Integration of sleep/wake network models across multiple temporal and spatial sca

描述（由申请人提供）：哺乳动物的睡眠在多个时间和空间尺度上受到调节。最近的实验发现揭示了脑干和下丘脑中神经元睡眠/觉醒控制系统在毫秒时间尺度上的重要性，这些系统影响生物体在小时时间尺度上的行为。这些系统包括相互抑制的促进睡眠和促进觉醒的核，它们共同构成“睡眠/觉醒开关”。有人提出，这种开关的输入，包括位于哺乳动物下丘脑视交叉上核（SCN）的主昼夜节律起搏器的输出，以及睡眠稳态过程产生了观察到的睡眠/觉醒周期。这种睡眠/觉醒开关理论已经成为理解一些睡眠障碍的基础（例如，嗜睡症）和衰老对睡眠的影响。在过去的6年中，已经提出了几个不同空间尺度的数学模型，包括神经元群体水平的神经元质量模型和神经元网络水平的神经元网络模型。这些模型已被用于将行为表型与潜在的生理学联系起来，并测试我们对睡眠理论模型的假设。然而，现有的模型在空间和时间尺度上受到限制，使得无法研究多尺度相互作用，例如，慢性睡眠限制（长时间尺度）和睡眠片段（短时间尺度）之间的相互作用。此外，关于潜在生理学的空间和时间特性的模型假设尚未得到测试。数学模型已被证明在定义正常和异常的生理关系，以及在许多健康相关领域测试潜在的治疗方法方面很重要。因此，在空间和时间尺度上整合睡眠模型将提高对睡眠生理和病理生理的理解，并有助于设计干预措施。 为了实现睡眠模型在空间和时间尺度上的整合，我们将追求四个相互关联的目标。 (i)确定睡眠/觉醒开关的神经质量模型和神经元网络模型预测相同动态的条件。我们将开发现有神经质量模型的神经网络版本，并测试参数异质性，网络大小和网络连接性的影响。 (ii)为了测试由于睡眠/唤醒开关的噪声输入而导致睡眠在短时间尺度上固有地碎片化的假设。为了实现这一目标，我们将把噪声输入到神经质量和神经网络模型中，并将预测结果与来自住院协议的人类数据进行比较。 (iii)为了检验慢性睡眠限制对睡眠和表现的影响是由于睡眠/觉醒开关和腺苷受体的长时间尺度动力学之间的相互作用的假设。为了实现这一点，我们将在我们的两个模型中添加腺苷受体密度的长时间尺度动态; A1受体的上调被认为是观察到的睡眠和对慢性睡眠限制的表现反应的基础。模型预测将与来自慢性睡眠限制协议的人类数据进行比较。 (iv)睡眠/清醒转换模型预测，睡眠和清醒状态的稳定性应该随着睡眠/清醒转换的临近而降低。因此，睡眠/唤醒开关中的神经元的放电速率和电压的可变性应该在转换之前增加。我们将通过比较两种模型的预测与自由行为大鼠睡眠/觉醒转换核的体内多单元记录来测试这一预测。 我们的工作将：（i）开发一种标准化的方法来建模睡眠生理学。(ii)导致适用于更广泛领域的睡眠预测模型的发展，包括睡眠碎片和慢性睡眠限制。(iii)提供睡眠/觉醒开关理论的第一个直接定量测试。这些重要目标是相互关联的，但也可以独立实现。 菲利普斯博士在睡眠和昼夜节律数学建模方面的深厚背景为他提供了解决这个项目的理想专业知识。他还将得到他的导师Klerman博士的实验和数学专业知识的极大帮助，Klerman博士是哈佛医学院布里格姆妇女医院睡眠医学部（DSM）分析和建模部门的负责人。HMS丰富的研究环境为跨学科和合作项目提供了极其肥沃的土壤。 在这些研究计划的同时，我们还准备了一份详细的个人发展计划，以使菲利普斯博士能够建立新的技能，并顺利过渡到独立。菲利普斯博士的近期目标是（i）扩大他在计算神经科学方面的技能;（ii）接受生物统计学方面的重点培训;（iii）建立他在教学，指导，领导和组织方面的经验;以及（iv）在睡眠和昼夜节律研究领域产生高影响力的出版物。他计划在第（一）、（一）和（三）方面接受有重点的培训，这一点在提案中有所说明。拟议的研究计划还应导致高影响力的出版物，由于其创新的方法，及时性和重要性。这项研究和职业发展计划将建立在菲利普斯博士现有的研究和专业知识的基础上，并将为他作为一名独立研究人员的职业生涯开辟许多新的研究方向。拟议的项目将给予菲利普斯博士必要的保护时间进行研究，取得必要的经验，并学习必要的技能，以实现这些长期目标。

DESCRIPTION (provided by applicant): Sleep in mammals is regulated on multiple temporal and spatial scales. Recent experimental findings have revealed the importance of neuronal sleep/wake control systems in the brainstem and hypothalamus operating on the millisecond timescale that affect the organism's behavior on the hour timescale. These systems include mutually inhibitory sleep-promoting and wake-promoting nuclei that together comprise the "sleep/wake switch". It has been proposed that inputs to this switch, including the output of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the mammalian hypothalamus, and the sleep homeostatic process produce the observed sleep/wake cycles. This sleep/wake switch theory has become the basis for understanding some sleep disorders (e.g., narcolepsy) and the effects of aging on sleep. In the last 6 years, several mathematical models of this system have been proposed at different spatial scales, including neural mass (neuronal population level) and neuronal network (single neuron level) models. These models have been used for relating behavioral phenotypes to underlying physiology and testing assumptions about our theoretical models of sleep. However, the existing models are limited in their spatial and temporal scales, making it impossible to study multi-scale interactions, e.g., interactions between chronic sleep restriction (long timescale) and sleep fragmentation (short timescale). Moreover, model assumptions about the spatial and temporal properties of the underlying physiology have not been tested. Mathematical models have proven important in defining normal and abnormal physiological relationships, and testing potential treatments in many health- related areas. Therefore, integrating models of sleep across spatial and temporal scales will improve understanding of sleep physiology and pathophysiology, and be instrumental in designing interventions. To achieve