ACETYLCHOLINE MODULATION OF ION CHANNELS AND FIRING PATTERNS

乙酰胆碱通过毒蕈碱受体调节 神经元的兴奋性通过改变各种钠，钙，钾 渠道这种兴奋性的调节在以下方面起着核心作用： 胆碱能调节觉醒、认知和记忆。的目标 拟议的研究是了解毒蕈碱的变化， 潜在的形成和发射模式的调制方面， 特别是离子通道。膜片钳技术将用于研究 控制交感神经中的钠、钾、钙通道， 海马和多巴胺神经元的毒蕈碱刺激。主 实验制备将是急性分离的神经元，这允许 具有足够速度的电压箝位，以表征 在动作电位期间流动的大而快速的电流。这样可以延长 以前的工作使用大脑切片，其中只有相对较小和缓慢的 可以在电压钳下研究电流。我们将直接检查 第一次记录动作时动作电位的电流 潜在的波形，并在同一单元格中，使用这些波形作为 电压钳实验中的指令电压。通过使用药理学 工具来分离单独的当前砂执行电流钳 和电压钳实验中存在的乙酰胆碱，它应该 可以确定特定通道的调制作用 类型对兴奋性总体变化的贡献。毒蕈碱 离子通道和神经元兴奋性的控制是 大脑的正常运作，有证据表明， 老化的大脑海马神经元毒蕈碱调节的变化可能 与阿尔茨海默病的症状密切相关， 了解所涉及的通道可能会导致新的治疗方法， 干预，例如通过使用离子通道阻断剂来模拟效应 乙酰胆碱

Acetylcholine acting through muscarinic receptors modulates the excitability of neurons by altering various sodium, calcium, and potassium channels. This modulation of excitability plays a central role in cholinergic regulation of wakefulness, cognition, and memory. The goal of the proposed research is to understand muscarinic changes in action potential formation and firing patterns in terms of modulation of particular ion channels. Patch clamp techniques will be used to study the control of sodium, potassium, calcium channels in sympathetic, hippocampal, and dopamine neurons by muscarinic stimulation. The primary experimental preparation will be acutely isolated neurons, which allow voltage-clamp with sufficient speed to characterize modulation of the large, rapid currents flowing during action potentials. This will extend previous work using brain slices, in which only relatively small and slow currents could be studied under voltage-clamp. We will directly examine currents flowing during action potentials by first recording action potential wave-forms and, in the same cell, using those wave forms as command voltages in voltage clamp experiments. By using pharmacological tools to separate individual current sand performing both current-clamp and voltage-clamp experiments in the presence of acetylcholine, it should be possible to determine the role of modulation of particular channel types in contribution to overall changes in excitability. Muscarinic control of ion channels and neuronal excitability is a basic process for the normal operation of the brain, and evidence suggests changes in the aging brain. Changes in muscarinic modulation of hippocampal neurons may be centrally involved in the symptoms of Alzheimer's disease, and better understanding of the channels involved may lead to novel therapeutic interventions, for example by using ion channel blockers to mimic effects of acetylcholine.