RESUMO
Traumatic memories may become less precise over time and lead to the development of fear responses to novel stimuli, a process referred to as time-dependent fear generalization. The conditions that cause the growth of fear generalization over time are poorly understood. Here, we found that, in male rats, the level of discrimination at the early time point contributes to determining whether fear generalization will develop with the passage of time or not, suggesting a link between the precision of recent memory and the stability of remote engrams. We also found that the expression of insulin-like growth factor 2 receptor in layer 2/3 of the auditory cortex is linked to the precision of recent memories and to the stability of remote engrams and the development of fear generalization over time. These findings provide new insights on the neural mechanisms that underlie the time-dependent development of fear generalization that may occur over time after a traumatic event.
Assuntos
Córtex Auditivo , Animais , Córtex Auditivo/fisiologia , Medo/fisiologia , Masculino , Memória/fisiologia , Memória de Longo Prazo , Ratos , Receptor IGF Tipo 2RESUMO
The mammalian brain can store and retrieve memories of related events as distinct memories and remember common features of those experiences. How it computes this function remains elusive. Here, we show in rats that recent memories of two closely timed auditory fear events share overlapping neuronal ensembles in the basolateral amygdala (BLA) and are functionally linked. However, remote memories have reduced neuronal overlap and are functionally independent. The activity of parvalbumin (PV)-expressing neurons in the BLA plays a crucial role in forming separate remote memories. Chemogenetic blockade of PV preserves individual remote memories but prevents their segregation, resulting in reciprocal associations. The hippocampus drives this process through specific excitatory connections with BLA GABAergic interneurons. These findings provide insights into the neuronal mechanisms that minimize the overlap between distinct remote memories and enable the retrieval of related memories separately.
Assuntos
Tonsila do Cerebelo , Hipocampo , Parvalbuminas , Animais , Hipocampo/fisiologia , Hipocampo/metabolismo , Ratos , Masculino , Tonsila do Cerebelo/fisiologia , Parvalbuminas/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Interneurônios/fisiologia , Interneurônios/metabolismo , Memória/fisiologia , Medo/fisiologia , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Neurônios/fisiologia , Neurônios/metabolismo , Vias Neurais/fisiologiaRESUMO
Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is critical for top-down modulatory processes, and despite previous studies adopting repetitive transcranial magnetic stimulation (rTMS) over this region provided encouraging results in enhancing extinction, no studies have hitherto explored the effects of stimulating the medial anterior PFC (aPFC, encompassing the Brodmann area 10) on threat memory and generalization. Here we showed that rTMS over the aPFC applied before threat memory retrieval immediately decreases implicit reactions to learned and novel stimuli in humans. These effects enduringly persisted 1 week later in the absence of rTMS. No effects were detected on explicit recognition. Critically, rTMS over the aPFC resulted in a more pronounced reduction of defensive responses compared to rTMS targeting the dorsolateral PFC. These findings reveal a previously unexplored prefrontal region, the modulation of which can efficiently and durably inhibit implicit reactions to learned threats. This represents a significant advancement toward the long-term deactivation of exaggerated responses to threats.
Assuntos
Medo , Córtex Pré-Frontal , Estimulação Magnética Transcraniana , Humanos , Medo/fisiologia , Córtex Pré-Frontal/fisiologia , Masculino , Adulto Jovem , Feminino , Adulto , Extinção Psicológica/fisiologiaRESUMO
Past aversive experiences shape our ability to deal with future dangers, through the encoding of implicit and explicit memory traces and through the ability to generalize defensive reactions to new stimuli resembling learned threats. Numerous evidence demonstrate that sleep is important for the consolidation of memories related to threatening events. However, there is a lack of studies examining the effects of sleep deprivation on the retrieval of consolidated threat memories, and previous studies on the role of sleep in threat generalization have produced mixed results. To address these issues, here we adopted a differential threat conditioning and a delayed (second half of the night) sleep deprivation during the first or the seventh night after learning. We found no effects of sleep deprivation on either implicit or explicit threat memories, regardless of its occurrence timing. Conversely, implicit but not explicit responses to novel cues similar to a learned threat displayed a widened generalization pattern, but only if sleep deprivation took place during the first night after conditioning and not if it occurred during the seventh night after conditioning. Therefore, we propose that sleeping after exposure to danger may support optimal implicit discrimination processes to evaluate new signals in the future and that even a brief period of sleeplessness may widen threat generalization to new stimuli, which is a hallmark of several threat-related disorders.
