Plasticité de l'efficacité des synapses du cortex préfrontal médian chez la souris : implications dans le maintien de l'extinction de la peur apprise

Partant de la théorie neurobiologique de l'apprentissage et de la mémoire qui suggère que les phénomènes de plasticité synaptique peuvent être impliqués dans le maintien des informations nouvellement acquises, nous avons émis l'hypothèse selon laquelle un apprentissage basé sur l'inhibition d'un comportement acquis peut être caractérisé, dans certains circuits cérébraux, par un changement de polarité de la plasticité synaptique initiale. Ce changement de polarité pourrait jouer un rôle fondamental dans la rétention du nouvel apprentissage et de ce fait s'opposer à la persévération de la réponse initialement acquise. Sachant que le cortex préfrontal médian (CPFm) est impliqué dans l'inhibition du phénomène de persévération, nous avons analysé, chez la souris C57BL/6, si les synapses excitatrices de cette structure codent l'inhibition de la persévération émotionnelle, c'est-à-dire le maintien de l'extinction de la peur apprise. Pour cela, nous avons principalement utilisé l'approche électrophysiologique couplée au conditionnement de la peur (association "son-choc"), qui était suivi par une exposition ultérieure des animaux au stimulus conditionnel (le son) seul (procédure d'extinction). Les résultats obtenus montrent que la procédure d'extinction, entraînant une diminution progressive de la peur apprise (diminution de l'immobilité conditionnelle à la perception du son), s'accompagne d'une séquence "dépression-potentialisation" de l'efficacité synaptique préfrontale. Nous avons ensuite analysé les relations liant la plasticité synaptique préfrontale (induite soit naturellement par l'épreuve d'extinction, soit artificiellement par des stimulations appropriées du thalamus médio-dorsal) au maintien ou à l'absence de maintien de l'extinction de la peur apprise. Nos résultats montrent que le maintien de la dépression (à l'aide d'une stimulation thalamique à basse fréquence) est associé à une persévération émotionnelle (absence de rétention à long terme de l'extinction), alors que la potentialisation naturelle (consécutive à l'extinction) ou artificielle (à l'aide d'une stimulation thalamique à haute fréquence) est associée à un maintien à long terme de l'extinction. Ces données électrophysiologiques ont été confirmées sur le plan immunohistochimique par l'observation, au cours de l'extinction, d'une conversion de la dépression préfrontale de l'immunoréactivité des gènes c-fos et zif268 en potentialisation, et un maintien de la potentialisation de l'immunoréactivité au cours du test de rétention de l'extinction. Ces travaux suggèrent que les synapses excitatrices préfrontales participent à l'inhibition de la persévération émotionnelle sous la forme d'une amplification durable de leur efficacité. Cette potentialisation synaptique préfrontale, en interaction avec les circuits amygdaliens, pourrait contribuer aux processus d'élimination de certains troubles anxieux.An influencial neurobiological theory of learning and memory suggests that synaptic plasticity is implicated in long-term memory retention of newly acquired information. Based upon this hypothesis we postulated that a new learning based on behavioral inhibition could be characterised, in certain brain areas, by modifications in the polarity of initially-induced synaptic plasticity. These modifications could play an important role in the long-term retention of this learning, acting against perseveration of the initial response. Since the medial prefrontal cortex (mPFC) has been implicated in the inhibition of cognitive and emotional perseveration, we analysed, in C57BL/6 mice, if mPFC excitatory synapses are implicated in the long-term retention of extinguished fear. To achieve this goal, we used extracellular electrophysiological recordings in mice which were submitted to a fear conditioning procedure consisting of several presentations of a tone (conditional stimulus = CS)-shock (unconditional stimulus = US) couple followed by several tone alone presentations (extinction procedure). Our results show that extinction of learned fear is associated both with a progressive decrease of learned fear and a sequence of inversion (from depression to potentiation) of mPFC synaptic efficacy. Moreover, induction of long-term potentiation in the mPFC by high-frequency stimulation of the medio-dorsal thalamus during extinction results in a lack of recovery of extinguished fear when tested one week following extinction, while long-term depression-like changes were associated with a return of fear. These results were confirmed by our immunohistochemical data showing that c-fos and zif268 immunoreactivity in the mPFC was strongly decreased at the onset of extinction, potentiated at the end of extinction and maintained across the long-term retention of extinguished fear. These results suggest that long lasting potentiation of synaptic efficacy in mPFC is implicated in the inhibition of emotional perseveration and could contribute, via an interaction with the amygdala, to elimination processes in certain anxiety disorders

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

Background: Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. Methods: We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Results: Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. Conclusions: These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.post-print1256 K

Axo-axonic cells in neuropsychiatric disorders: a systematic review

Imbalance between excitation and inhibition in the cerebral cortex is one of the main theories in neuropsychiatric disorder pathophysiology. Cortical inhibition is finely regulated by a variety of highly specialized GABAergic interneuron types, which are thought to organize neural network activities. Among interneurons, axo-axonic cells are unique in making synapses with the axon initial segment of pyramidal neurons. Alterations of axo-axonic cells have been proposed to be implicated in disorders including epilepsy, schizophrenia and autism spectrum disorder. However, evidence for the alteration of axo-axonic cells in disease has only been examined in narrative reviews. By performing a systematic review of studies investigating axo-axonic cells and axo-axonic communication in epilepsy, schizophrenia and autism spectrum disorder, we outline convergent findings and discrepancies in the literature. Overall, the implication of axo-axonic cells in neuropsychiatric disorders might have been overstated. Additional work is needed to assess initial, mostly indirect findings, and to unravel how defects in axo-axonic cells translates to cortical dysregulation and, in turn, to pathological states

Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories

Curr Opin Neurobiol

Our understanding of the neuronal circuits and mechanisms of defensive systems has been primarily dominated by studies focusing on the contribution of individual cells in the processing of threat-predictive cues, defensive responses, the extinction of such responses and the contextual modulation of threat-related behavior. These studies have been key in establishing threat-related circuits and mechanisms. Yet, they fall short in answering long-standing questions related to the integrative processing of distinct threatening cues, behavioral states induced by threat-related events, or the bridging from sensory processing of threat-related cues to specific defensive responses. Recent conceptual and technical developments has allowed the monitoring of large populations of neurons, which in addition to advanced analytic tools, have improved our understanding of how collective neuronal activity supports threat-related behaviors. In this review, we discuss the current knowledge of neuronal population codes within threat-related networks, in the context of aversive motivated behavior and the study of defensive systems.Innovations instrumentales et procédurales en psychopathologie expérimentale chez le rongeu

The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research

Translational research on post-traumatic stress disorder (PTSD) has produced limited improvements in clinical practice. Fear conditioning (FC) is one of the dominant animal models of PTSD. In fact, FC is used in many different ways to model PTSD. The variety of FC-based models is ill defined, creating confusion and conceptual vagueness, which in turn impedes translation into the clinic. This article takes a historical and conceptual approach to provide a comprehensive picture of current research and help reorient the research focus. This work historically reviews the variety of models that have emerged from the initial association of PTSD with FC, highlighting conceptual pitfalls that have limited the translation of animal research into clinical advances. We then provide some guidance on how future translational research could benefit from conceptual and technological improvements to translate basic findings in patients. This objective will require transdisciplinary approaches and should involve physicians, engineers, philosophers, and neuroscientists