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

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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.