Memory consolidation

Résumé

Memory consolidation is a category of processes that stabilize a memory trace after its initial acquisition. A memory trace is a change in the nervous system caused by memorizing something. Consolidation is distinguished into two specific processes. The first, synaptic consolidation, which is thought to correspond to late-phase long-term potentiation, occurs on a small scale in the synaptic connections and neural circuits within the first few hours after learning. The second process is systems consolidation, occurring on a much larger scale in the brain, rendering hippocampus-dependent memories independent of the hippocampus over a period of weeks to years. Recently, a third process has become the focus of research, reconsolidation, in which previously consolidated memories can be made labile again through reactivation of the memory trace. History Memory consolidation was first referred to in the writings of the renowned Roman teacher

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https://en.wikipedia.org/wiki/Memory_consolidation

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Humans show inter-individual differences in vulnerability to develop post-traumatic stress disorder (PTSD) following exposure to trauma. Several critical biobehavioral features have been consistently described in PTSD patients, including blunted cortisol levels, smaller hippocampal size, sleep disturbances. However, because of the delay between trauma exposure and the onset of symptoms characteristic of PTSD, only a few longitudinal studies have tried to dissect whether these features constitute pre-trauma risk factors or consequences of the trauma. Enormous effort in animal and human studies has been dedicated to understanding mechanisms of conditioned fear and fear extinction, processes that are at the core of PTSD. However, the same progress has not been translated into psychiatric practice for PTSD. Deepening our understanding of the contribution of key factors to PTSD-related alterations can serve to develop effective treatments.In particular, with regard to low cortisol levels in PTSD pathophysiology, a causative role for blunted glucocorticoid responsiveness in PTSD has not been demonstrated yet.Here, we have addressed this question in lines of Wistar rats genetically-selected for their differential habituation of glucocorticoid responses to stress (LOW-, INTER-, HIGH-CORT Responder rats) and focused on fear extinction, a hallmark of PTSD symptomology, as one of the key features. As a first step, we looked whether divergent trajectories of glucocorticoid responsiveness were associated with brain volume abnormalities, prompted by the influential role of glucocorticoid in brain development. Notably, rats with low or high corticosterone responsiveness exhibit smaller hippocampi, regardless of trauma exposure, compared to rats with normative corticosterone levels. Similarly, the distribution of corticosteroid receptors in the hippocampus presented similarities between the LOW-CR and the HIGH-CR rats with higher mineralocorticoid receptors (MR) and less glucocorticoid receptors (GR). Although LOW- and HIGH-CR rats displayed a similar hippocampal profile at the structural and molecular levels, only LOW-CR male rats exhibited strong deficits in extinction consolidation compared to rats with 'normative' glucocorticoid responses (INTER-CR rats), and showed higher fear response both at few days and at several weeks after trauma exposure. We next tested the causal involvement of corticosterone in the fear extinction consolidation, and found that post-extinction corticosterone treatment markedly prevented the deficits in extinction memory and attenuated fear relapse. In addition, pharmacological inhibition of corticosterone levels during extinction memory consolidation, but not during training, in the INTER-CR rats led to extinction deficits at retrieval one day later. These results indicate that blunted corticosterone levels contribute to confer major vulnerability than having a small hippocampus, and that consolidation processes following extinction are mainly affected by low corticosterone levels.It is well known that glucocorticoids play an important role in memory consolidation processes and that sleep disturbances are a diagnostic criterion of PTSD. Therefore, we investigated in greater detail the sleep architecture in undisturbed condition and during the consolidation period of the extinction phase, which is known to be supported by sleep-dependent processes. In polysomnographic recordings, we found that rats with blunted corticos

