ºìÐÓÊÓƵ

Topic

Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus

Division of Medical Sciences

Date & location

• Tuesday, December 3, 2024
• 9:00 A.M.
• Virtual Defence

Examining Committee

Supervisory Committee

• Dr. Marie-Eve Tremblay, Division of Medical Sciences, University of Victoria (Supervisor)
• Dr. Stephanie Willerth, Division of Medical Sciences, UVic (Member)
• Dr. Manu Rangachari, Department of Molecular Medicine, Université Laval, UVic (Outside Member)

External Examiner

• Dr. Jessica Rosin, Department of Oral Biological & Medical Sciences, University of British Columbia

Chair of Oral Examination

• Dr. Jean Buckler, School of Exercise Science, Physical and Health Education, UVic

Abstract

The brain presents various structural and functional sex differences, for which multiple influences are attributed: genetic, epigenetic, metabolic, and hormonal. While biological sex is determined by both sex chromosomes and sex hormones, little is known about how these two factors interact to establish this dimorphism. Sex differences in the brain also affect its resident immune cells, microglia, which actively survey the brain parenchyma and interact with sex hormones throughout life. However, microglial differences in density and distribution, morphology and ultrastructure patterns in physiological conditions during adulthood are largely unknown. Here, we investigated these aforementioned properties of microglia using the Four Core Genotypes (FCG) model, which allows for an independent assessment of gonadal hormones and sex chromosomal effects in four conditions: XX and Tg XY^- (both ovaries); Tg XX^Sry and Tg XY^Sry (both testes). We also compared the FCG results with XX and XY wild-type (WT) mice. In young adult mice, we focused our investigation on the ventral hippocampus across different layers: stratum radiatum (Rad), stratum lacunosum-moleculare (LMol) and the polymorphic layer of the dentate gyrus (PoDG). Double immunostaining for Iba1 and TMEM119 revealed that microglial density is influenced by both sex chromosomes and sex hormones. We show in the Rad and LMol that microglia are denser in XX mice compared to Tg XY^Sry mice, however, microglia were densest in WT XX mice. In the PoDG, ovarian animals had increased microglial density compared to testes animals. Additionally, microglial morphology was modulated by a complex interaction between hormones and chromosomes, affecting both their cellular soma and arborization across the hippocampal layers. