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Cellular and molecular mechanisms of remote fear attenuation

Periodic Reporting for period 4 - Remote memory traces (Cellular and molecular mechanisms of remote fear attenuation)

Reporting period: 2020-11-01 to 2021-10-31

In this project, we are interested in elucidating the brain circuits, cellular subpopulations and molecular mechanisms of remote fear memory extinction. Despite an elevated lifetime prevalence of related fear and anxiety disorders, effective treatments for long-lasting, i.e. remote, traumatic memories are scarce and the mechanisms behind successful memory attenuation poorly understood. This represents a problem relevant to the clinic and society alike, as fear and stress-related disorders are on the rise: Worldwide refugee crises and an ongoing pandemic have contributed substantially in the past years.
To achieve our goals, we are working with rodents as a surrogate to mimic post-traumatic stress disorder in a controllable setting. Specifically, we are using transgenic mouse models to visualise cells implicated in remote memory storage and attenuation, in combination with approaches to alter neuronal activity and with cell type-specific molecular analyses.
Over the course of this project, we have identified the brain areas (Psychopharmacology, 2019), circuits (Nature Neuroscience, 2021) and cellular subpopulations (Science, 2018; Frontiers in Molecular Neuroscience, 2019) underlying remote fear memory extinction, as well as the molecular mechanisms thereof (BioRXiv 2021, currently under review at PNAS). Importantly, the identification of the cells responsible for remote fear memory attenuation (Science, 2018) revealed that the key to successfully attenuate remote traumatic memories lies, contrary to long-held beliefs, in the same cells that were used to store the memory in the first place, i.e. the original memory trace of fear. In other words, it is better to face your fears than to suppress them.Furthermore the identification of the brain circuits engaged in the remote fear memory attenuation (Nature Neuroscience, 2021) revealed that the circuits required for the extinction of traumatic memories change with memory age. In other words, they revealed for the first time that similar to memory consolidation that is supported by a different brain areas as memories become older, there is a spatiotemporal shift in the circuits underlying fear memory extinction.
Together, these findings shed considerable new light on an underinvestigated area of memory research, remote fear memory attenuation.
In this grant, we have shown that the key to successfully attenuate long-lasting traumatic memories lies in the same cells that were used to store the trauma in the first place. In other words, we have found that upon fear memory attenuation,
fear memory recall-induced cells are significantly reactivated in parts of the brain. In particular, we have found that within the hippocampus, hippocampal area CA1 and the dentate gyrus, but not in CA3, are reactivated, while in the cortex, the infralimbic area is, but not the anterior cingulate area or the prelimbic area, and in the amygdala, it is the basolateral part, but not the central part that shows this reactivation. Importantly, all brain areas that show the reactivation are known to play a critical role in memory attenuation. What is more, when we blocked the activity of recall-induced neurons, the degree of fear memory attenuation was impaired. Conversely, when we increased the activity of recall-induced neurons during memory extinction, fear attenuation was facilitated. These results stipulate that a loss-of-function of the original memory trace of fear is detrimental for fear attenuation, which in turn favours the notion that the original memory trace of fear has been updated, i.e. relearned towards safety likely via reconsolidation-updating mechanisms, rather than having been suppressed via extinction learning. In other words, it is good to confront your fears.
On top of that, we have recently also identified the molecular mechanisms engaged in these reactivated cells during remote fear memory extinction. Interestingly, these mechanisms point to enhanced synaptic plasticity, which is a key feature of facilitated learning, and several candidate genes have emerged, which will now be followed up in functional studies for their potential to accelerate fear extinction.
This project reached beyond the state of the art on many fronts. First, there is a draught of literature on remote, i.e. long-lasting fear memories, which is surprising in light of the long-lasting nature of traumatic memories, the increased resistance of remote fear memories to disruption, and the decreased efficacy of exposure therapy with memory age. Second, they show that contrary to mainstream thinking about the cellular mechanisms underlying memory extinction, fear reduction is not achieved by the suppression of traumatic memories, but by their reactivation and, therefore, by a rewriting of the original memory trace of fear towards safety. Finally, with the identification of the cellular subpopulations implicated in remote fear memory reduction, we now have a unique window of opportunity to identify the molecular mechanisms relevant for it. We have taken advantage of this to identify key candidate genes, which in future studies can be tested to design refined, and more precise treatment strategies against long-lasting traumatic memories.
Fluorescent image showing how fear extinction (red) occurs in the original fear memory trace (green)