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

nNOS 皮层神经元在慢波活动产生和认知中的作用

• 批准号: 8951701
• 负责人: DMITRY GERASHCHENKO
• 金额: $ 19.31万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951701
• 关键词: Acoustic Stimulation; Affect; Angelman Syndrome; Area; Brain; Cells; Cerebral cortex; Cognition; Cognition Disorders; Cognitive; Defect; Dendritic Spines; Designer Drugs; Development; Disease; Down Syndrome; Enzymes; Fragile X Syndrome; Functional disorder; Impaired cognition; Impairment; Knock-out; Knockout Mice; Learning; Link; Measures; Mediating; Memory; Memory impairment; Modeling; Mus; Neurodevelopmental Disorder; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Performance; Prefrontal Cortex; Procedures; Production; Protocols documentation; Regulation; Reporting; Research; Role; Schizophrenia; Sleep; Subfamily lentivirinae; Synapses; Testing; Virus; Wakefulness; base; cognitive function; information processing; knockout animal; memory consolidation; memory recognition; neocortical; neuronal circuitry; neuronal patterning; novel; object recognition; optogenetics; promoter; public health relevance; receptor; recombinase; research study

 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.

 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、振荡新皮质活动的电生理学特征。据报道，SWA 的变化在多种神经发育障碍中存在，例如天使综合征、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发育缺陷引起的。认知障碍与 SWA 之间的因果关系尚未确定，但很可能与突触水平的解剖和功能异常有关。涉及皮质区域的学习任务的执行会导致 SWA 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 背后的神经元整体动力学缺陷可能会导致学习功能障碍。大脑皮层神经元一氧化氮合酶 (nNOS) 细胞的活性与 SWA 相关，并且 nNOS 敲除小鼠中 SWA 的产生受到干扰。基于这些结果，我们假设皮层中的 nNOS 神经元回路是正常认知功能和 SWA 产生所必需的。根据我们的假设，睡眠期间皮质区域的 nNOS 细胞被激活，这些区域在清醒时参与信息的主动处理。这些 nNOS 细胞的激活会导致局部一氧化氮 (NO) 的产生，从而影响神经元活动的模式，从而增强 SWA 和记忆巩固。我们将通过在新的物体识别任务中测量 SWA 和记忆来测试这一假设，如下：1）激活 vmPFC 中表达 nNOS 的细胞，2）挽救 nNOS 敲除小鼠腹内侧前额叶皮层（vmPFC）中表达 nNOS 的细胞产生一氧化氮。这些研究将有助于更好地理解 SWA 产生和记忆巩固的机制，并有助于开发针对多种认知障碍的新疗法。