Regulation of neuron and synapse function by neuropeptides

描述（由申请人提供）：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能力的基础。通过谷氨酸和氨基丁酸等快速、经典的神经递质来调节突触的机制，我们已经知道了很多。然而，大脑也包含一个多样化和广泛分布的突触系统，通过释放被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中的重要性以及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传导的生理后果知之甚少。同样，无论是触发神经肽释放的刺激，还是其对哺乳动物大脑经典突触传递的调节作用，都没有得到很好的理解。我们认为神经肽对神经元和突触的快速调节具有较高的时间和空间精度。我们将使用新颖的工具来检验这一假设，这些工具允许在脑组织内精确定时和空间划分神经肽的递送。我们将使用这种方法结合谷氨酸能和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学的调节作用。我们将首先关注速激肽和阿片家族肽的作用，并希望最终包括抗利尿激素、催产素和其他神经肽。这些多肽的作用将在海马体和基底神经节中进行检查，这两个脑区已经与人类疾病和行为建立了相关性，并且实验室对此很熟悉。总之，我们将使用创新的方法来研究神经生理学的基础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，并开始为最终理解受干扰的肽能信号对神经系统疾病的贡献奠定必要的基础。公共卫生相关性：哺乳动物大脑中的神经元使用肽发送信号并调节大脑功能。虽然这些“神经肽”信号系统的扰动有助于人类神经和精神疾病，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，我们建议生成工具来快速激活神经肽信号系统，并利用这些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.