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Circadian rhythms are critical for human health and are highly conserved across species, controlling physiological processes and behavior across the light/dark cycle. In addition to regulating basic physiological processes and brain function, disrupted circadian genes are linked to altered mood and substance use vulnerability. Circadian genes modulate behavior through specific cell types in the nucleus accumbens, particularly dopamine D1-expressing medium spiny neurons. However, diurnal rhythms in transcript expression have not been investigated in medium spiny neurons in the nucleus accumbens.

“Medium spiny neurons are critically important to how the nucleus accumbens regulates behavior, like reward and mood. Understanding their molecular rhythms will give us new insights into how rhythms in these behaviors are established and could be key to discovering novel treatment approaches in the future,” said Lauren DePoy, PhD, (Research Instructor in Psychiatry), first author of a study recently published in Molecular Psychiatry.

Investigators including Dr. DePoy, Kyle Ketchesin, PhD (Assistant Professor of Psychiatry); Madeline Scott, PhD (postdoctoral associate); and Colleen McClung, PhD (Professor of Psychiatry and Clinical and Translational Science), used mouse models to measure transcript expression rhythms in different cell types in the nucleus accumbens. The team identified and characterized rhythmic transcripts in D1- and D2-expressing neurons in that brain region, and compared rhythmicity results to whole nucleus accumbens homogenate as well as astrocyte samples.

Results from the study revealed  that all cell types have transcripts with diurnal rhythms and that top rhythmic transcripts are largely core clock genes, which peak at approximately the same time of day in each cell type and sex. While clock-controlled rhythmic transcripts are enriched for protein regulation pathways across cell type, cell signaling- and signal transduction-related processes are most commonly enriched in medium spiny neurons. In contrast to core clock genes, these clock-controlled rhythmic transcripts tend to reach their peak in expression about two hours later in females than in males. The team also found sex differences in pathway enrichment for rhythmic transcripts that peak at different times of day, and that several classic markers used to categorize medium spiny neurons are actually rhythmic in the nucleus accumbens.

"This study discovered some surprising differences in molecular rhythms across dopamine D1 and D2 receptor expressing neurons, as well as neighboring astrocytes in the nucleus accumbens, a region of the brain known for the regulation of emotion and reward value,” said Dr. McClung, the study’s senior and corresponding author. “These results are important in understanding how the brain normally functions across the day/night cycle and paves the way for future studies assessing the importance of these cell type specific rhythms in psychiatric disorders.”

Cell-type and sex-specific rhythmic gene expression in the nucleus accumbens
DePoy LM, Petersen KA, Zong W, Ketchesin KD, Matthaei RC, Yin R, Perez MS, Vadnie CA, Becker-Krail D, Scott MR, Tseng GC, McClung CA.
Molecular Psychiatry (2024). https://doi.org/10.1038/s41380-024-02569-7