# Contribution of hypocretin neuron activity to Alzheimer's related sleep disturbances

> **NIH NIH K99** · STANFORD UNIVERSITY · 2024 · $128,331

## Abstract

PROJECT SUMMARY
Sleep is a very well conserved behavioral state across all animals. Though the exact function of sleep remains unknown, it
is widely appreciated that good sleep quality is a cornerstone for any healthy organism. Indeed, several neurological
disorders are co-morbid with sleep disturbances. Furthermore, altered sleep as observed in sleep apnea, insomnia or sleep
deprivation show impairments in memory consolidation and increased risk for depression, cancer, Alzheimer’s disease
(AD), and other neuropsychiatric disorders. AD patients have been shown to display altered sleep architecture. Sleep plays
a role in clearance of beta-amyloid (Aβ) in interstitial space. Excessive accumulation of Aβ, a prominent feature of AD, has
been shown to alter sleep. Recent work in our lab has demonstrated that hyperexcitability of wake-promoting hypocretin
(Hcrt) neurons of the lateral hypothalamus (LH), resulting from natural aging, may underlie increased sleep fragmentation
during aging. It is likely that these same neurons may have altered excitability in AD, exacerbated by the presence of Aβ
accumulation, and may drive sleep fragmentation and sleep disturbances observed in AD patients. The overarching aim of
this proposal is to understand how Aβ accumulation impacts hypocretin neuron activity leading to altered homeostatic sleep
pressure and subsequent disrupted sleep architecture observed in Alzheimer’s disease. The central hypothesis is that
accumulation of Aβ accelerates natural Hcrt neuron death leading to hyperexcitability of surviving Hcrt neurons and
disrupted sleep pressure and architecture. This proposal focuses on Hcrt neurons as they have been suggested to be an
integration hub which consolidates several streams of input and sends signals to downstream arousal-promoting regions. To
understand this interaction, I will first need to demonstrate altered Hcrt neuron activity in the presence of Aβ accumulation,
its impact on sleep (Aim 1), and demonstrate changes to the intrinsic and synaptic excitability of Hcrt neurons (Aim 2).
Finally, I will consolidate the findings into a biophysically realistic computational network model with sleep-wake
transitions to make viable predictions about the relative contributions of various ionic / synaptic currents to changes in
intrinsic Hcrt neuron activity and its impact on overall sleep structure. These predictions will then be experimentally tested
using CRISPR-SaCas9 technologies in vivo, the results of which will then further inform/refine the computational model
(Aim 3). The end goal being a detailed theory / biophysical explanation for the impact of Aβ accumulation on Hcrt neuron
activity and their role in sleep architecture.

## Key facts

- **NIH application ID:** 10864516
- **Project number:** 1K99AG086609-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Oscar Christian Gonzalez
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,331
- **Award type:** 1
- **Project period:** 2024-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864516

## Citation

> US National Institutes of Health, RePORTER application 10864516, Contribution of hypocretin neuron activity to Alzheimer's related sleep disturbances (1K99AG086609-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10864516. Licensed CC0.

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