integration of sleep models across spatial and temporal scales, we will pursue four linked goals. (i) To determine the conditions under which neural mass models and neuronal network models of the sleep/wake switch predict the same dynamics. We will develop a neuronal network version of our existing neural mass model and test the effects of parameter heterogeneity, network size, and network connectivity. (ii) To test the hypothesis that sleep is inherently fragmented on short timescales due to noisy input to the sleep/wake switch. To achieve this, we will incorporate noisy inputs into both neural mass and neuronal network models and compare predictions to human data from an inpatient protocol. (iii) To test the hypothesis that chronic sleep restriction effects on sleep and performance are due to an interaction between the sleep/wake switch and long timescale dynamics of adenosine receptors. To achieve this, we will add long timescale dynamics of adenosine receptor density to both of our models; up-regulation of A1 receptors has been proposed to underlie the observed sleep and performance responses to chronic sleep restriction. Model predictions will be compared to human data from a chronic sleep restriction protocol. (iv) Sleep/wake switch models predict that the stability of sleep and wake states should decrease as a sleep/wake transition approaches. Consequently, variability in firing rates and voltages of neurons in the sleep/wake switch should increase prior to a transition. We will test this prediction by comparing the predictions of both models to in vivo multi-unit recordings of the sleep/wake switch nuclei in freely behaving rats. Our work will: (i) Develop a standardized approach to modeling sleep physiology. (ii) Lead to the development of predictive models of sleep that are applicable to a wider range of domains, including sleep fragmentation and chronic sleep restriction. (iii) Provide the first direct quantitative test of the sleep/wake switch theory. These important goals are related but can also be achieved independently. Dr. Phillips' strong background in mathematical modeling of sleep and circadian rhythms provides him with the ideal expertise to tackle this project. He will also be greatly assisted by the experimental and mathematical expertise of his mentor, Dr. Klerman, who is head of the Analytic & Modeling Unit within the Division of Sleep Medicine (DSM) at Brigham & Women's Hospital, Harvard Medical School (HMS). The rich research environment at HMS provides extremely fertile ground for interdisciplinary and collaborative projects. In parallel with these research plans, we have prepared a detailed personal development plan to enable Dr. Phillips to build new skills and transition smoothly to independence. Dr. Phillips' immediate goals are to (i) expand his skills in computational neuroscience; (ii) receive focused training in biostatistics; (iii) build his experiece in teaching, mentorship, leadership, and organization; and (iv) produce high impact publications in the fields of sleep and circadian research. His plan to receive focused training in areas (i), (i), and (iii) is described in the proposal. The proposed research plan should also lead to high impact publications, due to its innovative approach, timeliness, and importance. This research and career development plan will build upon Dr. Phillips' existing research and expertise, and will open many new research directions for his career as an independent researcher. The proposed project will grant Dr. Phillips the necessary protected time to conduct research, achieve the necessary experience, and learn the requisite skills to achieve these long-term goals.