The neurobiology of forgetting - spontaneous synaptic remodeling, cortical representation stability,memory retention and behavioral flexibility

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Why do we forget? The fascinating phenomenon of forgetting, originally studied by experimental psychologists and later by experimental, computational, and theoretical neuroscientists, has been a focus of research for over a century. Although forgetting is often regarded as detrimental, in particular in association with pathologies such as dementia, we now know that it is crucially important for behavioral flexibility – the adaptation to changing environments or the generalization of acquired knowledge – as well as for mitigating traumatic events. For decades, forgetting has been viewed as a consequence of ongoing life experiences, which interfere with prior memories, overwrite them or obfuscate their retrieval. More recently, forgetting has also been shown toinvolve biological mechanisms that actively and selectively ‘erase’ undesirable information. Much of this work has focused on synapses, the specialized junctions that interconnect nerve cells into vast and complex networks.This focus stems from the widely accepted doctrine that changes to synapses represent the main mechanism by which nervous systems learn new tasks and store new information. This doctrine is also associated with an implicit assumption that synaptic properties, when not driven to change by physiological cues or ‘erasure’ mechanisms, will persist indefinitely. Yet, unlike most human-built storage devices, in which information typically persists until actively erased, persistence of synaptic properties cannot be taken for granted: Synapses are made of dynamic, short-lived (days) components that continuously move in, out and between synapses over time scales of minutes and hours. Indeed, these dynamics drive spontaneous changes in synaptic properties which are of the same magnitude as those driven by physiological signals. While attempts have been made to reconcile this volatility of synaptic connections with canonical views of synapses as information storage devices, a straightforward possibility is that spontaneous changes in synaptic connection might simply drive forgetting.Surprisingly, this evident possibility has hardly been explored.The overall goal of this project is thus to explore relationships between spontaneous synaptic remodeling, forgetting and behavioral flexibility. The major thrust is to (a) devise perturbations that specifically and selectively affect spontaneous synapse remodeling rates, (b) introduce the most effective molecular modifications into mouse models, (c) validate their effects on synaptic remodeling dynamics in vivo, (d) examine how these perturbations affect the stability of cortical representations in these animals, and (e)examine by behavioral testing, how these perturbations affect memory, forgetting, and behavioral flexibility. To attain this goal, we propose a collaborative, multilevel (molecular, synaptic, network, behavior) program which deeply integrates experimentation, advanced analytical methods and theory. (....)