THE ROLE OF HYPOCRETIN IN POST-TRAUMATIC BRAIN INJURY SLEEP-WAKE DISTURBANCE

Abstract

Traumatic brain injury (TBI) is a major cause of disability, affecting millions of individuals in the United States alone. Disorders of sleep and wakefulness occur in over half of people who sustain a TBI. Sleep-wake disturbances predict poorer cognitive, social, and functional recovery from TBI and negatively impact quality of life. Currently, there is a dearth of highly effective therapies, largely due to a fundamental lack of understanding of the causes of increased sleep need and excessive daytime sleepiness after TBI. In the present set of experiments, I used a controlled cortical impact (CCI) model of TBI to investigate the role of hypocretin in post-TBI sleep-wake disturbance. In the first set of experiments (Chapter 2), I determined the effects of mild and moderate TBI on sleep-wake behavior using electroencephalographic (EEG) recordings and on neuronal populations important for regulating sleep and wake behavior using immunohistochemistry (IHC). I found that moderate TBI resulted in chronic decreases in wakefulness and increases in non-rapid eye movement (NREM) sleep during the dark period. Moderate TBI also chronically decreased numbers of hypocretinergic neurons in the hypothalamus and cholinergic neurons in the basal forebrain without affecting numbers of melanin-concentrating hormone neurons in the hypothalamus or histaminergic neurons in the tuberomammillary nucleus. In the second set of experiments (Chapter 3), I analyzed the effects of TBI on sleep-wake behavior over a 30-day period in intact and hypocretin knockout (KO) mice. Hypocretin KO mice did not display significant changes in sleep-wake behavior, either in terms of percent time spent in different sleep-wake states or in length of wake bouts. In intact animals, post-TBI sleep-wake disturbance and reductions in hypocretin neuron numbers persist out to 30 days post-surgery. I conclude that in this injury model, TBI produces chronic deficits in wakefulness and in numbers of hypocretin neurons and that a change in the hypocretinergic system is necessary for post-TBI changes in sleep wake behavior. Thus, this project has important implications for the use of hypocretin-based therapeutics in chronic TBI.