EPFL2022

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The formation and storage of memories has been under deep investigation for several decades. Nevertheless, the precise contribution of each brain region involved in this process and the interplay between them across memory consolidation is still largely debated. Although memory encoding requires the hippocampus (HPC), it is becoming apparent that other brain regions are also important in early phases of memory formation, such as the medial prefrontal cortex (mPFC). In addition, engram cells have been found in the mPFC at memory encoding: these cells represent a close approximation of the "memory trace" insofar as they are activated at the time of learning, as they undergo enduring molecular modifications after learning, and as their reactivation drives memory recall. In contrast to HPC engram cells, mPFC engram cells are thought to be kept silent during a recent recall and until the memory is fully consolidated, becoming active only at remote recall. To explain the dynamics of these mPFC engram cells, we hypothesized that inputs to the mPFC could be differentially activated over the course of memory consolidation.We first determined that the prelimbic cortex (PL), a subregion of the mPFC, was specifically activated during the encoding phase of a fear memory in mice by measuring the expression of the Immediate Early Gene cFos, transcribed upon neuronal activation. We then traced the inputs of PL cells that were active during encoding, the putative PL engram cells, in order screen for relevant connections for further investigations. To achieve this, we used an activity-dependent monosynaptic retrograde tracing method based on rabies tracing. Then, to determine the activation patterns of these specific PL inputs, we measured their activity throughout consolidation of a contextual fear memory using an unbiased retrograde tracer coupled with cFos immunostaining. We further tested their functional relevance by chemogenetically inhibiting these projections during the different learning phases. This approach confirmed the roles of the Entorhinal Cortex and the Basolateral Amygdala inputs during the encoding phase of a fear memory to later recall remote memories. In addition, we found that the Claustrum (CLA) to PL projection was also required during the encoding phase, but to recall recent memories specifically. Moreover, the Insular Cortex (INS) to PL projection was necessary during recent recall. Eventually, we observed that the CLA and INS manipulations led to a modification of PL engram cells reactivation during recent recall.Overall, our results suggest that there is a functional shift in PL inputs during the course of memory consolidation, which is also impacting how PL engram cells are reactivated. In addition, we observed that the activity of PL inputs is part of a broader brain network, both through the presence of axon collaterals targeting other brain regions and by the existence of parallel and perhaps redundant pathways that could ensure efficient memory consolidation.Collectively, our data help to further refine the working model of memory formation by deciphering the interplay between brain regions during the process of systems consolidation of a fear memory, and open several questions for future investigations.

EPFL2022

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Fear and other anxiety disorders are extraordinarily robust and difficult to treat. Among the most effective treatments for anxiety disorders are exposure-based therapies, during which a patient is repeatedly confronted with the originally fear-eliciting stimulus in a safe environment so that the once fearful stimulus can be newly interpreted as neutral or safe. A fundamental element for successful exposure-based therapies is the reactivation/recall of the traumatic memory, which initiates a time-limited process called memory reconsolidation, during which a memory becomes susceptible to disruption. Presently, the neuronal subpopulations and molecular mechanisms underlying successful fear memory attenuation remain completely unknown, which represents a big gap in memory research. Therefore, the aim of this work is to first identify the neuronal subpopulations that are causally implicated in effective attenuation of remote fear memories. This will help to determine whether the original traumatic memory trace has been permanently modified or a new memory trace of safety has been superimposed over the original one. The second aim is to develop a tool that allows for the isolation of the neuronal subpopulations causally implicated in remote memory attenuation, in order to be able to delineate the epigenetic and transcriptional mechanisms at play within these subpopulations. This will help to identify a molecular signature of effective remote fear memory attenuation. The results of my research suggest for the first time that there is a small population of neurons in the dentate gyrus - that was active during the recall of fear â that needs to be reactivated during extinction to attain successful remote fear attenuation. While the inactivation of such population during extinction impairs fear attenuation, its activation ameliorates behavioral extinction. Furthermore, I have successfully established a method to isolate this neuronal subpopulation from the brain, namely by fluorescence-activated cell sorting. This tool will allow follow up studies to pursue the quest for the molecular signature of successful remote memory attenuation. Overall, these findings could help us to better understand the intricate principles of effective remote fear memory attenuation, and thus to develop new strategies that improve the treatment of anxiety disorder.

EPFL2017

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EPFL2022

EPFL2017