Acetylcholinergic Neurotransmission During Aging

项目摘要 该提案旨在确定乙酰胆碱能神经传递变化对突触的作用 生理学和行为学。长期以来，人们一直认为乙酰胆碱调节在以下方面起着至关重要的作用： 随着有机体年龄的增长， 在这个过程中，迄今为止仍然没有得到很好的解释。我们正在使用一个微小的突变， 乙酰胆碱转运蛋白（VAChT）是负责乙酰胆碱包装的蛋白质，用于胞吐释放， 确定胆碱能神经传递在衰老过程中的作用。苍蝇的寿命很短， 该系统特有的其他遗传工具将使我们能够评估改变ACh释放对 行为和突触生理学在动物的整个生命周期。我们的初步数据显示 老年果蝇胆碱能神经元的动作电位放电时间;我们还表明，Vacht突变具有 最严重的突变对生物体存活的差异影响比 野生型这些和其他结果使我们能够推进中心假设，即 VAChT功能导致神经元兴奋性和行为相应降低， 在目标1中，我们将确定VAChT相对轻度减少的影响 在衰老过程中对中枢胆碱能突触的突触生理功能。在目标2中，我们将衡量 Vacht的减少会影响整个生命周期中定义点的认知。未来的研究将针对 使用我们在这里开发的系统来理解优惠背后的机制， 胆碱能神经元在阿尔茨海默病等病理条件下的易感性。

Project Summary This proposal is aimed at determining the role of changes in acetylcholinergic neurotransmission on synaptic physiology and behavior during aging. Acetylcholine regulation has long been thought to play a crucial role in the mediation of cognitive and behavioral function as an organism ages, yet the precise function of acetylcholine in this process has, till date remained poorly elucidated. We are using a subtle mutation in the vesicular acetylcholine transporter (VAChT) the protein responsible for the packaging of ACh for exocytotic release to determine the role of cholinergic neurotransmission during aging. The short life span of the fly coupled, with additional genetic tools unique to this system will allow us to assess the impact of altered ACh release on behavior and synaptic physiology throughout the lifespan of the animal. Our preliminary data show for the first time action potential firing in aged Drosophila cholinergic neurons; we also show that Vacht mutations have a differential effect on organismal survival with the most severe mutation have a significantly shorter lifespan than wildtype. These and other results have allowed us to advance the central hypothesis that a decrease in VAChT function produce a corresponding decrease in neuronal excitability and behavior that are amplified with age In Aim 1, we will determine the effect of a relatively mild reduction decrease in VAChT function on synaptic physiology at central cholinergic synapses during aging. In Aim 2, we will measure whether the reduction in Vacht affects cognition at defined points across the lifespan. Future studies will be aimed at using the system that we have developed here to understand the mechanisms behind the preferential susceptibility of cholinergic neurons in pathological conditions such as Alzheimer’s disease.