Biological Psychiatry: Astrocyte Molecular Clock Function in the Nucleus Accumbens Is Important for Reward-Related Behavior

Individuals with substance use disorders have disrupted circadian and sleep/wake rhythms, and growing evidence suggests a bidirectional relationship between circadian rhythm disruption and substance abuse. Notably, circadian clocks are integral to the modulation of reward behaviors, and astrocytes—a highly abundant glial cell type that contains a circadian molecular clock—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, a hub for reward regulation, or determined the importance of these rhythms for reward-related behavior.

In a recent Biological Psychiatry paper, investigators including first author Darius Becker-Krail, PhD (PhD, neurobiology, University of Pittsburgh; Postdoctoral fellow, West Virginia University), Kyle Ketchesin, PhD (Assistant Professor of Psychiatry), Jennifer Burns, BS (PhD candidate), Mariah Hildebrand, BS (research associate), Lauren DePoy, PhD (postdoctoral scholar), Chelsea Vadnie, PhD (postdoctoral scholar), Yanhua Huang, PhD, (Associate Professor of Psychiatry), and senior author Colleen McClung, PhD (Professor of Psychiatry and Clinical and Translational Science), elucidated the role of astrocyte circadian molecular clock function in the regulation of the nucleus accumbens and reward-related behaviors. 

The investigators measured diurnal (24-hour) rhythms in gene expression, specifically in astrocytes, in the mouse nucleus accumbens. They then determined the consequences of disrupting these specific molecular rhythms on excitability of neighboring neurons, markers of astrocyte function, and reward-related behavior. 

Results of the study revealed that astrocytes in the nucleus accumbens have strong molecular rhythms, and this circadian function is important for overall nucleus accumbens function. Forty-three percent of detected genes in the nucleus accumbens astrocyte transcriptome showed significant diurnal variation, with circadian and metabolic processes as the top enriched pathways/processes among these rhythmic genes. They further demonstrated that mice with genetic disruption of nucleus accumbens astrocyte molecular clock function have significantly altered reward-related behavior, including phase-dependent increases in exploratory drive, as well as increases in food self-administration and motivation. At the molecular level, the mice also show disrupted metabolic gene expression, along with significant downregulation of both lactate and glutathione levels in the nucleus accumbens. Loss of nucleus accumbens astrocyte clock function also significantly altered glutamatergic signaling onto neighboring medium spiny neurons, alongside upregulated glutamate-related gene expression.

“This study demonstrates the impressive strength of molecular rhythms in astrocytes in one of the brain’s key reward and emotion regulation centers, and how important these rhythms are to neuronal function and reward-related behavior,” said Dr. McClung.

Astrocyte Molecular Clock Function in the Nucleus Accumbens Is Important for Reward-Related Behavior
Becker-Krail DD, Ketchesin KD, Burns JN, Zong W, Hildebrand MA, DePoy LM, Vadnie CA, Tseng GC, Logan RW, Huang YH, McClung CA. 
Biological Psychiatry, 2022, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2022.02.007.