CONTROL OF SLEEP AND AROUSAL

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DESCRIPTION (adapted from applicant's abstract): Extensive evidence supports the idea that the magnocellular basal forebrain (MBF) plays a critical role in EEG activation and behavioral arousal. Evidence suggests that the onset of non-rapid eye movement (NREM) sleep, in part, involves the inhibition of the arousal mechanism located within the MBF. Adenosine and GABA have been implicated in sleep-regulation and hypothesized to inhibit the MBF arousal system. While putative wake- (WRNs) and sleep-regulating neurons (SRNs) within MBF have been electrophysiologically studied in detail, very little is known about the in vivo neurochemical regulation of these cell types across the sleep-wake cycle in freely moving animals. The proposed experiments will evaluate the contributions of adenosinergic and GABAergic mechanisms in the discharge modulation of WRNs and SRNs in the MBF across sleep-waking states, during sleep-deprivation, and recovery sleep. We hypothesize that adenosine suppresses WRNs in the MBF via A1 adenosine receptors and activates SRNs via A2 adenosine receptors. We hypothesize that GABA-mediated inhibition contributes to the suppression of WRNs in the MBF during NREM sleep. We hypothesize that the extracellular levels of adenosine in the MBF will be higher during waking as compared with sleep. In contrast, extracellular levels of GABA during sleep will be higher than during waking. We hypothesize that extracellular levels of adenosine will increase during short-term sleep deprivation, whereas GABA levels will be higher during recovery sleep. We hypothesize that WRNs in the MBF will exhibit decreased spontaneous discharge during recovery sleep as compared to its baseline. Adenosine and GABA antagonists will partially attenuate changes in neuronal discharge and excitability that occur during sleep deprivation and recovery sleep. The effects of adenosinergic and GABAergic agents on MBF neurons will be studied by combining chronic microwire methods for extracellular unit recording with the delivery of pharmacological agents adjacent to the neurons with a microdialysis probe in freely behaving rats. The extracellular levels of adenosine and GABA in the MBF will be measured across the sleep-wake cycle during sleep-deprivation and recovery sleep. These pharmacological manipulations and analytical procedures will help understanding of the adenosinergic and GABAergic mechanisms that shape the discharge patterns of the MBF neurons across the sleep-waking cycle.