Role of nNOS cortical neurons in slow wave activity production and cognition

 描述（由申请人提供）：脑电图慢波活动（SWA）是缓慢（0.5至4.0 Hz）、同步、振荡新皮层活动的电生理特征。SWA的变化已在广泛的神经发育障碍中报道，如Angelman综合征、唐氏综合征、脆性X综合征和精神分裂症。这些疾病被认为是由大脑连接的发育缺陷引起的。认知障碍和SWA之间的因果关系尚未建立，但它可能与突触水平的解剖和功能异常有关。涉及皮层区域的学习任务的执行产生SWA的局部增加，并且与学习后树突棘的分支特异性形成相关。因此，SWA背后的神经元系综动力学缺陷可能导致学习功能障碍。大脑皮层神经元型一氧化氮合酶（nNOS）细胞的活性与SWA相关，并且在nNOS敲除小鼠中SWA的产生受到干扰。基于这些结果，我们假设，nNOS神经元回路在皮层所需的正常认知功能和SWA生产。根据我们的假设，nNOS细胞在睡眠过程中被激活，在清醒时参与主动处理信息的皮层区域。这些nNOS细胞的激活导致局部一氧化氮（NO）产生，这影响神经元活动的模式，导致增强的SWA和记忆巩固。我们将通过测量新物体识别任务中的SWA和记忆来验证这一假设，该任务如下：1）在vmPFC中激活nNOS表达细胞，2）在nNOS敲除小鼠中挽救腹内侧前额叶皮层（vmPFC）中nNOS表达细胞的一氧化氮产生。这些研究将有助于更好地理解SWA产生和记忆巩固的机制，并有助于开发各种认知障碍的新治疗方法。

 DESCRIPTION (provided by applicant): Electroencephalographic slow-wave activity (SWA) is an electrophysiological signature of slow (0.5 to 4.0 Hz), synchronized, oscillatory neocortical activity. Changes in SWA have been reported in a wide range of neurodevelopmental disorders, such as Angelman syndrome, Down syndrome, fragile-X syndrome, and schizophrenia. These disorders are believed to be caused by developmental defects in brain connectivity. The causal link between cognitive impairments and SWA has not been established yet, but it is likely to be related to anatomical and functional abnormalities at the synapse level. Performance of learning tasks involving the cortical regions produces a local increase in SWA and is associated with branch-specific formation of dendritic spines after learning. Therefore, defects in the neuronal ensemble dynamics that underlie SWA could result in learning dysfunctions. Activity of neuronal nitric oxide synthase (nNOS) cells in the cerebral cortex correlates with SWA, and SWA production is disturbed in nNOS knockout mice. Based on these results, we hypothesize that nNOS neuronal circuits in the cortex are required for both normal cognitive functions and SWA production. According to our hypothesis, nNOS cells become activated during sleep in the cortical regions that have been involved in active processing of information during wakefulness. The activation of these nNOS cells leads to local nitric oxide (NO) production, which affects the pattern of neuronal activity, resulting in enhanced SWA and memory consolidation. We will test this hypothesis by measuring SWA and memory in the novel object recognition task following 1) the activation of nNOS-expressing cells in the vmPFC and 2) rescuing the nitric oxide production by nNOS-expressing cells in the ventromedial prefrontal cortex (vmPFC) in nNOS knockout mice. These studies will contribute to better understanding of the mechanisms of SWA production and memory consolidation and help to develop new treatments in a wide range of cognitive disorders.