# Neuronal mechanisms mediating the effects of chronic alcohol consumption on sleep homeostasis.

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $363,468

## Abstract

Alcohol use disorder (AUD), a chronic relapsing brain disorder, characterized by compulsive and excessive
alcohol use, is a leading preventable cause of premature disability and death. Insomnia and associated sleep
disturbances are amongst the most severe and protracted symptoms of AUD. In fact, subjective and objective
indicators of sleep disturbances are predictors of relapse. Thus, while there is a direct relationship between
insomnia and AUD, the underlying pathophysiology is not well understood. Evidence suggest that sleep
homeostatic mechanism [adenosinergic/cholinergic mechanisms in the basal forebrain (BF)] may play a crucial
role in mediating the effects of alcohol on sleep. Hence, we hypothesize that chronic alcohol consumption directly
and indirectly, via neuroinflammation, disrupts sleep homeostasis leading to insomnia and sleep disturbances.
We will use wild type (C57BL/6J) and transgenic ChAT-cre (expression of Cre-recombinase exclusively in
cholinergic neurons) mice and expose them to the common maladaptive pattern of alcohol consumption: chronic
intermittent access two-botte choice paradigm (IA2BC). A novel combination of multidisciplinary techniques
including in vivo calcium imaging, pharmacogenetics, viral-mediating gene overexpression, microdialysis and
local pharmacological manipulations will be used. Three aims are designed to test our hypothesis.
In Aim 1, live Ca+2 imaging coupled with electrophysiological monitoring of sleep-wakefulness will be performed
to examine the relationship between cholinergic neuronal activity, wakefulness and chronic alcohol intake. We
predict that mice exposed to IA2BC will consume alcohol in an escalating pattern and display a positive
relationship between cholinergic neuronal activity, disrupted sleep homeostasis and severity of sleep disruptions.
While pharmacogenetic silencing of BF cholinergic neurons will attenuate the effects of chronic alcohol and
normalize sleep, pharmacogenetic activation will attenuate sleep-promoting effects of acute alcohol.
Aim 2 will examine the effects of chronic alcohol consumption on sleep homeostasis. We predict that 1) alcohol
will downregulate MAPK signaling cascade and acetylated histones, to reduce the expressions of equilibrative
nucleoside transporter 1 (ENT1) and adenosine A1 receptor (A1R) in the BF. 2) Virally mediated overexpression
of ENT1 in the BF will attenuate the effects of alcohol on sleep homeostasis and improve the quality and quantity
of sleep. 3) Local infusion of trichostatin-A (histone deacetylase inhibitor) will normalize sleep by upregulation of
acetylated histones along with the expression of ENT1 and A1R in the BF, without affecting MAPK signaling.
Aim 3 will examine chronic alcohol induced neuroinflammation in the BF and its effect on sleep homeostasis.
Our predictions are that selective blockade of 1) neuroinflammatory changes by minocycline, 2) Toll-like
receptors by TAK-242 and/or c) adenosine kinase by ABT-702, in the BF will at...

## Key facts

- **NIH application ID:** 10019446
- **Project number:** 5R01AA028175-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** MAHESH M THAKKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,468
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019446

## Citation

> US National Institutes of Health, RePORTER application 10019446, Neuronal mechanisms mediating the effects of chronic alcohol consumption on sleep homeostasis. (5R01AA028175-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10019446. Licensed CC0.

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