# Preoptic/Hypothalamic Mechanisms of Sleep-Wake Regulation

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2022 · —

## Abstract

ABSTRACT
 Chronic sleep disturbance is a frequent and challenging problem of human aging. In the US an
estimated 39.6 million people including 8.5 million Veterans are aged 65 or older and at risk of developing
chronic sleep disturbance. Chronic insufficient or disrupted sleep is associated with multiple adverse health
outcomes, including increased risk of fall, cognitive decline, anxiety, depressive disorders, and Alzheimer's
disease. Also, elderly Veterans have a high prevalence of medical and psychiatric disorders that can further
aggravate sleep disturbance.
 Recently, we found that chronic suppression of hypothalamic cell proliferation in young mice
produced sleep-wake features of aging including sleep disruption and poor response to sleep loss. Here,
we proposes a series of novel preclinical studies that will use complimentary and cutting edge approaches
to examine: a) if hypothalamic neurogenesis regulates sleep function by maintaining a supply of new cells to
replace senescent sleep-regulatory ventrolateral preoptic area galanin (VLPOGAL) and GABA (VLPOGABA)
neurons; b) if a disruption of hypothalamic neurogenesis, caused by chronic inflammation that accompanies
aging, contributes to physiological dysfunction and or loss of the critical sleep-regulatory VLPOGAL and
VLPOGABA neurons and consequent sleep disturbance in aging; and c) if sleep disturbance in aging could be
mitigated by neuro-regenerative and anti-inflammatory approaches.
Specific aim-1: will determine if hypothalamic neurogenesis is vital for maintaining the functioning of the
VLPO sleep regulatory neuronal groups and that its impairment is a driver of their functional decline and
sleep disruption in aging. We will determine the extent of cell proliferation, migration, and differentiation of
precursor cells into sleep regulatory VLPOGAL and VLPOGABA neurons and their sleep-associated activation
in young and old mice, and in young mice after chronic suppression of neurogenesis (experiment-1). We
predict that old mice or mice with impaired hypothalamic neurogenesis will exhibit: a) a decline in cell
proliferation and differentiation of precursor cells into VLPOGAL and VLPOGABA neurons, b) fewer VLPOGAL
and VLPOGABA neurons exhibiting seep-associated Fos-immunoreactivity; and c) more sleep disruption. We
will use calcium imaging to determine if VLPOGAL neurons exhibit a functional decline, paralleling the deficits
in spontaneous and impaired homeostatic sleep responses in aging (experiment-2). We will use
chemogenetic activation to determine the ability of VLPOGAL neurons to promote sleep after disrupting
neurogenesis, a low grade inflammation, and after disrupting neurogenesis in the presence of a neurogenic
factor to determine if a decline in the ability of VLPOGAL neurons to promote sleep after chronic suppression
of hypothalamic neurogenesis is attenuated by ciliary neurotrophic factor (CNTF).
Specific aim-2: will determine if increasing hypothalamic cell proliferation and n...

## Key facts

- **NIH application ID:** 10341046
- **Project number:** 5I01BX005167-02
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Noor Alam
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341046

## Citation

> US National Institutes of Health, RePORTER application 10341046, Preoptic/Hypothalamic Mechanisms of Sleep-Wake Regulation (5I01BX005167-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10341046. Licensed CC0.

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