RESUMO
One strategy to address new potential dangers is to generate defensive responses to stimuli that remind learned threats, a phenomenon called fear generalization. During a threatening experience, the brain encodes implicit and explicit memory traces. Nevertheless, there is a lack of studies comparing implicit and explicit response patterns to novel stimuli. Here, by adopting a discriminative threat conditioning paradigm and a two-alternative forced-choice recognition task, we found that the implicit reactions were selectively elicited by the learned threat and not by a novel similar but perceptually discriminable stimulus. Conversely, subjects explicitly misidentified the same novel stimulus as the learned threat. This generalization response was not due to stress-related interference with learning, but related to the embedded threatening value. Therefore, we suggest a dissociation between implicit and explicit threat recognition profiles and propose that the generalization of explicit responses stems from a flexible cognitive mechanism dedicated to the prediction of danger.
Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Memória/fisiologia , Encéfalo/fisiologia , Condicionamento Operante/fisiologia , Medo/psicologia , Feminino , Resposta Galvânica da Pele/fisiologia , Generalização Psicológica/fisiologia , Humanos , Aprendizagem/fisiologia , Masculino , Reconhecimento Psicológico/fisiologia , Adulto JovemRESUMO
Memories of fearful events can be maintained throughout the lifetime of animals. Here we showed that lesions of the lateral nucleus (LA) performed shortly after training impaired the retention of long-term memories, assessed by the concomitant measurement of two dissociable defensive responses, freezing and avoidance in rats. Strikingly, when LA lesions were performed four weeks after training, rats did not show freezing to a learned threat stimulus, but they were able to direct their responses away from it. Similar results were found when the central nucleus (CeA) was lesioned four weeks after training, whereas lesions of the basal nucleus (BA) suppressed avoidance without affecting freezing. LA and BA receive parallel inputs from the auditory cortex, and optogenetic inhibition of these terminals hampered both freezing and avoidance. We therefore propose that, at variance with the traditional serial flow of information model, long-term fearful memories recruit two parallel circuits in the amygdala, one relying on the LA-to-CeA pathway and the other relying solely on BA, which operate independently and mediate distinct defensive responses.
Assuntos
Complexo Nuclear Basolateral da Amígdala/patologia , Núcleo Central da Amígdala/patologia , Medo/fisiologia , Memória/fisiologia , Estimulação Acústica , Animais , Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento Animal , Núcleo Central da Amígdala/metabolismo , Halorrodopsinas/genética , Halorrodopsinas/metabolismo , Masculino , Microscopia Confocal , Ratos , Ratos WistarRESUMO
In the presence of new stimuli, it is crucial for survival to react with defensive responses in the presence of stimuli that resemble threats but also to not react with defensive behavior in response to new harmless stimuli. Here, we show that in the presence of new uncertain stimuli with sensory features that produce an ambiguous interpretation, discriminative processes engage a subset of excitatory and inhibitory neurons within the lateral amygdala (LA) that are partially different from those engaged by fear processes. Inducing the pharmacogenetic deletion of this neuronal ensemble caused fear generalization but left anxiety-like response, fear memory and extinction processes intact. These data reveal that two opposite neuronal processes account for fear discrimination and generalization within the LA and suggest a potential pathophysiological mechanism for the impaired discrimination that characterizes fear-related disorders.