Friday, November 22, 2024
11/22/2024
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.
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