DESCRIPTION (provided by applicant): The broad objective of this research program is to use a mouse model to understand the cellular mechanisms underlying alterations in sleep spindles in schizophrenia (Sz), a disease which is highly prevalent in the VA and which consumes ~40 % of the VA mental healthcare budget. Recent studies in Sz patients have provided consistent evidence for abnormalities in the number and intrinsic frequency of sleep spindles, a waxing and waning electroencephalographic (EEG) pattern observed during light non-REM (NREM) sleep. However, human studies are limited in their ability to decipher the underlying cellular mechanisms. Thus, here we propose to use state-of-the-art optogenetic techniques in mice to investigate the underlying neurobiology. Previous basic science work suggested that sleep spindles require the activity of GABAergic neurons in the thalamic reticular nucleus (TRN), most of which contain the calcium binding protein, parvalbumin (PV). Postmortem findings in Sz indicate reductions in the activity of cortical GABAergic neurons containing PV. Since TRN PV neurons are derived from the same developmental pathway, a plausible and so far untested hypothesis is that sleep spindle abnormalities are due to downregulation of the activity of TRN PV neurons. Recent studies in Sz patients using the hypnotic, eszopiclone, which targets the a3-subunit-containing GABAA receptors expressed by TRN neurons, ameliorates sleep & sleep spindle abnormalities and improves memory consolidation. Thus, if successful, our experiments in mice could lead to novel therapies to correct Sz spindle abnormalities based on the manipulation of the activity of TRN PV neurons and thereby improve cognition, a core impairment in Sz. Our experiments have specific predictions that shed light on the role of TRN PV neurons in the cellular mechanisms of spindles. We test the effect on TRN PV neurons and cortical EEG using optogenetic stimulation with Channelrhodopsin2 (ChR2) (gain of function for spindles and NREM sleep) and inhibition using the proton pump ArchT (loss of function for spindles and NREM sleep). Experiments in Specific Aim (SA) 1 will test if bilateral ChR2 stimulation will elici sleep spindles and increase NREM sleep, thereby also reducing auditory sensory transmission during NREM episodes. Unit recordings will show identified TRN PV neurons will fire in bursts associated with spindles. Experiments in SA 2 will test if bilateral optical inhibition of TRN PV neurons will reduce spindles and NREM sleep, modeling spindle abnormalities in Sz. Experiments in SA 3 will investigate an important and so far poorly investigated input pathway to TRN, arising in the basal forebrain. We will test if optical excitation of the basal forebrain GABA/PV input to TRN will reduce sleep spindles in vivo and inhibit TRN PV neurons in vitro, thereby testing the functional role of this anatomically documented pathway, with predicted inhibition ...