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

项目摘要/摘要 神经系统的一个基本属性是对它们重新获得的信号做出功能适应的能力。 收下吧。尽管使用现有的方法已经学到了很多，但神经回路研究的一个主要限制是 需要分割大脑，破坏大部分网络，并将其与感觉输入或行为分离 产出。哺乳动物的昼夜节律系统，包括下丘脑视交叉上核(SCN)，就是这样一种循环。 Cuit，其独特之处在于，它代表了定义明确的细胞群体，这些细胞参与了代表整个 神经系统：网络直接受到易于操纵的感觉输入的影响，处理这种输入以 改变其功能，并生成直接影响行为的输出。我们研究计划的总体目标是-- 了解大脑如何处理感觉光输入，将其整合到正在进行的昼夜节律行为/调节中 程序，并生成调节行为和生理活动的输出。我们认为，这是一个涉及到 分级可塑性，即眼睛中的感觉神经元影响初级振荡器神经元的内部时钟时间， 然后，它们作用于大脑中的第二和第三系统，改变整体生理和睡眠/醒来的时间。 通过使用微型显微镜进行体内广域荧光成像，这个昼夜节律神经网络现在可以 在对环境输入、目标导向行为和异常功能的反应过程中实时观察。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(秒-分钟)内应用 和长时间(几周到几个月)的时间尺度。我们的研究计划全面攻击了一系列重要的系统级别 以前无法解决的昼夜节律生物学特征：对系统输入的细胞类型特异性急性反应 (光)，响应该光输入而进行的网络级处理，以及这些机制如何开始 随着年龄增长而衰弱。这种对感觉输入的分层处理的研究，导致了系统级的可塑性和行为- 在长时间尺度上的有性变化将有助于理解处于稳定状态和衰老的哺乳动物 神经系统作为一个整体。

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.