Mechanisms Controlling the Function and Development of Neuronal Nicotinic Synapses

突触是一种特殊的细胞连接，将神经元连接成功能网络，从而为所有整合的神经信号提供基础。突触传递包括从突触前神经元终末释放神经递质，并被特定的突触后受体捕获，这些受体传递离子来改变靶细胞的兴奋性。烟碱型乙酰胆碱受体(NAChRs)与乙酰胆碱(ACh)受体结合，在自主神经节中介导兴奋性突触传递，控制内稳态，并调节大脑回路的输出，控制协调运动和潜在的愉悦和奖励行为。尽管它们具有广泛的相关性，但调节烟碱突触功能和发育的分子机制仍然知之甚少。该项目将探索由脑下垂体释放的神经肽(PACAP)在自主睫状神经节(CG)神经元上的尼古丁突触引发的变化。最近的研究表明，PACAP对培养的CG神经元上的突触具有快速调节作用。电生理、成像和生化方法将被用来识别改变的突触属性，并确定介导这一调节的蛋白质-蛋白质相互作用。由于PACAP水平是受发育调节的，并且外源性PACAP以一种活动依赖的方式增强神经元的存活，因此PACAP持续影响突触形成和功能的可能性也将被探索。预计PACAP触发的信号对于构建尼古丁突触和控制它们的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动态平衡调节、行为和发育相关的分子机制，同时培养未被充分代表的群体的科学素养和培训。

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.