# Specification of sleep-wake control neurons in the basal forebrain

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2021 · —

## Abstract

Deployment and combat exposure substantially increase the risk for insomnia and other sleep disorders
in military personnel. These findings match with the 6-fold increase in the diagnosis of sleep disorders in the
VA in recent years. The most prevalent sleep disorder, insomnia, is associated with an increased risk for
suicide. Furthermore, disrupted sleep and abnormal cortical activity are common in severe neuropsychiatric
conditions affecting veterans such as dementia and schizophrenia. Thus, a better mechanistic understanding
of the brain circuitry controlling sleep-wake cycles and cortical oscillations are urgently needed to develop
novel treatments for veterans and other vulnerable populations. Accordingly, the broad objective of this
research program in mice is to identify new therapeutic targets to correct abnormalities of sleep and cortical
electrical activity. We will use an innovative approach in mice which characterizes subgroups of neurons based
on their developmental origin and identifies the transcription factors which control their activity in adults,
allowing targeted therapies which recalibrate their activity to restore normal sleep and cortical rhythms. We
focus on the basal forebrain, a region involved in sleep-wake activity, attention and reward which degenerates
in dementia, and on the largest group of neurons in this region which release the inhibitory neurotransmitter,
gamma-amino-butyric acid (GABA). We target neurons which express three transcription factors linked to
insomnia and other neuropsychiatric disorders common in veterans by genetic and postmortem studies.
 The roadmap to helping veterans is: We will identify new groups of neurons based on their
developmental origin (Aim 1). We will use transgenic mice which allow manipulation of their activity to
determine how they affect sleep-wake behavior and cortical oscillations (Aim 2). Finally, we will state-of-the-art
genetic techniques to identify the transcription factors which control their activity in adults (Aim 3), allowing us
to correct abnormal sleep-wake behavior and cortical electrical activity in neuropsychiatric disorders by
designing viral vector based therapies which act on those transcription factors (long-term goal).
 Forebrain GABAergic neurons are generated in the subpallium, an area of the developing brain
implicated in the risk for developing diverse neuropsychiatric disorders affecting veterans. Within the
subpallium, different groups of GABAergic neurons are generated by progenitors in the caudal, medial and
lateral ganglionic eminences and embryonic preoptic regions. In each region, different transcription factors
specify unique groups of neurons. We will use genetically modified mice which express an enzyme, Cre
recombinase (Cre), under the control of these transcription factors to identify them and manipulate their
activity. Crossing these mouse strains with another mouse strain which expresses a red fluorescent protein in
the presence of Cre, in...

## Key facts

- **NIH application ID:** 10148549
- **Project number:** 5I01BX004673-02
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** Ritchie Edward Brown
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148549

## Citation

> US National Institutes of Health, RePORTER application 10148549, Specification of sleep-wake control neurons in the basal forebrain (5I01BX004673-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148549. Licensed CC0.

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