Mechanisms Controlling the Function and Development of Neuronal Nicotinic Synapses

突触是将神经元连接到功能网络的特殊细胞连接，从而提供所有综合神经信号的基础。突触传递包括从突触前神经元终端释放神经递质，并被特定的突触后受体捕获，这些受体转运离子以改变目标细胞的兴奋性。烟碱乙酰胆碱受体（nAChRs）结合乙酰胆碱介导自主神经节的兴奋性突触传递，控制体内平衡，调节控制协调运动和行为的脑回路输出。尽管它们具有广泛的相关性，但调节尼古丁突触功能和发育的分子机制仍然知之甚少。本项目将探讨垂体释放的一种神经肽（PACAP）在自主睫状神经节（CG）神经元的烟碱突触上引发的变化。最近的研究表明，在培养中，PACAP可以快速调节CG神经元上的突触。电生理、成像和生化方法将用于识别突触特性的改变，并确定介导这种调节的蛋白质-蛋白质相互作用。由于PACAP水平受发育调控，外源性PACAP以活动依赖的方式增强神经元存活，因此也将探讨PACAP持续影响突触形成和功能的可能性。预计pacap触发的信号对于尼古丁突触的建立和控制其功能都是至关重要的。最后，通过托莱多大学管理的外展项目将用于培训来访的本科生、高中生和高中教师。因此，该项目将进一步阐明与体内平衡调节、行为和发展相关的分子机制，同时促进科学素养和对代表性不足群体的培训。

Synapses are specialized cell junctions that link neurons into functional networks, thereby providing the basis of all integrative neural signaling. Synaptic transmission involves release of neurotransmitter from presynaptic neuron terminals and capture by specific postsynaptic receptors that transit ions to alter the target cell's excitability. Nicotinic acetylcholine (ACh) receptors (nAChRs) bind ACh to mediate excitatory synaptic transmission in autonomic ganglia controlling homeostasis and modulating the output of brain circuits that control coordinated movement and behaviors underlying pleasure and reward. Despite their broad relevance, the molecular mechanisms regulating function and development of nicotinic synapses remain poorly understood. This project will explore changes triggered by a neuropeptide (PACAP) released from the pituitary at nicotinic synapses on autonomic ciliary ganglion (CG) neurons. Recent findings indicate that PACAP rapidly regulates synapses on CG neurons in culture. Electrophysiological, imaging, and biochemical approaches will be used to identify altered synaptic properties and determine the protein-protein interactions that mediate this regulation. Since PACAP levels are developmentally regulated, and exogenous PACAP enhances neuronal survival in an activity dependent fashion, the possibility that PACAP persistently influences synapse formation and function will also be explored. It is expected that PACAP-triggered signaling will be critical both for building nicotinic synapses and controlling their function. Lastly, outreach programs administered through the University of Toledo will be used to train visiting undergraduates, high school students, and high school teachers. Thus, this project will further elucidate molecular mechanisms relevant to homeostatic regulation, behavior, and development while simultaneously fostering the scientific literacy and training of underrepresented groups.