Brain region- and sex-specific transcriptional profiles of microglia

Kelly Barko; Micah Shelton; Xiangning Xue; Yvette Afriyie-Agyemang; Stephanie Puig; Zachary Freyberg; George C Tseng; Ryan W Logan; Marianne L Seney

doi:10.3389/fpsyt.2022.945548

Brain region- and sex-specific transcriptional profiles of microglia

Front Psychiatry. 2022 Aug 24:13:945548. doi: 10.3389/fpsyt.2022.945548. eCollection 2022.

Authors

Kelly Barko¹, Micah Shelton¹, Xiangning Xue², Yvette Afriyie-Agyemang^{1

3}, Stephanie Puig^{4

5}, Zachary Freyberg^{1

3

6}, George C Tseng², Ryan W Logan^{4

5

7}, Marianne L Seney^{1

3}

Affiliations

¹ Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
² Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, United States.
³ Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
⁴ Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States.
⁵ Center for Systems Neuroscience, Boston University, Boston, MA, United States.
⁶ Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
⁷ Genome Science Institute, Boston University School of Medicine, Boston, MA, United States.

Abstract

Microglia are resident macrophages of the brain, performing roles related to brain homeostasis, including modulation of synapses, trophic support, phagocytosis of apoptotic cells and debris, as well as brain protection and repair. Studies assessing morphological and transcriptional features of microglia found regional differences as well as sex differences in some investigated brain regions. However, markers used to isolate microglia in many previous studies are not expressed exclusively by microglia or cannot be used to identify and isolate microglia in all contexts. Here, fluorescent activated cell sorting was used to isolate cells expressing the microglia-specific marker TMEM119 from prefrontal cortex (PFC), striatum, and midbrain in mice. RNA-sequencing was used to assess the transcriptional profile of microglia, focusing on brain region and sex differences. We found striking brain region differences in microglia-specific transcript expression. Most notable was the distinct transcriptional profile of midbrain microglia, with enrichment for pathways related to immune function; these midbrain microglia exhibited a profile similar to disease-associated or immune-surveillant microglia. Transcripts more highly expressed in PFC isolated microglia were enriched for synapse-related pathways while microglia isolated from the striatum were enriched for pathways related to microtubule polymerization. We also found evidence for a gradient of expression of microglia-specific transcripts across the rostral-to-caudal axes of the brain, with microglia extracted from the striatum exhibiting a transcriptional profile intermediate between that of the PFC and midbrain. We also found sex differences in expression of microglia-specific transcripts in all 3 brain regions, with many selenium-related transcripts more highly expressed in females across brain regions. These results suggest that the transcriptional profile of microglia varies between brain regions under homeostatic conditions, suggesting that microglia perform diverse roles in different brain regions and even based on sex.

Keywords: RNA-sequencing; Tmem119; disease-associated microglia; microglia; sex difference.

Abstract

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