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.

项目摘要/摘要 主要研究组件2 人类研究和临床前动物模型的收敛数据表明酒精暴饮暴食 青春期早期的饮酒/暴露与大脑结构和连通性的变化有关。 青少年间歇性乙醇暴露（AIE）啮齿动物中的持续脑损伤，狂暴模型 饮酒，需要减少海马神经发生和内侧隔膜中胆碱能神经元的丧失 和对角线Broca（MS/DB）。这些区域之间形成的电路，septohampocampal 途径，对于学习和记忆至关重要。从MS/DB到海马的胆碱能预测 以高度地形模式排列，但试验数据表明， 海马在衰老过程中破坏了独特的体积组织。此外，我们 观察到，随着AIE年龄的大鼠，出现了空间记忆障碍，与 在海马内降低与活动相关的乙酰胆碱释放。该提议的目的是揭示 青春期期间间歇性地间歇性暴露如何改变大脑连通性，神经可塑性和 整个生命周期的行为功能。具体来说，我们将确定遵循AIE（a）的衰老如何改变 胆碱能septohampocampal途径的地形组织，阻碍了表达 MS/DB内的胆碱能神经表型，该表型调节活动依赖性海马 乙酰胆碱释放（AIM 1）； （b）破坏胆碱能septohappocampal的神经生理特征 途径并导致海马隔离轴跨隔离轴的行为和乙酰胆碱功能障碍 （目标2）。最后，鉴于Septohappocampal电路在环境条件下极为柔韧，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/细胞丧失， 并停止功能障碍的重新映射到由AIE衰老引起的海马，我们假设铅 为了损害空间行为和活性依赖性乙酰胆碱的释放（AIM 3）。我们的初步数据 揭示了Septohappocampal功能障碍的特征，类似于酒精相关的痴呆 AIE开始老化，该提案的目的是了解这一复杂过程，以便可以纠正到 降低认知功能障碍和不成功衰老的风险。