Sex Differences in Molecular Rhythms in the Human Cortex

Document Type

Article

Publication Date

1-1-2022

Publication Title

Biological psychiatry

Keywords

JMG, Molecular rhythm, Postmortem brain, Sex difference

JAX Source

Biol Psychiatry . 2022 Jan 1;91(1):152-162.

Volume

91

Issue

1

First Page

152

Last Page

162

PMID

33934884

DOI

10.1016/j.biopsych.2021.03.005

Grant

This work was supported by the National Institutes of Health (NIH) National Institute of Mental Health (NIMH) (Grant No. R01MH120066 [to MLS], Grant No. R01MH111601 [to CAM and GT], and Grant Nos. R01MH109677, R01MH109897, and R01MH110921 [to PR]), NIH National Institute on Drug Abuse (Grant No. DA051390 [to MLS and RWL]), Department of Veterans Affairs Merit Review Award (Grant No. BX 002395 [to PR]), and Brain & Behavior Research Foundation (Independent Investigator Grant [to CAM]). Data were generated as part of the CommonMind Consortium, sup- ported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd., NIH NIMH (Grant Nos. R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, R01MH075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897, U01MH103392, and U01MH116442), NIMH Scienti c Cores Intramural Research (Project No. MH002903), and NIMH Intramural Research Program (Contract No. HHSN271201300031C). Brain tissue for the study was obtained from the following brain bank collections: Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue Repository, Uni- versity of Pittsburgh Brain Tissue Donation Program, and NIMH Human Brain Collection Core.

Abstract

BACKGROUND: Diurnal rhythms in gene expression have been detected in the human brain. Previous studies found that males and females exhibit 24-hour rhythms in known circadian genes, with earlier peak expression in females. Whether there are sex differences in large-scale transcriptional rhythms in the cortex that align with observed sex differences in physiological and behavioral rhythms is currently unknown. METHODS: Diurnal rhythmicity of gene expression was determined for males and females using RNA sequencing data from human postmortem dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Sex differences among rhythmic genes were determined using significance cutoffs, threshold-free analyses, and R difference. Phase concordance was assessed across the DLPFC and ACC for males and females. Pathway and transcription factor analyses were also conducted on significantly rhythmic genes. RESULTS: Canonical circadian genes had diurnal rhythms in both sexes with similar amplitude and phase. When analyses were expanded to the entire transcriptome, significant sex differences in transcriptional rhythms emerged. There were nearly twice as many rhythmic transcripts in the DLPFC in males and nearly 4 times as many rhythmic transcripts in the ACC in females. Results suggest a diurnal rhythm in synaptic transmission specific to the ACC in females (e.g., GABAergic [gamma-aminobutyric acidergic] and cholinergic neurotransmission). For males, there was phase concordance between the DLPFC and ACC, while phase asynchrony was found in females. CONCLUSIONS: There are robust sex differences in molecular rhythms of genes in the DLPFC and ACC, providing potential mechanistic insights into how neurotransmission and synaptic function are modulated in a circadian-dependent and sex-specific manner.

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