The metabolic-epigenetic axis in memory

摘要 了解学习背后的分子机制对于改进记忆相关疗法至关重要 继续给我们的社会带来负担的疾病。我们最近发现了细胞新陈代谢之间的联系， 表观遗传调控和记忆相关的神经元可塑性。我们发现ACSS2，一种代谢酶， 乙酰辅酶A是海马神经元中染色质结合的产物，是长期空间记忆所必需的， 依赖于组蛋白乙酰化和基因表达的认知过程。 虽然这些结果在核乙酰辅酶A的生成之间建立了很强的功能联系 ACSS2，组蛋白乙酰化，转录和记忆，这种代谢的确切分子基础- 表观遗传轴尚待阐明。在这里，我们建议进一步从机械论的角度来探讨这一现象 细节。特别是，我们的目标是鉴定ACSS2相关蛋白，研究ACSS2的机制 募集到特定的基因，并确定有助于ACSS2介导的高阶结构 通过染色质环路进行转录调控。此外，我们将探索背侧海马区转录 在依赖海马体的哺乳动物学习中伴随着记忆形成的表观遗传学变化 模型(空间对象识别)。我们将评估全基因组范围内转录丰度和 染色质的可及性，研究组蛋白翻译后修饰的富集性，以及重新分布 ACSS2和选择组蛋白乙酰标记。最后，使用一系列的药理和遗传工具，我们将 评估ACSS2对观察到的转录、表观遗传和行为表型的贡献。 此外，我们在目标3下的初步数据表明，乙醇衍生的乙酰基迅速 以ACSS2依赖的方式整合到神经元染色质中。这一惊人的表观遗传学 大量饮酒者的反应可能是酒精诱导的转录和行为适应不良的基础。 事实上，我们发现用醋酸盐(酒精衍生的代谢物和 ACSS2的直接底物上调学习和记忆相关基因以及ACSS2的减少 消除条件性位置偏好中与酒精相关的联想学习。我们将探索海马体 与体内酒精暴露相关的小鼠转录和表观遗传学变化 ACSS2在酒精诱导的分子和细胞改变中的作用。此外，我们会评估 小分子ACSS2抑制剂对酒精相关行为的影响，为今后的治疗奠定基础 干预措施。 总体而言，这项工作将通过表征新陈代谢-表观遗传轴来显著推进这一领域 学习神经生物学的背景。此外，我们希望我们的研究能够识别出有效的小说 治疗记忆障碍及相关的神经和精神疾病的途径。

Abstract Understanding the molecular machinery underlying learning is critical to improve therapies for memory-related disorders that continue to burden our society. We recently identified a connection between cellular metabolism, epigenetic regulation, and memory-related neuronal plasticity. We found that ACSS2, a metabolic enzyme that generates acetyl-CoA is chromatin-bound in hippocampal neurons and required for long-term spatial memory, a cognitive process that relies on histone acetylation and gene expression. While these results established a strong functional link between nuclear acetyl-CoA generation by ACSS2, histone acetylation, transcription and memory, the exact molecular underpinnings of this metabolic- epigenetic axis remain to be elucidated. Here we propose to explore this phenomenon in further mechanistic detail. In particular, we aim to identify ACSS2-associated proteins, examine the mechanism of ACSS2 recruitment to specific genes, and identify higher-order structures that contribute to ACSS2-mediated transcriptional regulation via chromatin looping. Moreover, we will explore dorsal hippocampal transcriptional and epigenetic changes that accompany memory formation in a hippocampus-dependent mammalian learning model (spatial object recognition). We will assess genome-wide changes in transcript abundance and chromatin accessibility, study the enrichment of histone post-translational modifications, and the re-distribution of ACSS2 and select histone acetyl marks. Finally, using an array of pharmacological and genetic tools, we will assess the contribution of ACSS2 to the observed transcriptional, epigenetic and behavioral phenotypes. In addition, our preliminary data under Aim 3 indicate that ethanol-derived acetyl-groups are rapidly incorporated into neuronal chromatin in an ACSS2-dependent manner. This remarkably rapid epigenetic response might underlie alcohol-induced transcriptional and behavioral maladaptations in heavy drinkers. Indeed, we found that treating primary hippocampal neurons with acetate (the alcohol-derived metabolite and direct substrate of ACSS2) upregulates learning and memory-related genes and that ACSS2 reduction eliminates alcohol-related associative learning in conditioned place preference. We will explore hippocampal transcriptional and epigenetic changes associated with alcohol exposure in mice in vivo and assess the contribution of ACSS2 to molecular and cellular alterations induced by alcohol. Further, we will assess the effect of small molecule ACSS2 inhibitors on alcohol-related behaviors, as a basis for future therapeutic interventions. Overall, this work will significantly advance the field by characterizing the metabolic-epigenetic axis in the context of learning neurobiology. Furthermore, we expect our studies to identify efficacious novel therapeutic avenues for memory impairments and associated neurological and psychiatric conditions.