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Role of VIP-expressing SCN neurons in circadian physiology and behavior

表达 VIP 的 SCN 神经元在昼夜节律生理和行为中的作用

基本信息

批准号：
9115474
负责人：
Cristina Mazuski
金额：
$ 3.02万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9115474
关键词：
Action Potentials Acute Adult Aging Behavior Brain Cells Characteristics Circadian Rhythms Code Cues Data Environment Exhibits Experimental Designs Frequencies GABA Antagonists Gene Expression Hormones Individual Jet Lag Syndrome Light Measurement Measures Mediating Metabolism Monitor Moods Mus Neurons Neuropeptides Neurotransmitters Output Pattern Phase Physiologic pulse Physiology Population Regulation Research Role Signal Pathway Signal Transduction Sleep Slice System Testing Time Transgenic Mice Vasoactive Intestinal Peptide base circadian pacemaker gamma-Aminobutyric Acid in vivo insight multi-electrode arrays nervous system disorder neurotransmission neurotransmitter release normal aging optogenetics protein expression public health relevance relating to nervous system selective expression shift work suprachiasmatic nucleus

项目摘要

DESCRIPTION (provided by applicant): The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in the mammalian brain. It generates robust circadian behaviors, entrained to environmental cues such as light input. To date, little is known about how firing from SCN neurons integrates input and generates coherent output rhythms in circadian behaviors such as wake/sleep, hormone levels, metabolism, and mood. The SCN is composed of various populations of genetically distinct neurons including vasoactive intestinal polypeptide (VIP) - expressing neurons. This proposal aims to understand how the neural code from VIP-expressing neurons of the SCN alters firing rate, circadian gene expression and locomotor behavior. I will identify the neural code of VIP SCN neurons and use optogenetic and pharmacological manipulations to test the role of distinct neurotransmitter signaling pathways. Specifically, I will identify characteristic VIP firing patterns during early subjective day (Aim I. Using these patterns, I can stimulate VIP neurons and test changes in SCN firing activity (Aim II), circadian gene expression (Aim III) and locomotor behavior (Aim IV). In addition, the use of pharmacological antagonists will allow me to parse out the role of VIP and GABA in these dual-transmitter expressing neurons. My preliminary data establishes the feasibility of these approaches; I demonstrated that ChR2 can be selectively expressed within VIP SCN neurons, stimulation can generate action potentials at physiologically relevant frequencies, and 15Hz 30min stimulation may cause decreases in gene expression synchrony and fragmentation of locomotor behavior. Overall, this proposal expands on my current research by answering key questions about how the endogenous neural code in VIP neurons sustains circadian synchrony and output. This is an important proposal because the results can help understand circadian disruption associated with neurological disorders, aging, and jet lag.

描述(申请人提供)：视交叉上核(SCN)是哺乳动物大脑中主要的昼夜节律起搏器。它产生强大的昼夜节律行为，与环境线索有关，如光输入。到目前为止，关于SCN神经元的放电如何整合输入并在昼夜行为中产生一致的输出节奏，如觉醒/睡眠、激素水平、新陈代谢和情绪，人们知之甚少。SCN由多种不同遗传特征的神经元组成，其中包括表达血管活性肠多肽(VIP)的神经元。这一建议旨在了解来自SCN中VIP表达神经元的神经密码如何改变放电频率、昼夜基因表达和运动行为。我将确定VIP SCN神经元的神经密码，并使用光遗传学和药物操作来测试不同的神经递质信号通路的作用。具体地说，我将确定主观一天早期的VIP放电模式(目标I)。利用这些模式，我可以刺激VIP神经元，并测试SCN放电活动(AIM II)、昼夜节律基因表达(AIM III)和运动行为(AIM IV)的变化。此外，使用药理拮抗剂将使我能够解析VIP和GABA在这些双递质表达神经元中的作用。我的初步数据证实了这些方法的可行性；我证明了ChR2可以在VIP SCN神经元中选择性地表达，刺激可以产生生理相关频率的动作电位，15赫兹30分钟刺激可能会导致基因表达同步性降低和运动行为的碎片化。总体而言，这项建议通过回答有关VIP神经元中的内源性神经代码如何维持昼夜同步和输出的关键问题，扩展了我目前的研究。这是一项重要的建议，因为研究结果可以帮助理解与神经疾病、衰老和时差相关的昼夜节律紊乱。