Publication

Epigenetic plasticity as a signature for memory allocation

Giulia Santoni
2022
EPFL thesis
Abstract

Long-lasting memories are stored in a small set of neurons scattered throughout the brain, so-called engram cells. To define a stable engram each region of the brain involved in memory storage recruits between 5 and 20 percent of excitatory neurons. In parallel, recent studies have revealed that neuronal competition to participate in the memory engram is not random, rather, post-synaptic neurons with a higher excitability or elevated CREB levels than their neighbors are more likely to be selected into the memory trace. However, the precise mechanism that enables a neuron to acquire such profile has not yet been investigated. With this project we want to further explore the process of memory allocation by studying how epigenetic mechanisms in terms of histone acetylation contribute to neuronal selection. To this end, we manipulated the histone acetyltransferase (HAT) content of a sparse population of excitatory cells in the lateral amygdala (LA) of wild type mice. The overexpression of distinct members of the HAT family led to an increase in the H3K27Ac levels, an epigenetic marker known to be associated with transcription facilitation and enhancer activation. Furthermore, HAT overexpression increased the probability of individual LA neurons to be selected as part of the encoding ensemble, which was accompanied by facilitated memory retention. Importantly, by selectively expressing the inhibitory opsin ArchT in the epigenetically modified neuronal ensemble, we proved that inactivating HAT-overexpressing LA cells during the recall phase impaired memory expression. Mechanistically, with single nuclei multi-omics experiment we revealed that HAT-overexpressing LA neurons exhibited a global increase in chromatin accessibility and the specific priming of regulatory promoters. Moreover, we found that compared to controls, manipulated neurons increased the expression of genes related to synapse architecture, signaling and intrinsic excitability. What is more, by ex vivo patch clamping HAT-infected LA principal neurons we confirmed that these cells showed an enhanced intrinsic excitability profile compared to their non-infected neighbors. Crucially, the increase in histone acetylation, memory allocation as well as the enhanced IE profile, were completely ablated in HAT-dead mutants overexpressing neurons. Lastly, by designing molecular beacons that allow for the simultaneous recording of neuronal histone acetylation and calcium dynamics in vitro, we show that epigenetic plasticity underlies neuronal excitability within the same cells. These findings identify chromatin-templated plasticity as key factor catalyzing memory allocation.

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Related concepts (37)
Memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, it would be impossible for language, relationships, or personal identity to develop. Memory loss is usually described as forgetfulness or amnesia. Memory is often understood as an informational processing system with explicit and implicit functioning that is made up of a sensory processor, short-term (or working) memory, and long-term memory.
Memory consolidation
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.
Histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression. In general, histone acetylation is linked to transcriptional activation and associated with euchromatin.
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