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

主要研究部分 2：青春期期间的暴饮暴食会改变晚期衰老过程中的隔海马回路

• 批准号: 10686844
• 负责人: Lisa M Savage
• 金额: $ 28.37万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686844
• 关键词: Abstinence; Acetylcholine; Acute; Adolescence; Adult; Affective; Age; Age-associated memory impairment; Aging; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Atrophic; Behavioral; Behavioral Assay; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Cells; Chronic; Cognitive aging; Complex; Coupled; Data; Dementia; Development; Diagonal Band of Broca; Dorsal; Exercise; Exposure to; Functional disorder; Goals; Health; Hippocampus; Impaired cognition; Impairment; Lateral; Learning; Longevity; Maps; Medial; Mediator; Memory; Memory impairment; Modeling; Neuroanatomy; Neuronal Plasticity; Neurons; Pathology; Pathway interactions; Pattern; Phenotype; Pliability; Pre-Clinical Model; Process; Prosencephalon; Rattus; Recovery; Reporting; Research; Risk; Risk Reduction; Rodent; Running; Spatial Behavior; Structure; Synaptic plasticity; Testing; Virus; adolescent alcohol exposure; age related; aged; alcohol exposure; alcohol research; binge drinking; cholinergic; cholinergic neuron; critical period; differential expression; early adolescence; human data; neural; neuroadaptation; neurogenesis; neurophysiology; novel; pre-clinical; prevent; problem drinker; septohippocampal; social; spatial memory; tool; way finding

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.

项目概要/摘要 主要研究部分2 人类研究和临床前动物模型的综合数据表明，酗酒 青春期早期的饮酒/接触与大脑结构和连通性的变化有关。 啮齿类动物青少年间歇性乙醇暴露（AIE）后持续性脑损伤，这是一种暴饮暴食的模型 饮酒会导致海马神经发生减少和内侧隔膜胆碱能神经元损失 和 Broca 对角线带 (MS/DB)。这些区域之间形成的回路，即隔海马 途径，对于学习和记忆至关重要。从 MS/DB 到海马体的胆碱能投射 以高度地形模式排列，但试验数据表明神经发生的损失 海马体在衰老过程中会破坏独特的体位组织。此外，我们 观察到，随着 AIE 后大鼠年龄的增长，出现了空间记忆障碍，与此并行的是 海马内与活动相关的乙酰胆碱释放减少。该提案的目标是揭示 青春期期间间歇性大量饮酒如何改变大脑连接性、神经可塑性和 整个生命周期的行为功能。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，调节活动依赖性海马 乙酰胆碱释放（目标 1）； (b) 破坏胆碱能隔海马的神经生理学特征 途径并导致海马间隔颞轴的行为和乙酰胆碱功能障碍 （目标 2）。最后，考虑到隔海马回路对环境条件的适应性极强，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/细胞损失， 并停止因 AIE 老化而导致的海马体功能失调重新映射，我们假设 AIE 会导致这种情况 空间行为受损和活动依赖性乙酰胆碱释放减弱（目标 3）。我们的初步数据 揭示了当老鼠暴露于酒精中时，中隔海马功能障碍类似于酒精相关的痴呆症 AIE 开始老化，该提案的目标是理解这个复杂的过程，以便将其纠正为 降低认知功能障碍和衰老失败的风险。