Role of cortical interneurons in synchronization of brain electroencephalogram

描述（由申请人提供）：大脑区域内和跨区域的神经元活动同步是正常大脑功能所需的皮层和皮层下网络的基本特性。脑电图（EEG）在1-4赫兹的频率范围内的同步，被称为慢波活动（SWA），在慢波睡眠期间被观察到，被认为对睡眠的恢复功能至关重要。我们实验室最近的工作发现，在三种哺乳动物物种中，SWA的变化与神经元一氧化氮合酶（nNOS）免疫反应细胞活性的变化是平行的。这些结果表明，皮层中的nNOS神经元是参与SWA生成的脑回路的一部分。由于SWA是体内平衡睡眠驱动的标志，nNOS神经元回路被体内平衡机制激活。拟议的研究将检验以下假设：(1)活动的变化nNOS细胞皮层与SWA, (2) nNOS皮层细胞的活性的变化独立于生理输入从视交叉上核,(3)解剖nNOS细胞的性质是一致的与脑电图同步,这些神经元的作用(4)一氧化氮产量nNOS参与SWA一代,和(5)的选择性消融nNOS细胞导致干扰SWA生产和睡眠体内平衡。这项研究将是表征大脑皮层中新发现的睡眠活跃神经元的第一步。它将提供关于nNOS神经元调节大脑活动的重要信息，不仅可以促进我们对睡眠障碍的病理生理学的理解，还可以促进我们对涉及大脑皮层的神经和精神疾病的理解。

DESCRIPTION (provided by applicant): Synchronization of neuronal activity within and across brain regions is a fundamental property of cortical and subcortical networks needed for normal brain functions. Synchronization of electroencephalogram (EEG) in the frequency range of 1-4 Hz, referred to as slow wave activity (SWA), is observed during slow wave sleep and is thought to be essential for the recuperative function of sleep. Recent work in our laboratory found that changes in SWA parallel the changes in the activity of neuronal nitric oxide synthase (nNOS)-immunoreactive cells in the cortex in three mammalian species. These results suggest that nNOS neurons in the cortex are part of the brain circuit that is involved in the generation of SWA. Since SWA is an established marker of the homeostatic sleep drive, the nNOS neuronal circuit is expected to be activated by homeostatic mechanisms. The proposed studies will test the following hypotheses: (1) changes in the activity of nNOS cells in the cortex correlate with SWA, (2) changes in the activity of nNOS cells in the cortex are independent of circadian input from the suprachiasmatic nucleus, (3) anatomical properties of nNOS cells are consistent with the role of these neurons in EEG synchronization, (4) nitric oxide production by nNOS is involved in SWA generation, and (5) selective ablation of nNOS cells leads to disturbances in SWA production and sleep homeostasis. This research will be a first step in characterizing newly discovered sleep-active neurons in the cortex. It will provide important information about regulation of brain activity by nNOS neurons and may advance our understanding not only of the pathophysiology of sleep disorders, but also of neurological and psychiatric diseases that involve the cerebral cortex. PUBLIC HEALTH RELEVANCE: Research on the role of sleep-active neurons recently discovered in the cerebral cortex will provide new information about regulation of brain activity. An understanding of the functions and mechanisms of these neurons may lead to new approaches for treating a variety of neurological and psychiatric diseases involving the cerebral cortex, as well as for ameliorating common sleep disorders.