Fractal Regulatory Function of the Circadian System

描述（由申请人提供）：现代生理学中最令人困惑的现象之一是在广泛的生理系统中存在分形图案（即，波动的结构在不同的时间尺度上是相似的或不可区分的）。分形控制的生理重要性在许多研究中得到证明，并通过随着年龄增长和病理条件下的分形心脏和活动控制减少来举例说明，最重要的是，通过减少分形心脏控制对生存率降低的预测值。分形生理学似乎赋予了一些适应性优势，在这种情况下，分形模式的存在挑战了传统的保持生理恒定的内稳态理论。尽管这种分形现象的明显重要性，迄今为止，还没有建立在任何神经或生理系统的分形控制的基本机制。PI最近的研究表明，内源性昼夜节律系统在多个时间尺度上对运动活动的分形控制至关重要。该提案将正式评估生理意义和昼夜节律系统的分形调节功能的神经生物学基础。主要目标是识别昼夜节律系统赋予分形活动控制的神经元节点和通路。为了补充PI在分形生理学方面的既定专业知识，该提案概述了在这些领域三位备受推崇的科学家的监督下，在昼夜节律生物学，人类生理学/病理学，神经生物学，系统生物学方面进行两年的多学科培训。培训将使PI获得必要的技能，在昼夜节律生物学和分形生理学的跨学科领域的可持续和多产的职业生涯。随后三年的独立研究阶段将使PI实现主要研究目标，并帮助PI成为该领域的独立研究人员。具体目标是：1）确定中枢昼夜节律系统的变化对分形活动控制的影响; 2）确定昼夜节律失调对分形活动控制的影响; 3）识别和验证活动控制网络中的神经元节点及其相互作用，这些节点有助于分形活动控制。实现这些目标将为分形控制的第一个模型提供神经生理学基础。更好地了解神经回路参与昼夜节律和活动调节应该提供有用的指导，以改善诊断和治疗昼夜节律相关的睡眠和行为障碍。 公共卫生相关性：该项目旨在了解导致活动分形模式的神经生理机制（即，为什么活动波动的结构在不同的时间尺度上是不可区分的）。更好地了解参与活动调节的神经元回路应该为改善昼夜节律相关的睡眠和行为障碍的诊断和治疗提供有用的指导。

DESCRIPTION (provided by applicant): One of the most puzzling phenomena in modern physiology is the existence of fractal patterns in a wide range of physiological systems (i.e., the structure of fluctuations are similar or indistinguishable at different time scales). The physiological importance of fractal control is demonstrated in numerous studies and exemplified by reduced fractal cardiac and activity controls with aging and under pathological conditions, and most importantly, by the predictive value of reduced fractal cardiac control for decreased survival. Fractal physiology appears to impart some adaptive advantage, and in this context, the existence of fractal patterns challenges the traditional theory of homeostasis of maintaining physiologic constancy. Despite the clear importance of this fractal phenomenon, to date, no underlying mechanism has been established for fractal control in any neural or physiological system. The PI's recent studies indicate that the endogenous circadian system is critically involved in the fractal control of motor activity at multiple time scales. The proposal will formally assess the physiological significance and the neurobiological basis of the fractal regulatory function of the circadian system. The primary goal is to identify the neuronal nodes and pathways through which the circadian system imparts fractal activity control. To complement the PI's established expertise in fractal physiology, the proposal outlines two years of multidisciplinary training in circadian biology, human physiology/pathology, neurobiology, system biology under supervision of three highly regarded scientists in these fields. The training will enable the PI to acquire the requisite skills necessary for a sustainable and prolific career in the interdisciplinary field of circadian biology and fractal physiology. The subsequent three years of the independent research phase will allow the PI to achieve the main research goal and help establish the PI as an independent researcher in the field. The specific aims are 1) to determine the effects of changes in the central circadian system on fractal activity control; 2) to determine the effects of circadian misalignment on fractal activity control; and 3) to identify and validate neuronal node(s) in the activity control network and their interactions that contribute to fractal activity control. Achieving these aims will provide the neurophysiologic basis for the first model of fractal control. Better understanding of the neuronal circuitry involving in circadian and activity regulation ought to provide useful guidance for improved diagnosis and treatment of circadian-related sleep and behavioral disturbances. PUBLIC HEALTH RELEVANCE: This project is aimed at understanding the neurophysiological mechanisms causing fractal patterns of activity (i.e., why the structure of activity fluctuations are indistinguishable at different time scales). Better understanding of the neuronal circuitry involving in activity regulation ought to provide useful guidance for improved diagnosis and treatment of circadian-related sleep and behavioral disturbances.