Astrocyte molecular rhythm disruption in nucleus accumbens promotes increased binge-like drinking in mice
- 1University of Pittsburgh
Abstract
Alcohol misuse is a leading cause of preventable death worldwide. Chronic alcohol is associated with disrupted circadian rhythms, yet molecular mechanisms linking circadian rhythm dysregulation and alcohol consumption are poorly understood. Current FDA-approved treatments for alcohol use disorder (AUD) do not target molecular rhythms or sleep-wake cycles. Mammalian circadian rhythms are regulated by transcription-translation feedback loops that regulate expression of 'clock genes' (e.g., Arntl encoding for BMAL1). Both human and rodent studies demonstrate associations between clock gene variants and changes in reward-seeking behavior. Evidence suggests astrocytes, non-neuronal brain cells with cell-autonomous rhythms, may regulate both circadian rhythms and reward. In the nucleus accumbens (NAc), a region responsible for modulating alcohol- and reward-related behavior, over 43% of the astrocyte transcriptome is expressed rhythmically. However, no studies to date have investigated roles of NAc astrocyte rhythmicity in regulating alcohol drinking. We used AAV8-Gfap-Cre to functionally ablate molecular rhythms in NAc astrocytes of BMAL1 floxed mice. Two-bottle choice (2BC), drinking-in-the-light (DIL), and drinking-in-the-dark (DID) assessed alcohol drinking. Behavioral assays included locomotor response to novelty, sucrose preference, and social interaction. Disrupting molecular clock function in NAc astrocytes increased binge-like drinking during both DIL and DID paradigms (d = 1.44), but not with any other drinking paradigm or behavior. This study carves out a unique role for astrocytes in controlling the temporal organization of reward circuitry and susceptibility to binge-drinking. Future studies will investigate clock-controlled astrocyte mechanisms, such as glutamate uptake and ATP release, that may underlie binge-like drinking behavior.
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BibTeX
@misc{keefauver2026astrocyte,
title = {{Astrocyte molecular rhythm disruption in nucleus accumbens promotes increased binge-like drinking in mice}},
author = {T. Keefauver and N. L. Horan and N. J. Fairbanks and L. Morgan and A. Saxena and R. Logan and G. E. Homanics and S. P. Farris and M. L. Seney and K. D. Ketchesin},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747847},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747847v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Astrocyte molecular rhythm disruption in nucleus accumbens promotes increased binge-like drinking in mice
AU - T. Keefauver
AU - N. L. Horan
AU - N. J. Fairbanks
AU - L. Morgan
AU - A. Saxena
AU - R. Logan
AU - G. E. Homanics
AU - S. P. Farris
AU - M. L. Seney
AU - K. D. Ketchesin
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747847
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747847v1
AB - Alcohol misuse is a leading cause of preventable death worldwide. Chronic alcohol is associated with disrupted circadian rhythms, yet molecular mechanisms linking circadian rhythm dysregulation and alcohol consumption are poorly understood. Current FDA-approved treatments for alcohol use disorder (AUD) do not target molecular rhythms or sleep-wake cycles. Mammalian circadian rhythms are regulated by transcription-translation feedback loops that regulate expression of 'clock genes' (e.g., Arntl encoding for BMAL1). Both human and rodent studies demonstrate associations between clock gene variants and changes in reward-seeking behavior. Evidence suggests astrocytes, non-neuronal brain cells with cell-autonomous rhythms, may regulate both circadian rhythms and reward. In the nucleus accumbens (NAc), a region responsible for modulating alcohol- and reward-related behavior, over 43% of the astrocyte transcriptome is expressed rhythmically. However, no studies to date have investigated roles of NAc astrocyte rhythmicity in regulating alcohol drinking. We used AAV8-Gfap-Cre to functionally ablate molecular rhythms in NAc astrocytes of BMAL1 floxed mice. Two-bottle choice (2BC), drinking-in-the-light (DIL), and drinking-in-the-dark (DID) assessed alcohol drinking. Behavioral assays included locomotor response to novelty, sucrose preference, and social interaction. Disrupting molecular clock function in NAc astrocytes increased binge-like drinking during both DIL and DID paradigms (d = 1.44), but not with any other drinking paradigm or behavior. This study carves out a unique role for astrocytes in controlling the temporal organization of reward circuitry and susceptibility to binge-drinking. Future studies will investigate clock-controlled astrocyte mechanisms, such as glutamate uptake and ATP release, that may underlie binge-like drinking behavior.
ER -