Role of the basal forebrain in sleep loss induced attention impairments

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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 the attention and 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 our current Merit grant indicates that selective excitation of BF PV neurons in mice produces cortical activation, wakefulness, and behavioral arousal. Our new preliminary data suggest that excitation of BF PV neurons can enhance attention, cognition, and rescue reaction time performance impairments produced by sleep loss. The findings described led us to two testable hypotheses: 1) BF PV neurons mediate rapid changes in alertness/attention by quickly activating the cortex in response to meaningful or surprising sensory stimuli. 2) Excitation of BF PV neurons does not alter motivation (e.g., hunger) and is not rewarding indicating these neurons can enhance attention and cognition with limited side effects and low addictive potential. Our model prediction: In response to meaningful or surprising sensory stimuli, BF PV neurons briefly activate the cortex, enhancing cortical processing and alertness which facilitates attention-dependent reaction time performance and associative learning. The work will address a gap in our knowledge by demonstrating that regulation of cortical activation by BF PV neurons is important for the control of attention. Methods used include fiber photometry to measure the activity of BF PV neurons and optogenetics to excite and inhibit these neurons in mice; both will be combined with behavioral tests and measures of cortical electrical activity. The 3 aims are: Aim 1 will demonstrate that increasing and decreasing the activity of BF PV neurons can modulate cortical responses to repetitive presentations of sensory stimuli. This finding will provide a plausible mechanism for how these neurons enhance the attention dependent behavioral performance studied in Aims 2 & 3. Aim 2 will demonstrate that BF PV excitation enhances sustained attention and performance in a mouse reaction time test like the test used in humans to detect sleepiness and sustained attention deficits. Experiments will demonstrate that sleep deprivation (SD) and BF PV inhibition slows reaction times, whereas BF PV excitation will quicken reaction times and will rescue deficits produced by SD. Aim 3. Attention is also important for learning and here BF PV manipulations are used to alter the attention needed for associative learning. Our predictions, supported by preliminary data, are that BF PV excitation enhances associative learning by broadcasting `surprise' signals to the cortex that are encoded in high frequency cortical gamma oscillations, and that BF PV excitation does not affect reward pathways. We also predict that BF PV inhibition and SD will impair attention-dependent associative learning. If successful, this project will show that the BF PV neuron excitation model enhances attention and cognition with limited side effects and low addictive potential. This model can be readily applied to mouse models of other conditions that are prevalent in the US Veteran population. Future work could also identify novel therapeutics to pharmacologically target receptors on BF PV neurons in order to activate them.