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

项目摘要/摘要 主要研究部分2 来自人类研究和临床前动物模型的汇聚数据显示，酗酒 青春期早期饮酒/暴露与大脑结构和连接性的变化有关。 青春期间歇性酒精暴露对啮齿类动物持续性脑损伤的影响 饮酒导致海马神经发生减少和内侧隔区胆碱能神经元丢失 和Broca斜带(MS/Db)。在这些区域之间形成的回路，即隔海马体 途径，是学习和记忆的关键。MS/Db区向海马区的胆碱能投射 以高度地形的模式排列，但试点数据表明，在 在衰老过程中，海马体破坏了独特的体位组织。此外，我们 观察到，随着AIE后年龄的增长，出现了空间记忆障碍，与之平行的是 减少活动相关的乙酰胆碱在海马区的释放。这项提议的目的是揭示 青春期大量间歇性酒精暴露如何改变大脑连通性、神经可塑性和 在整个生命周期中的行为功能。具体地说，我们将确定AIE(A)之后的老化如何改变 胆碱能隔-海马区通路的地形性组织及抑制其表达 MS/DB内胆碱能神经表型，调节活动依赖的海马区 乙酰胆碱释放(AIM 1)；(B)扰乱胆碱能隔海马区的神经生理学特征 途径，并导致行为和乙酰胆碱功能障碍跨越海马区的隔颞轴 (目标2)。最后，考虑到隔区-海马体回路对环境条件非常敏感，我们 将以运动为工具恢复海马神经元再生，防止MS/DB胆碱能萎缩/细胞丢失， 并阻止由于AIE老化而导致的到海马体的功能障碍的重新映射，我们假设这是 空间行为受损和活动依赖性乙酰胆碱释放迟钝(目标3)。我们的初步数据 揭示了暴露于酒精相关痴呆的大鼠隔海马区功能障碍的特征 AIE开始老化，本提案的目标是了解这一复杂的过程，以便纠正它 降低认知功能障碍和不成功衰老的风险。

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.