Neuroscience of Learning and Memory Study for Brain Preservation

Introduction

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Through what physical means do brains retain information for use weeks, months, or years later? Recall of long-term memories - be it recoiling from a distinct taste after a food-induced illness six months prior, or singing the lyrics of a song one hasn’t heard in years - enable an animal’s behaviors to be shaped by a lifetime’s worth of accumulated experience. For this to be possible, earlier experiences must create some kind of ‘memory trace’ in an animal’s brain, meaning there must be some enduring physical record that bridges the gap between an initial experience and its subsequent recall. But out of all the potential recording mechanisms available to brains, which ones actually enable long-term memory? There is evidence that robust, long-lived memories are likely retained by relatively stable and static aspects of neurophysiology. Long-term memories can be recalled even after periods of prolonged global neuronal depolarization and inactivity, as can occur in deep hypothermic circulatory arrest (Percy et al., 2009, Ann. Thorac. Surg., Stecker et al., 2001, Ann. Thorac. Surg.),or despite temporary protein synthesis inhibition (Davis & Squire, Larry R, 1984, Psychol. Bull.).In contrast to working and short-term memory then, it is thus unlikely that sustained, dynamic neural activation or incessant protein synthesis is required for long-term memory retention. Instead, over the past century, neuroscientists have suggested a variety of structural candidates for the physical basis of long-term memory. A non-exhaustive list includes: synaptic strength alterations mediated by receptor insertion, removal, or subunit modification; synaptogenesis; intracellular phosphorylation, epigenetic, or other molecular modifications; changes in axonalmyelination; modifications of perineuronal nets and the extracellular matrix; among many others. These candidates are not necessarily mutually exclusive, as long-term memory may well depend on a variety of these mechanisms and their interactions. Breakthroughs in the past decade have seen the search for or the neural substrates responsible for long-term memories, termed ‘engrams’, pursued with renewed vigor. These advances were kicked off by the seminal 2012 publication of a method for artificially forcing the recall of a specific memory through tagging and optogenetically stimulating a subset of hippocampal neurons (Liu etal., 2012, Nature). Subsequent experiments have since demonstrated selective memory erasure(Hayashi-Takagi et al., 2015, Nature), artificial memory formation (Vetere et al., 2019, Nat.Neurosci.), and artificial memory linkage (Ohkawa et al., 2015, Cell Rep.), among other impressive feats. Indeed, given that ensembles of hippocampal and cortical neurons have arguably shown to be both necessary (erasure experiments) and sufficient (forced recall and insertion experiments) for memory-related behaviors, it could be argued that the physical basis of long-term memories has now been established. Indeed, in the words of many of the scientists who have furthered engram research in the past decade, “There is a clear consensus on where the memory engram is stored—specific assemblies of synapses activated or formed during memory acquisition”(Poo et al., 2016, BMC Biol.).But is it really true that there is now a consensus that long-term memories are stored in synaptic ensembles? For if so, this would imply there is a common understanding among neuroscientists as to which aspects of neurophysiology are critical for long-term memory storage, and which are irrelevant. Some properties, perhaps such as the specific polymer subunit count of synaptic microtubules, or the exact positions of cholesterol molecules in the neuronal membrane, would presumably be deemed below the physical scale relevant for encoding memories. At the other extreme, some macroscopic neurophysiological properties, like total hippocampal volume, would likely be considered mere macroscopic epiphenomena of the mechanisms actually responsible for memory storage. But if a consensus truly exists, then neuroscientists must have some agreement that somewhere between these lower and upper bounds there lies a ‘critical scale’, wherein there exists the properties or mechanisms responsible for long-term memory. To determine whether or not neuroscientists agree on where this critical scale lies, we performed a survey of memory experts. Expert surveys in other fields, such as philosophy (Bourget &Chalmers, 2021, Francken et al., 2022, Neurosci. Conscious.) and artificial intelligence(Grace et al., 2024), have proven instrumental in ascertaining what is and is not consensus within an academic community. While there exists a survey of the general US population on their beliefs about how memory works (Simons & Chabris, 2011, PLoS ONE), and there have been surveys of memory scientists on the psychological properties of memories (Diamond et al., 2020, Psychol. Sci.), we are unaware of any previous surveys of the opinions of memory neuroscientists as to the mechanics of long-term memory storage. This survey was divided into three major components. The first queried participants about whetherthey believed long-term memories were stored in structural aspects of neurophysiology, and if so, through which physical mechanisms and at which critical scale(s). The second explored whether participants agreed with the implications that memories being stored structurally would have, byasking them for their probability estimates that information contained in long-term memories could theoretically be extracted from static, perfectly-preserved brains. The final section explored atheoretical test for whether long-term memories are stored structurally, by probing participants onwhether readout and reinstantiation of these memory-storing neurophysiological structures inanother physical form, such as through whole brain emulation (Sandberg & Bostrom, 2008), could someday provide proof that long-term memories are indeed stored structurally and at a particular critical scale(s).

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Team

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Andy McKenzie, Ariel Zeleznikow-Johnston