanced both fear expression and fear retention in adult Wistar rats. Likewise, midazolam intra-basolateral amygdala (BLA) infusion prior to stress attenuated the enhancement of fear memory thus suggesting the involvement of a stress-induced reduction of the GABAergic transmission in BLA in the stress-induced enhancing effect. It has been suggested that, unlike the immediate-early gene Zif268 which is related to the reconsolidation process, the expression of hippocampal brain-derived neurotrophic factor (BDNF) is highly correlated with consolidation. We therefore evaluate the relative contribution of these two neurobiological processes to the fear memory resulting from the above-mentioned interaction. Intra-dorsal hippocampus (DH) infusions of either the antisense Zif268 or the inhibitor of the protein degradation (Clasto-Lactacystin ß-Lactone), suggested to be involved in the retrieval-dependent destabilization process, did not affect the resulting contextual memory. In contrast, the knockdown of hippocampal BDNF mitigated the stress-induced facilitating influence on fear retention. In addition, the retrieval experience elevated BDNF level in DH at 60 min after recall exclusively in stressed animals. These findings suggest the involvement of a hippocampal BDNF sensitive mechanism in the stress-promoting influence on the fear memory following retrieval.
Assuntos
Tonsila do Cerebelo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Estresse Psicológico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Medo/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Lactonas/farmacologia , Masculino , Memória/efeitos dos fármacos , Midazolam/farmacologia , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Ratos , Ratos WistarRESUMO
The association of a neutral context with an aversive stimulus, such as foot-shock, result in a contextual fear memory. A growing number of evidence have revealed that prior exposure to diverse threatening situations facilitates the encoding of fear memory during acquisition and such reports support the widespread notion that emotionally arousal results in stronger and long-lasting memories. However, few studies have investigated if a threatening experience can affect the recall and the persistence of such fear memory trace. To test the hypothesis that an emotionally negative experience could modify the retrieval of a memory and potentiate the expression of a fear memory, the present study used the chemical stimulation (microinjection of NMDA) of the dorsolateral periaqueductal gray matter (dlPAG) of rats in order to induce an aversive emotional state. Such stimulation was performed one day after a weak fear training protocol, and the fear expression was analyzed in subsequent re-exposures to the conditioned context. The results showed that the negative emotional state induced by the dlPAG stimulation enhanced the fear memory trace when this trace was reactivated one day after this aversive experience. Additionally, the potentiation of the fear response was contingent to the associated context since no potentiation was evident when NMDA-stimulated animals were subsequently placed in a non-associated context. Finally, the model suggests that the enhancement of fear responses is long-lasting since NMDA-treated animals performed a robust fear response six days after memory retrieval.