Persistent sleepiness is, like hypertension, a major consequence of the obstructive sleep apnea syndrome (OSA), a debilitating disorder affecting 3-5 percent of the adult population. The long-term goal of this project is to determine the mechanisms responsible for detrimental effects of sleep loss on the central nervous system (CNS) and cardiorespiratory control. We focus on the hypothalamic perifornical (PF) region involved in many homeostatic processes, including cardiorespiratory regulation and sleep. Cells in the PF contain peptides orexin (ORX) and melanin-concentrating hormone (MCH), and have connections throughout the CNS. With regard to the processes occurring in the PF region, we hypothesize that inhibitory GABAA and galanin (GAL) type 1 receptors control the sleep-wake related changes in the activity of PF neurons, with the upregulation of these receptors occurring in response to sleep debt. Regarding the consequences of altered activity in PF neurons, we hypothesize that motor and cardiorespiratory activation originating in the PF region is mediated by brainstem arousal-related neuronal groups (serotonergic, noradrenergic), and by direct projections of PF neurons to relevant outputs. To test these hypotheses, we plan to:
Aim 1 - determine whether the arousal-like effects following disinhibition of PF neurons are secondary to activation of ORX neurons. We will assess the magnitude and selectivity of the effects of GABAA and GAL-1 receptor antagonists on ORX cell activity and the arousal-like cardiorespiratory changes. In anesthetized rats, we shall record from PF neurons to determine their activity patterns;
Aim 2 - determine whether, in chronically instrumented rats, the effects of GABAA and GAL receptor antagonists on the sleep-wake pattern depend on the duration of prior wakefulness. We will also determine whether these effects are associated with changes in GABAA and GAL receptor mRNA levels by quantitative assessment of mRNA changes regionally and in single identified neurons;
and Aim 3 - delineate the pathways mediating the cardiorespiratory and motor consequences of PF cell activation. We will determine: i - the magnitude of serotonergic and noradrenergic neuronal activation in response to stimulation of PF neurons; ii- whether this activation is necessary to produce the cardiorespiratory and motor effects; and iii- whether activation PF cells impedes the animal's ability to generate pharmacologically induced REM sleep-like changes. With OSA being associated with hypertension, obesity and diabetes, the proposed studies will assess the basis for treating these conditions by targeting the neuronal systems of the posterior hypothalamus.
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