Sleep disorders affect millions of people and can be co-morbid with neurodegenerative diseases such as Parkinson's disease (PD). In addition to the iconic motor impairments of PD, sleep disorders, including excessive sleepiness, plague many individuals with PD and significantly reduce their quality of life. However, the neurobiological mechanisms underlying excessive sleepiness in PD remain to be elucidated. Although degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN) is considered the primary neuropathology of PD responsible for the disease's motor impairments, these neurons do not mediate sleep- wake cycles. An understudied population of DA neurons in the ventral periaqueductal gray (vPAG) promote wakefulness, and although these DA neurons do not degenerate in PD, dysfunction of these neurons may occur in PD due to reduced noradrenergic input. Indeed, catastrophic loss of noradrenergic locus coeruleus (LC) neurons occurs in PD and actually precedes the death of SN neurons, the LC promotes arousal and its activity tracks with sleep-wake cycles, and the LC projects to the vPAG. Therefore, I hypothesize that dysfunction of an LC-vPAG arousal circuit underlies excessive sleepiness in PD. To test this hypothesis, this project will utilize in vitro electrophysiology, behavioral assays of arousal, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and site-specific behavioral pharmacology in genetically engineered mice.
Aim 1 will determine whether suppression of LC transmission in the vPAG decreases arousal, Aim 2 will test whether direct activation of vPAG DA neurons increases arousal, and Aim 3 will determine the neurophysiology and pharmacology mediating the LC-vPAG arousal circuit. These experiments will investigate the role of this novel LC-vPAG circuit in arousal and how dysfunctions of this circuit may underlie the excessive sleepiness that occurs in PD and other sleep disorders.
In addition to the well-known motor impairments, patients with Parkinson's disease (PD) often suffer from non-motor symptoms, including excessive sleepiness, which reduces their quality of life. This project examines a novel circuit in the brain that could be responsible for excessive sleepiness in PD.
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