Dysregulation of sleep/wake control can result in life-long disturbances in arousal and REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of neuropsychiatric disorders such as schizophrenia, anxiety disorder, bipolar disorder, and narcolepsy. Study of the control of sleep and waking has the potential for making a major impact on a number of disorders, making translational neuroscience research on this area critical. One element of the reticular activating system (RAS) is the pedunculopontine nucleus (PPN), which is the cholinergic arm of the RAS, and projects to the thalamus to trigger thalamocortical rhythms, and to the brainstem to modulate muscle tone and locomotion. Leptin is an adipokine that regulates appetite, body weight, and reproduction by way of receptors in the hypothalamus. The hormone also has receptors in various other regions of the brain, including the PPN. While leptin is known to be an active regulator in the hypothalamus, the hormone's role in the PPN (and thus in wakefulness) is not established. It has been shown that leptin levels are decreased in individuals with obesity, who also have sleep dysregulation. Studies have shown that leptin significantly decreases the duration of REM sleep and increases the duration of slow wave sleep. The proposed experiment will entail testing the effect of leptin on the PPN in single cells, populations of cells, and in the whole animal. This will be established by performing whole-cell patch clamp and population response recordings in vitro, and by recording the sleep state-dependent auditory P13 evoked potential in freely moving rats, a measure of level of arousal that is generated by the PPN. After determining the effects of leptin using these three techniques, the biological mechanisms by which leptin acts will be determined by performing single cell recordings using several intracellular pathway blockers. This project will lay out the role of leptin in sleep-wake control from the single cell all the way up to the whole animal. This experiment is clinically important because, by determining the role of leptin in the PPN and, therefore, sleep and waking, the potential role of leptin in sleep disorders and perhaps a number of psychiatric and neurological disorders will also be determined.

F30HL108429

2011-07-01

2014-06-30