Regulation of neuron and synapse function by neuropeptides

描述(申请人提供)：大脑中突触的经验依赖性修改被认为是动物学习新行为和形成记忆的能力的基础。关于调节突触的机制，人们知道很多，这些突触通过谷氨酸和GABA等快速、经典的神经递质传递信号。然而，大脑也包含一个多样化和广泛分布的突触系统，这些突触通过释放称为神经肽的短肽来发出信号。尽管神经肽和神经肽受体在调节哺乳动物行为方面很重要，而且它们在人类疾病发病机制中的已知作用，但在细胞水平上对肽能信号的生理后果知之甚少。同样，在哺乳动物大脑中，触发神经肽释放的刺激或其对经典突触传递的调节作用都不是很清楚。我们认为神经肽以高的时间和空间精度快速调节神经元和突触。我们将使用新的工具来检验这一假设，这些工具允许在脑组织内精确地、时间和空间地传递神经肽。我们将结合对谷氨酸和GABA能突触的光学和电生理分析来确定神经肽对哺乳动物大脑内细胞和突触生理的调制作用。我们首先将重点放在速激肽和阿片家族多肽的作用上，并希望最终包括加压素、催产素和其他神经肽。这些多肽的作用将在海马体和基底节进行检测，这是与人类疾病和行为相关的大脑区域，也是实验室熟悉的区域。总而言之，我们将使用创新的方法来研究神经生理学的基本和相对未被探索的方面。这些研究将促进我们对哺乳动物大脑的基本了解，并开始为最终了解扰乱的肽能信号对神经系统疾病的贡献奠定必要的基础。与公共健康相关：哺乳动物大脑中的神经元使用肽来发送信号并调节大脑功能。尽管这些“神经肽”信号系统的扰动导致了人类的神经和精神疾病，但它们如何调节神经元功能在很大程度上是未知的。在这里，我们建议开发工具来快速激活神经肽信号系统，并利用这些工具来了解神经肽如何调节哺乳动物大脑中的神经元和突触。

DESCRIPTION (provided by applicant): The experience-dependent modification of synapses in the brain is thought to underlie the ability of animals to learn new behaviors and form memories. A great deal is known about the mechanisms that regulate synapses that signal via fast, classical neurotransmitters such as glutamate and GABA. However, the brain also contains a diverse and wide-spread system of synapses that signal through the release of short peptides called neuropeptides. Despite the importance of neuropeptides and neuropeptide receptors in modulating mammalian behavior and their known role in the pathogenesis of human disease, relatively little is known at a cellular level about the physiological consequences of peptidergic signaling. Similarly, neither the stimuli that trigger neuropeptide release nor its modulatory effects on classical synaptic transmission in the mammalian brain are well understood. We propose that neuropeptides rapidly regulate neurons and synapses with high temporal and spatial precision. We will examine this hypothesis using novel tools that allow the precisely-timed and spatially-delimited delivery of neuropeptides within brain tissue. We will use this approach in conjunction with optical and electrophysiological analysis of glutamatergic and GABAergic synapses to determine the modulatory effects of neuropeptides on cellular and synaptic physiology within the mammalian brain. We will initially focus on the actions of Tachykinin and Opioid family peptides and hope to eventually include Vasopressin, Oxytocin, and other neuropeptides. The action of these peptides will be examined in the hippocampus and basal ganglia, brain regions that have established relevance in human disease and behavior and with which the laboratory is familiar. In summary, we will use innovative approaches to study fundamental and relatively unexplored aspects of neurophysiology. These studies will advance our basic understanding of the mammalian brain and begin to lay the groundwork necessary to eventually understand the contribution of perturbed peptidergic signaling to neurological diseases. PUBLIC HEALTH RELEVANCE: Neurons in the mammalian brain use peptides to send signals and modulate brain function. Although perturbations of these "neuropeptide" signaling systems contribute to human neurological and psychiatric diseases, how they regulate neuron function is largely unknown. Here we propose to generate tools to rapidly activate neuropeptide signaling systems and to use these to understand how neuropeptides regulate neurons and synapses in the mammalian brain.