# Hypothalamic Sleep-Wake Neuron Defects in Alzheimer’s disease

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $306,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10731103
- **Project number:** 5P20GM130447-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Peng Zhong
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $306,000
- **Award type:** 5
- **Project period:** 2022-11-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10731103

## Citation

> US National Institutes of Health, RePORTER application 10731103, Hypothalamic Sleep-Wake Neuron Defects in Alzheimer’s disease (5P20GM130447-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10731103. Licensed CC0.

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