Visualizing hierarchical processing of photic input to the circadian clock in vivo

项目概要/摘要 神经系统的一个基本属性是功能适应的能力，以响应它们所接收的信号。 接受。尽管使用现有的方法已经学到了很多东西，但神经回路研究的一个主要限制是， 我们需要分割大脑，破坏大部分网络，并将其与感官输入或行为输入分离。 产出哺乳动物的昼夜节律系统，包括下丘脑视交叉上核（SCN），就是这样一个循环。 它的独特之处在于它代表了一个明确定义的细胞群，这些细胞参与了一整套功能，这些功能代表了整个 神经系统：网络直接受到容易操纵的感觉输入的影响，处理这些输入， 改变其功能，并产生直接影响行为的输出。我们研究项目的总体目标是： 了解大脑如何处理感觉光输入，将输入整合到正在进行的昼夜行为/调节中， 程序，并产生调节行为和生理活动的输出。我们认为这是一个过程， 分级可塑性，其中眼睛中的感觉神经元影响初级振荡神经元的内部时钟时间， 然后作用于大脑内的二级和三级系统，以改变整体生理学和睡眠/觉醒的时间。 通过使用小型化显微镜的体内宽视野荧光成像，现在可以将这种昼夜神经网络 在对环境输入、目标导向行为和异常功能的反应期间，在真实的时间内观察到。这个ap- proach提供了前所未有的解剖学和表型特异性，可以在短时间内（秒-分钟）应用 和长（周-月）的时间尺度。我们的研究计划全面攻击一系列重要的系统级 以前无法解决的昼夜节律生物学特征：细胞类型特异性对系统输入的急性反应 （光），响应于该光输入而发生的正在进行的网络级处理，以及这些机制如何开始 会随着年龄的增长而衰退这种对感觉输入的分级处理的研究，导致了系统水平的可塑性和非线性， 长期跟踪的口头变化将有助于理解哺乳动物的稳定状态和衰老 整个神经系统。

Project summary / Abstract A fundamental property of neural systems is the capability for functional adaptation in response to the signals they re- ceive. Though much has been learned using existing approaches, a major limitation in investigations of neural circuits has been the need to section the brain, destroying most of the network, and divorcing it from its sensory inputs or behavioral outputs. The mammalian circadian system, including the hypothalamic suprachiasmatic nucleus (SCN), is one such cir- cuit, unique in that represents a well-defined population of cells that engage in a full suite of functions that typify an entire nervous system: the network is affected directly by sensory input which is easily manipulated, processes such input to alter its function, and generates outputs that directly impact behavior. The overall goal of our research program is to un- derstand how the brain processes sensory light input, integrates that input into the ongoing circadian behavioral/regulatory program, and generates outputs that regulate behavior and physiological activity. We propose that it is a process involving hierarchical plasticity, where sensory neurons in the eyes affect the internal clock time of primary oscillator neurons, which then act on secondary and tertiary systems within the brain to alter global physiology and the timing of sleep/wake. With in vivo widefield fluorescence imaging using a miniaturized microscope, this circadian neural network can now be observed in real time during responses to environmental input, goal-directed behaviors, and abnormal function. This ap- proach provides unprecedented anatomical and phenotypic specificity and can be applied over short (seconds-minutes) and long (weeks-months) timescales. Our research program comprehensively attacks a range of important systems-level features of circadian biology which were previously not addressable: cell-type specific acute response to systemic input (light), the on-going network level processing that occurs in response to that light input, and how those mechanisms begin to fail with aging. Such studies of hierarchical processing of sensory input, leading to systems-level plasticity and behav- ioral change, followed over long timescales will pay dividends in understanding the steady-state and aging mammalian nervous system as a whole.