Obstructive sleep apnea (OSA) is characterized by frequent arousals from sleep due to closure of the upper airway, producing hypercapnia (increased carbon dioxide levels) and hypoxia (decreased oxygen levels). The consequences of OSA include excessive daytime sleepiness, cognitive deficits, as well as respiratory, metabolic, and cardiovascular disorders. Despite its importance in OSA-induced arousals and sleep fragmentation, very little is known about the neural mechanisms that mediate arousals during OSA. Recent work indicates that the brainstem glutamatergic neurons of the parabrachial complex (PB), which receive visceral and respiratory input, are important for hypercapnic arousal. We hypothesize that the PB projections to the basal forebrain (BF), a region containing cortically projecting & wakefulness promoting neurons, mediate the cortical arousal response to the hypercapnia. Sleep apnea will be modeled in mice by exposure to hypercapnia during sleep, termed repetitive carbon dioxide-mediated arousals (RCA). Optogenetic techniques will be used to investigate the roles of three neurotransmitter-defined subpopulations of cortically-projecting BF neurons in apnea-induced arousals: GABAergic parvalbumin positive (PV), cholinergic, and glutamatergic neurons. For each identified BF neurotransmitter phenotype we will address the criteria of: 1) sufficiency for arousal by optogenetic excitation using Channelrhodopsin 2 (ChR2); 2) necessity for arousal by optogenetic inhibition of RCA using Archaerhodopsin (ArchT); and 3) relevance of our optogenetic findings to natural physiological conditions by recording the electrical activity of RCA -related BF neurons whose neurotransmitter phenotype has been defined by short latency excitation by ChR2. Each neuronal BF population will be evaluated as mice are exposed to RCA or acoustic stimuli; we predict both stimuli will arouse, as our data point to the BF as a final common pathway leading to cortical arousal from both visceral and external sensory stimuli. Our preliminary data point to PV GABergic neurons as the most important for RCA and acoustic arousals: 1) ChR2 excitation of BF PV neurons causes arousal and EEG activation including high frequency oscillations; 2) PV ArchT inhibition markedly prolongs the latency to RCA arousal; and 3) PV unit recordings show activation in concert with cortical activation. In contrast, ChR2 stimulation of BF cholinergic neurons shows more modulatory, less powerful and less immediate effects on cortical activation than PV neurons. We predict that glutamatergic BF neurons will play a role in promoting arousal, but not high frequency oscillations. If successful, these experiments would suggest that blocking BF activation, especially that from GABAergic PV neurons, would increase the cortical arousal threshold, and thus would treat the sleep fragmentation evident in apnea and responsible for many of the symptoms of OSA. Improved understanding of the neural mechanisms controlling cortical arousals in OSA will guide therapeutic treatment aiming to decrease cortical arousals while maintaining airway patency.
Sleep, an essential part of human life, is needed for optimal health & performance. Approximately 7% of the adult population suffers from sleep apnea, in which frequent arousals from sleep lead to excessive daytime sleepiness & cognitive impairments, as well as respiratory, metabolic and cardiovascular disorders. This proposal investigates brain mechanisms in the basal forebrain underlying arousals from sleep in order to provide a rational basis for the development of therapies to reduce arousals from sleep.
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