Hypothalamic Sleep-Wake Neuron Defects in Alzheimer’s disease

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As a hallmark of Alzheimer’s Disease (AD), sleep disruption often precedes the onset of the severe memory and cognitive deficits associated with the clinical phase of AD by decades. It is estimated to affect 30-66% of AD patients, and its effects are debilitating and stressful for both the patient and the caregiver. However, the neural mechanisms underlying the association between sleep and AD are still poorly understood. Rapid eye movement (REM) sleep, a sleep state that is associated with vivid dreaming and obvious cognitive processing, plays an important role in the regulation of learning and memory. Its disturbances manifest as decreased REM sleep duration and increased REM latency and are positively correlated with impaired cognitive functions in AD patients. Melanin-concentrating hormone (MCH) neurons are exclusively located in the lateral hypothalamus (LH) and project broadly throughout the brain. They are thought to play a critical role in the generation and maintenance of REM sleep and are maximally active during this state. Remarkably, these REM-active MCH neurons also mediate memory impairment by their projections to the hippocampus CA1 region. In clinical phase of AD, tau pathology, neurofibrillary tangles, can be observed in the LH. Furthermore, MCH levels are significantly elevated in the cerebral spinal fluid (CSF) of AD patients and are positively correlated to CSF tau level, REM sleep disruption and severity of cognitive impairment. These pieces of evidence suggest a role for MCH neurons in neuropathology of AD. In the proposed project, we will test the central hypothesis that LH MCH neurons become dysfunctional in the tauopathy condition of AD. Accordingly, using in vivo microendoscopic calcium imaging, ex vivo slice recording and PS19 mouse model of tauopathy, we will determine whether and how tau pathology affects the firing patterns of MCH neurons across the sleep-wake cycles in Aim 1. Using chemogenetic approaches, we will further determine whether manipulation of their neuronal activities improves sleep quality and enhances cognitive performance in Aim 2. The results of this project should help open the door to the development of circuit-based therapeutic interventions for AD-related sleep disorders and cognitive impairments.