Role of cortical interneurons in synchronization of brain electroencephalogram

描述（由申请人提供）：大脑区域内和跨大脑区域的神经元活动的同步是正常大脑功能所需的皮质和皮质下网络的基本特性。在慢波睡眠期间观察到1-4 Hz频率范围内的脑电图（EEG）同步，称为慢波活动（SWA），并且认为这对于睡眠的恢复功能是必不可少的。 我们实验室最近的工作发现，SWA的变化平行的神经元型一氧化氮合酶（nNOS）的免疫反应细胞在三种哺乳动物的皮质中的活性的变化。这些结果表明，皮质中的nNOS神经元是参与SWA生成的脑回路的一部分。由于SWA是稳态睡眠驱动的既定标志物，因此预期nNOS神经元回路通过稳态机制激活。 拟议的研究将检验以下假设：（1）皮层中nNOS细胞活性的变化与SWA相关，（2）皮层中nNOS细胞活性的变化与来自视交叉上核的昼夜节律输入无关，（3）nNOS细胞的解剖学特性与这些神经元在EEG同步化中的作用一致，（4）nNOS产生的一氧化氮参与SWA的产生，（5）nNOS细胞的选择性消融导致SWA产生和睡眠稳态的紊乱。 这项研究将是表征新发现的大脑皮层睡眠活跃神经元的第一步。它将提供有关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。 公共卫生相关性：最近在大脑皮层中发现的睡眠活跃神经元的作用研究将为大脑活动的调节提供新的信息。了解这些神经元的功能和机制可能会导致治疗各种涉及大脑皮层的神经和精神疾病以及改善常见睡眠障碍的新方法。

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.