# Long-lasting consequences of early ethanol on network activity during sleep

> **NIH NIH R01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $408,844

## Abstract

ABSTRACT/SUMMARY
Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations,
with neurobehavioral hallmarks such as deficits in learning, memory and mood. We propose that developmental
ethanol (EtOH) exposure may induce long-lasting disruption of neural activity patterns during sleep which are
known to be important for memory consolidation and synaptic homeostasis. If so, this would create a situation
wherein the normal ability of the nervous system to repair and readjust itself during sleep would be impaired,
resulting in a daily insult to nervous system function long after the EtOH exposure ended. In support of this
hypothesis, during the past funding cycle we have demonstrated that developmental EtOH 1) disrupts and
fragments adult non-REM sleep, 2) the extent of sleep disruption in adults predicts cognitive impairment, 3) the
sleep impairment is associated with severe loss of parvalbumin (PV) and somatostatin (SST) expressing
GABAergic interneurons which are known to contribute to sleep-wake architecture, 4) disruption of PV cell
function through neuropentraxin knock-out replicates some aspects of developmental ethanol but not sleep, and
5) preventing cell loss induced by developmental EtOH with LiCl prevents sleep, anatomical, and cognitive
impairments. In this renewal, we plan to further explore the mechanisms of developmental EtOH effects on sleep
and waking with cell specific analyses. Aim 1 will test the hypothesis that selective optogenetic activation of
spared GABAergic neurons will restore the deficits in sleep and cognition induced by developmental EtOH in
transgenic mice (e.g., SST-Cre; Aim 1.1). In the same animals, we will correlate sleep-wake
function/dysfunction/repair with anatomical structure of several identified GABAergic circuits (e.g., SST, reelin,
vasoactive intestinal peptide (VIP)) in sleep-related regions including basal forebrain nuclei, hippocampus and
neocortex. Data will include synaptic interactions of identified cell types using confocal and electron microscopy
as well as Golgi analyses (Aim 1.2). Performing the anatomical analyses on animals that we have assayed for
sleep/wake and cognitive function will allow us to directly relate structure (e.g., synaptic density) with
neurobehavioral function/dysfunction/repair (e.g., slow-wave activity, excitatory/inhibitory [E/I] balance). Aim 2.1
examines to what extent PV/SST cells are killed by developmental EtOH, or alternatively have down-regulated
phenotypic expression by tracking the fate of fluorescently labeled PV/SST neuron progenitors in Nkx2.1-Cre;Ai9
mice exposed to EtOH. This will provide information needed to guide attempts to restore GABAergic function
after EtOH exposure. Aim 2.2 will transplant PV/SST interneuron progenitors into EtOH treated mice, to examine
if re-populating GABAergic neurons in identified brain regions will restore sleep and/or cortical activity (e.g., slow-
wave activity, E/I balanc...

## Key facts

- **NIH application ID:** 10227902
- **Project number:** 5R01AA023181-07
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** JOHN F SMILEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $408,844
- **Award type:** 5
- **Project period:** 2014-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227902

## Citation

> US National Institutes of Health, RePORTER application 10227902, Long-lasting consequences of early ethanol on network activity during sleep (5R01AA023181-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10227902. Licensed CC0.

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