Main Research Component 2: Binge-type alcohol exposure during adolescence alters the septohippocampal circuit during advanced aging

项目总结/摘要 主要研究构成部分2 来自人类研究和临床前动物模型的汇总数据显示， 在青春期早期饮酒/暴露与大脑结构和连接的变化有关。 青少年间歇性乙醇暴露（AIE）后啮齿动物的持续性脑损伤，一种狂欢模型 饮酒导致海马神经发生减少和内侧隔胆碱能神经元丢失 和Broca对角线带（MS/DB）。在这些区域之间形成的回路，隔海马 是学习和记忆的关键。MS/DB向海马的胆碱能投射 排列在一个高度地形图案，但试点数据表明，在神经发生的损失， 海马体在衰老过程中破坏了独特的躯体组织。而且我们 观察到随着AIE大鼠年龄的增长，出现了空间记忆障碍，这是由一个 海马内活动相关乙酰胆碱释放减少。这项提案的目的是揭示 青春期间歇性酒精暴露如何改变大脑连接性，神经可塑性， 在整个生命周期中的行为功能。具体来说，我们将确定AIE（a）后的衰老如何改变 胆碱能隔海马通路的拓扑结构，并阻碍 MS/DB内的胆碱能神经表型，其调节活动依赖性海马 乙酰胆碱释放（Aim 1）;（B）破坏胆碱能隔海马的神经生理学特征 途径，并导致行为和乙酰胆碱功能障碍的隔颞轴的海马 (Aim 2）。最后，鉴于隔海马回路对环境条件的适应性非常强，我们 将使用运动作为恢复海马神经发生的工具，防止MS/DB胆碱能萎缩/细胞丢失， 并停止海马体的功能失调，这是由AIE衰老引起的，我们假设这导致了 空间行为受损和活动依赖性乙酰胆碱释放减弱（目的3）。我们的初步数据 揭示了一个类似于酒精相关性痴呆的隔海马功能障碍的轮廓， AIE开始老化，本提案的目标是了解这一复杂的过程，以便能够纠正， 降低认知功能障碍和衰老失败的风险。

PROJECT SUMMARY/ABSTRACT MAIN RESEARCH COMPONENT 2 Converging data from human studies and preclinical animal models have revealed that alcohol binge drinking/exposure during early adolescence is associated with changes in brain structure and connectivity. Persistent brain damage after adolescent intermittent ethanol exposure (AIE) in rodents, a model of binge drinking, entails reduced hippocampal neurogenesis and a loss of cholinergic neurons in the medial septum and diagonal band of Broca (MS/DB). The circuit formed between those regions, the septohippocampal pathway, is critical for learning and memory. The cholinergic projections from the MS/DB to the hippocampus are arranged in a highly topographical pattern, but pilot data suggest a loss of neurogenesis in the hippocampus disrupts the unique somatotopic organization during the aging process. Furthermore, we observed that as rats aged following AIE, a spatial memory impairment emerged, which was paralleled by a reduction in activity-related acetylcholine release within the hippocampus. The goal of this proposal is to reveal how heavy intermittent alcohol exposure during adolescence alters brain connectivity, neural plasticity and behavioral function across the lifespan. Specifically, we will determine how aging following AIE (a) alters the topographical organization of the cholinergic septohippocampal pathway and impedes the expression of cholinergic neural phenotypes within the MS/DB, which modulate activity-dependent hippocampal acetylcholine release (Aim 1); (b) disrupts the neurophysiological profile of cholinergic septohippocampal pathway and leads to behavioral and acetylcholine dysfunction across septotemporal axis of the hippocampus (Aim 2). Finally, given that the septohippocampal circuit is extremely pliable to environmental conditions, we will use exercise as a tool to restore hippocampal neurogenesis, prevent MS/DB cholinergic atrophy/cell loss, and halt dysfunctional remapping to the hippocampus, caused by aging with AIE, which we hypothesized leads to impaired spatial behavior and blunted activity-dependent acetylcholine release (Aim 3). Our preliminary data revealed a profile of septohippocampal dysfunction that resembled alcohol-related dementia as rats exposed to AIE begin to age, and the goal of this proposal is to understand this complex process so it can be corrected to reduce the risk of cognitive dysfunction and unsuccessful aging.