During wakefulness, the cortical electroencephalogram (EEG) is characterized by low voltage, high-frequency rhythms reflecting active brain processing. In particular, gamma band oscillations (GBO;30-80 Hz or broader, centered on 40 Hz) have been hypothesized to be important in cognition through synchronization of neural assemblies and by providing a temporal framework for spike time-dependent synaptic plasticity. Work from the clinical section of our laboratory and from others has demonstrated GBO abnormalities in prefrontal and primary auditory cortices in schizophrenic patients. Furthermore, GBO deficits are a prominent feature of autism, sleep disorders, coma, and Alzheimers disease. However, relatively little is known about the subcortical control of GBO. Basic science work during previous funding cycles of this grant has focused on one important subcortical region, the basal forebrain (BF), and its control of wakefulness, cortical activation and sleep homeostasis. In particular, we recently found that selective optogenetic stimulation of a particular cell type, BF cortically-projecting, parvalbumin (PV) neurons entrained cortical GBO whereas inhibition impaired GBO and cognition. Thus, the overarching hypothesis to be tested is that BF PV cortically-projecting neurons enhance cortical GBO and cognition, an investigation topic that we see as novel. In this revised application for 4 years of support, each of the specific aims (SA) testing the overarching hypothesis in mice is buttressed by extensive new Preliminary Data. SA1 directly tests the hypothesized role of BF PV neurons in cortical GBO by optogenetic excitation (Channelrhodopsin) and inhibition (ArchT) experiments. SA1 also uses optogenetic excitation combined with unit recording to identify BF PV neurons and their firing patterns in relation to the cortical GBO and behavioral state. We will also determine the spatial topography of cortical activation produced by BF PV excitation using novel high-density EEG recordings. SA2 investigates a molecular mechanism which may enhance cortical GBO during wakefulness, namely, an activity-dependent upregulation of connexin36 proteins which mediate electrical coupling between PV neurons. SA3 will determine the relationship between GBO and behavior by using a simple behavioral task requiring attention, the novel object recognition task. We will determine the effect of sleep deprivation (SD) on GBO and behavior and also test if the inhibition of BF PV neurons will impair cortical GBO and behavioral performance, thus mimicking the effects of SD. The experiments here will use integrated state-of-the-art in vitro, in vivo and behavioral methods to provide optimal understanding of the molecular, cellular and brain connectivity underlying cortical GBO and their implications for behavior, and thereby lay the groundwork for treatments of disorders involving impaired GBO such as schizophrenia and sleep disorders.

Public Health Relevance

This research will help us understand the role of subcortical regions in control of brain oscillations (rhythmic activity);the high frequency oscillations, termd gamma band oscillations, are important for coherence of thought and perception. These oscillations are abnormal in mental disorders, including schizophrenia, where gamma abnormalities have been found to be associated with disordered thinking and hallucinations. By understanding the mechanisms by which cortical gamma band oscillations are controlled by a particular brain cell type, this research will point the way for targeted correction of their abnormalities in mental disorders.

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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Vicentic, Aleksandra
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Harvard Medical School
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