The broad objective of this proposal is to investigate the brain-region-specific role of the neuronal gap- junction protein, connexin 36 (Cx36), in the regulation of sleep-wake behavioral state- and stimulus-specific cortical oscillations. Gap junction coupling leads to the formation of electrical synapses which promote neuronal synchronization; influencing network-wide oscillations which are likely involved in sensory and cognitive functions. Aberrant oscillatory activity and network connectivity underlie a wide range of sleep disorders, and neurological/neuropsychiatric disorders. The thalamic reticular nucleus (TRN) is a key component of cortico-thalamic circuitry and is critical for regulation of cortical oscillatory activity associated with sleep/wake state and sensory processing. GABAergic neurons of the TRN work in concert to control the activity of thalamic relay neurons, influencing cortical oscillatory activity. A key feature of the TRN is that local inter-neuronal communication occurs exclusively via Cx36 containing electrical synapses. While the functional contributions of various receptors and ion channels in TRN have been widely studied in association with its role in thalamocortical activity, the role of electrical synapses and gap junction proteins is underexplored. Our preliminary findings along with prior studies have shown that disruption of Cx36 globally can impair the synchronization of neural rhythms. However, the role of Cx36 electrical synapses specifically in the TRN has yet to be examined. The TRN regulates cortical oscillatory activity in delta (0.5-4 Hz), sigma (10-15 Hz; sleep spindles) range during sleep, and gamma (30-80 Hz) during wakefulness and wake-associated sensory processes. Therefore, investigating the importance of Cx36 within TRN is key towards understanding how the TRN neurons communicate locally to coordinate modulation of distal cortical oscillatory activity. Here we propose to test the hypothesis that the TRN electrical synapses containing Cx36 are essential for modulation of cortical network dynamics. Towards this goal, we propose to use the state-of-the-art, highly efficient gene editing technique, clustered regularly interspaced short palindromic repeats (CRISPR) - and its associated protein - Cas9, to knockdown the Cx36 protein, in vivo, specifically in parvalbumin positive neurons of the TRN. Utilizing this model, we will examine the role of the TRN-specific Cx36 expression on 1) cortical oscillatory activity associated with sleep and wakefulness, and 2) regulation of sensory processing via alteration of functional connectivity between first order and higher order regions of the cortex. 3) Finally, we will rescue the deficits caused by Cx36KO by reintroducing Cx36 gene in parvalbumin neurons of the TRN. Successful completion of the proposed studies will provide insight into the TRN- a uniquely composed brain structure and GABAergic nucleus where gap-junction proteins are predominantly responsible ...