Abstract
Background
Substance use disorders are associated with disruptions in circadian rhythms. Both
human and animal work have shown the integral role for circadian clocks in the modulation
of reward behaviors. Astrocytes have emerged as key regulators of circadian rhythmicity.
However, no studies to date have identified the role of circadian astrocyte function
in the nucleus accumbens (NAc), a hub for reward regulation, or determined the importance
of these rhythms for reward-related behavior.
Methods
Using astrocyte-specific RNA sequencing across time of day, we first characterized
diurnal variation of the NAc astrocyte transcriptome. We then investigated the functional
significance of this circadian regulation through viral-mediated disruption of molecular
clock function in NAc astrocytes, followed by assessment of reward-related behaviors,
metabolic-related molecular assays, and whole-cell electrophysiology in the NAc.
Results
Strikingly, approximately 43% of the astrocyte transcriptome has a diurnal rhythm,
and key metabolic pathways were enriched among the top rhythmic genes. Moreover, mice
with a viral-mediated loss of molecular clock function in NAc astrocytes show a significant
increase in locomotor response to novelty, exploratory drive, operant food self-administration,
and motivation. At the molecular level, these animals also show disrupted metabolic
gene expression, along with significant downregulation of both lactate and glutathione
levels in the NAc. Loss of NAc astrocyte clock function also significantly altered
glutamatergic signaling onto neighboring medium spiny neurons, alongside upregulated
glutamate-related gene expression.
Conclusions
Taken together, these findings demonstrate a novel role for astrocyte circadian molecular
clock function in the regulation of the NAc and reward-related behaviors.
Keywords
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Article Info
Publication History
Published online: February 18, 2022
Accepted:
February 11,
2022
Received in revised form:
January 25,
2022
Received:
September 30,
2021
Identification
Copyright
© 2022 Society of Biological Psychiatry.
