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MECHANISMS OF CIRCADIAN CLOCK OUTPUT

昼夜节律时钟输出机制

基本信息

批准号：
10322450
负责人：
Paul H Taghert
金额：
$ 29.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322450
关键词：
Activity Cycles Address Behavior Behavioral Brain Brain imaging Brain scan C-terminal Calcium Cause of Death Cell Communication Cells Complex Data Analyses Disease Drosophila genus Elements Exhibits Foundations Frequencies Genes Genetic Goals Heart Arrest Image In Vitro Individual Jet Lag Syndrome Learning Lighting Link Locomotion Maps Mediating Methods Modernization Modification Molecular Nature Neuronal Plasticity Neurons Neuropeptides Neurosciences Organ Output Pacemakers Pattern Periodicity Personal Satisfaction Phase Phosphorylation Site Physiological Physiology Positioning Attribute Property Psyche structure Publishing Receptor Signaling Regulation Research Research Proposals Rest Sampling Scanning Signal Transduction Sleep Stroke Structure System Testing Time Variant Work brain behavior circadian circadian biology circadian pacemaker fly genetic regulatory protein in vivo infancy innovation interest neural circuit neuronal circuitry neuronal patterning nodal myocyte programs promoter receptor relating to nervous system shift work theories

项目摘要

In this proposal, I outline a set of three related yet independent studies of circadian neural output. Recent advances in imaging and data analysis capture information regarding network phenomena with increasing spatial and temporal precision. The circadian pacemaker system we study is advantageous in that it produces physiological activity both spontaneously and rhythmically. In the previous cycle, we used planar illumination methods to perform 24 hr in vivo brain-wide scans of the circadian neural circuit. That work introduced a new concept to theories of how the circadian network encodes time: we showed that the molecularly synchronous pacemaker network displays sequential activation by different identified pacemaker groups across the day. Further we found pacemaker cell interactions, in the form of neuropeptide-mediated delay, represents a key mechanism to effect sequential pacemaker activation. The scientific premise for this project rests on the need to extend those observations on circadian pacemaker neuronal plasticity and to understand how these activity patterns are transmitted to downstream centers. Here I propose work that continues real-time in vivo studies of neuronal activity patterns for the core Drosophila circadian pacemaker neurons. It also continues the focused analysis of neuropeptide modulatory mechanisms that critically regulate the specific timing of pacemaker activity. To extend the scope of our initial studies, and to provide a better understanding of neuronal properties of pacemakers and pacemaking networks, this program will pursue three Aims. Aim 1 will better define daily Ca2+ dynamics in pacemakers by (i) performing in-depth, high frequency sampling, and (ii) by determining the sub-cellular mechanisms underlying these fluctuations. Aim 2 will pursue a Structure-Function analysis of the PDF receptor (PDFR), especially its C-terminus, to understand the regulatory mechanisms that control the quantitative extent of daily PDF signaling. It also seeks to identify key PDFR regulatory proteins. Aim 3 seeks to extend the scope of our work beyond the circadian pacemaker network to identify downstream circuit elements: we will focus on subsets of neurons in the Central Complex for which preliminary evidence suggests an involvement in daily rhythmic physiology associated with locomotion. Jet-lag, shift-work and disturbances in sleep-activity cycles all contribute to degrade mental and physical well-being. Two major causes of death (stroke and cardiac arrest) display clear time- of-day variation, yet, we have little understanding of the causal links between circadian clock functions and disease mechanisms. This research program is dedicated to a better understanding of fundamental circadian output mechanisms.

在这一建议中，我概述了一组三个相关但独立的昼夜神经研究