Chronic or intermittent sleep disorders including narcolepsy, REM behavior disorder, sleep apnea, and insomnia afflict nearly 50-70 million people in the United States. Yet the neural mechanisms controlling both normal sleep and its pathologies remain poorly understood. Considerable evidence indicates that mesopontine cholinergic neurons and serotonergic dorsal raphe neurons along with other neurons at the mesopontine junction are critical for this control and that their dysregulation is involved with numerous disorders including narcolepsy, REM behavior disorder, Parkinson's disease, supranuclear palsy and depression. The long term goal of this project is to understand the mechanisms regulating activity of these neurons and their functions in regulating normal homeostatic brain functions including sleep and sleep pathologies. Compelling evidence indicates that disruption of the Hypocretin/Orexin (Hcrt/Orx) peptide system results in narcolepsy - a sleep disorder characterized by excessive daytime sleepiness, sleep fragmentation and the intrusion of rapid eye movement sleep behaviors into wakefulness. Building on the findings from the previous funding period, which discovered a novel mechanism by which orexin alters the intrinsic properties of mesopontine cholinergic neurons and dorsal raphe serotonergic neurons, we will investigate the hypothesis that Hcrt/Orx peptides have pleiotropic actions which in the short term tune somatic and dendritic excitability to enhance phasic synaptic inputs while attenuating tonic synaptic inputs and in the long-term regulate the strength of synaptic inputs and circuit function. To do so we will 1) Identify the ion channels underlying the new class of orexin actions on the post-spike afterhyperpolarization in mesopontine cholinergic neurons and dorsal raphe serotonergic neurons. 2) Determine the role of these novel actions on modulating the dendrites of mesopontine cholinergic neurons and dorsal raphe serotonergic neurons. 3) Investigate the hypothesis that orexin regulates the strength of synaptic inputs to 5-HT and GABA neurons in the LDT and DR and that the orexin-enhanced AHP and noisy orexin conductance preferentially boost high frequency synaptic inputs arising from prefrontal cortex and that these processes are perturbed in narcolepsy. These experiments will use whole-cell patch clamp recording, calcium imaging and dynamic clamp methods in brain slices from normal and orexin receptor knockout mice and will utilize focal uncaging of glutamate and optogenetic stimulation methods in normal and narcoleptic mice. Collectively, these results will advance our understanding of the molecular, cellular and circuit mechanisms underlying sleep regulation and its pathology.
Sleep disorders including narcolepsy, REM behavior disorder, sleep apnea, and insomnia afflict 50-70 million people in the United States. Yet the neural mechanisms controlling both normal sleep and its pathologies remain poorly understood. The proposed research will advance our understanding of these mechanisms by elucidating the actions of hypocretin/orexin neuropeptides on brain circuits thought to be critical for regulating arousal, sleep and cognition. We will also examine synaptic circuits in normal and narcoleptic mice to gain a better understanding of how the loss of hypocretin/orexin signaling leads to the sleep disorder narcolepsy. In addition to contributing to a better understanding of how sleep and waking are regulated by the brain, clarifying these mechanisms will help identify neural circuits that might be ultimately exploited for therapeutic interventions in these disorders.
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