Acetylcholinergic Neurotransmission During Aging

项目摘要 这项建议旨在确定乙酰胆碱能神经传递的变化对突触的作用 衰老过程中的生理和行为。长期以来，乙酰胆碱的调节一直被认为在 随着生物体的衰老，认知和行为功能的调节，但乙酰胆碱的确切功能 在这一过程中，到目前为止仍然没有得到很好的阐明。我们在水泡中使用了一种微妙的突变 乙酰胆碱转运蛋白(VAChT)是负责包装ACh的蛋白质，负责将ACh胞吐释放到 确定胆碱能神经传递在衰老过程中的作用。苍蝇短暂的寿命，加上 该系统独有的其他遗传工具将使我们能够评估ACh释放改变对 动物一生中的行为和突触生理学。我们的初步数据显示，第一次 老年果蝇胆碱能神经元的时间动作电位放电；我们还表明Vacht突变具有 最严重突变对生物生存的不同影响显著短于 野性的。这些和其他结果使我们能够推进中心假设，即 Vacht功能会相应地降低神经元的兴奋性和行为 在目标1中，随着年龄的增长，我们将确定相对温和的Vacht下降的效果 衰老过程中中枢胆碱能突触对突触生理的影响。在目标2中，我们将衡量 Vacht的减少会影响整个寿命中特定时间点的认知能力。未来的研究将致力于 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.