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

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 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.