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属性。脑电(EEG)在1-4赫兹频率范围内的同步性，称为慢波活动(SWA)，是在慢波睡眠中观察到的，被认为是睡眠恢复功能所必需的。我们实验室最近的工作发现，在三种哺乳动物中，SWA的变化与皮质神经元型一氧化氮合酶(NNOS)免疫反应细胞的活性变化是平行的。这些结果表明，皮层中的nNOS神经元是参与SWA产生的大脑回路的一部分。由于SWA是稳态睡眠驱动的既定标记物，nNOS神经元回路有望被稳态机制激活。这些研究将检验以下假设：(1)皮层nNOS细胞活性的变化与SWA相关；(2)皮层nNOS细胞活性的变化与视交叉上核的昼夜输入无关；(3)nNOS细胞的解剖特性与这些神经元在脑电同步中的作用一致；(4)nNOS产生的一氧化氮参与SWA的产生；(5)选择性消融nNOS细胞导致SWA的产生和睡眠稳态的紊乱。这项研究将是鉴定新发现的大脑皮层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，并可能不仅促进我们对睡眠障碍的病理生理学的理解，而且还可能促进我们对涉及大脑皮层的神经和精神疾病的理解。 与公共健康相关：最近在大脑皮层发现的睡眠活跃神经元的作用的研究将提供关于大脑活动调节的新信息。对这些神经元的功能和机制的了解可能会导致治疗涉及大脑皮层的各种神经和精神疾病的新方法，以及改善常见的睡眠障碍。

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.