BLRD Research Career Scientist Award Application

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Sleep loss and sleep disorders (e.g., sleep apnea) lead to excessive daytime sleepiness and impaired attention & cognition. The symptoms of sleep disturbance are now recognized as major contributors to accident rates and decreased workplace productivity. Attention, concentration, and cognitive problems are also a major feature of other disorders that are prevalent in US veterans – e.g., TBI, PTSD, Alzheimer's disease, depression, substance use disorder, and schizophrenia. Understanding the brain circuitry controlling attention will guide the development of treatments to ameliorate cognitive impairments of these conditions. Abundant evidence indicates that the basal forebrain (BF) region contains cortically projecting & wakefulness promoting neurons that are important for cortical activation, behavioral arousal/alertness, and attention. Although previous work has focused on the role of BF cholinergic neurons in attention, advances in optogenetic methods allow the investigation of BF parvalbumin (PV) containing GABAergic neurons. Work on my current Merit grant indicates that selective excitation of BF PV neurons in mice produces cortical activation, wakefulness, and behavioral arousal. Our new data show that excitation of BF PV neurons enhances vigilant attention to rescue reaction time deficits produced by sleep loss and also enhances attention-dependent associative learning without affecting motivation (i.e. hunger, a potential side effect) or reward (i.e. abuse potential). Our overarching hypothesis to explain these findings is that BF PV neurons mediate rapid changes in alertness/attention by quickly activating the cortex in anticipation of, or in response to, meaningful or surprising sensory stimuli. Research methods used to evaluate this hypothesis include i) fiber photometry to measure the activity of BF PV neurons, and, ii) optogenetic methods to either excite or inhibit these neurons in mice; both approaches are combined with behavioral tests and measures of cortical electrical activity. The translational relevance of this basic science project is that BF PV excitation may be used to enhance cognition with limited side effects and low abuse potential. The overarching goal of this research program is to understand the mechanisms of basal forebrain regulation of cortical activity and cognition which could lead to treatments for a variety of disorders that impact US Veterans. For example, the pro-cognitive properties of the BF PV model described above can be readily applied to additional mouse models of diseases that are prevalent in the US Veteran population including Alzheimer’s disease (AD) and traumatic brain injury (TBI). Indeed, other ongoing studies with research fellow (Dr. Felipe Schiffino) and collaborators (Drs. Jay McNally & Lee Goldstein) are testing BF PV excitation benefits in mouse models of AD and TBI. 1