Neural mechanisms underlying circadian rhythms in behavior

行为昼夜节律的神经机制

基本信息

批准号：
9258619
负责人：
Anna King
金额：
$ 4.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258619
关键词：
ARNT gene Ablation Activity Cycles Address Aging Anatomy Behavior Behavior Control Behavioral Biological Assay Biological Clocks Biological Process Brain Brain imaging Brain region Cations Cells Circadian Rhythms Corticotropin-Releasing Hormone Data Disease susceptibility Drosophila genus Drosophila melanogaster Environment Functional disorder G-Protein-Coupled Receptors Genetic Genetic Transcription Goals Health Hour Human Hypothalamic structure Imaging Techniques Knowledge Ligands Link Measures Mediating Molecular Motor Activity Neuromedin U Neurons Neuropeptides Neurosecretory Systems Orthologous Gene Output Periodicity Physiology Potassium Channel Process RNA interference screen Reporter Reporting Research Rest Signal Transduction Site Sleep Wake Cycle System Testing Time Translating Work base behavior test circadian pacemaker experimental study fly in vivo in vivo imaging insight internal control knock-down mutant nervous system disorder neural circuit neuromechanism neuroregulation postsynaptic neurons presynaptic neurons receptor receptor binding relating to nervous system response sensor shift work therapeutic development tool vesicular release

项目摘要

Project Abstract The brain's circadian clock controls daily rhythms in physiology and behavior. Disruptions of circadian rhythms with shift work are associated with many human health problems. In addition, behavioral rhythms are often disrupted with aging and neurological disorders. Understanding the direct links between the circadian system and specific biological processes and behaviors will provide insights into disease susceptibility. In Drosophila melanogaster, we have a detailed understanding of the transcriptional oscillator mechanism and the specific neurons that are necessary for generating 24-hour behavioral rhythms. However, little is known about how circadian clocks communicate time-of-day information to output circuits controlling behaviors. Recent work showed that clock neurons project to neurons in the pars intercerebralis (PI), a brain region containing neurosecretory cells implicated in regulating various behaviors. PI neurons expressing DH44 neuropeptide are necessary for circadian rhythms of locomotor activity. In this proposal, I will leverage our knowledge of this circadian output circuit to understand the mechanisms by which timing signals are translated into behavioral rhythms. In Aim 1, I will identify a mechanistic basis for rhythmic output from Dh44 neurons. Since the Dh44 neurons and clock neurons have direct anatomical connections, I hypothesize that these connections provide a neural substrate that regulates the diurnal neural activity of Dh44 neurons and DH44 neuropeptide signaling. To address this, I will investigate how the circadian system regulates neural activity in and neuropeptide release from Dh44 neurons and the signaling ability of DH44 itself. By identifying a mechanism for rhythmic output at the level of DH44 signaling, we will gain insights into how this circuit encodes time-of-day information downstream of clock neurons. In Aim 2, I will determine the site of DH44 neuropeptide action. DH44 neuropeptide signals through its receptors, DH44-R1 and DH44-R2. Preliminary data show that Dh44-R1 is the receptor required for normal rest:activity rhythms. In Aim 2, I will identify the neurons where DH44-R1 is required. I will also establish functional connectivity between Dh44 and downstream neurons with in vivo imaging techniques. Together, the proposed experiments will elucidate the mechanisms by which DH44 neuropeptide signaling regulate a circadian output circuit controlling rest:activity rhythms.

项目摘要大脑的生物钟控制着生理和行为的日常节律。昼夜节律紊乱轮班工作节奏与许多人类健康问题有关。此外，行为节奏是经常因衰老和神经系统疾病而中断。了解昼夜节律之间的直接联系系统以及特定的生物过程和行为将提供对疾病易感性的见解。在果蝇，我们详细了解了转录振荡器机制并产生 24 小时行为节律所必需的特定神经元。然而，鲜为人知关于生物钟如何将一天中的时间信息传递给控制行为的输出电路。最近的研究表明，时钟神经元投射到大脑间部 (PI) 的神经元，这是一个大脑区域含有参与调节各种行为的神经分泌细胞。表达 DH44 的 PI 神经元神经肽对于运动活动的昼夜节律是必需的。在这个提案中，我将利用我们的了解该昼夜节律输出电路，以了解定时信号转换的机制进入行为节奏。在目标 1 中，我将确定 Dh44 神经元节律输出的机制基础。由于 Dh44 神经元并且时钟神经元具有直接的解剖学连接，我假设这些连接提供了神经元调节 Dh44 神经元和 DH44 神经肽信号传导的昼夜神经活动的底物。到为了解决这个问题，我将研究昼夜节律系统如何调节神经活动和神经肽释放来自 Dh44 神经元和 DH44 本身的信号传导能力。通过识别有节奏的输出机制 DH44 信号水平，我们将深入了解该电路如何编码时间信息时钟神经元的下游。在目标 2 中，我将确定 DH44 神经肽的作用位点。 DH44 神经肽通过其信号受体，DH44-R1 和 DH44-R2。初步数据显示Dh44-R1是正常细胞所需的受体休息：活动节奏。在目标 2 中，我将识别需要 DH44-R1 的神经元。我还将建立通过体内成像技术，Dh44 和下游神经元之间的功能连接。在一起，拟议的实验将阐明 DH44 神经肽信号传导调节的机制昼夜节律输出电路控制休息：活动节律。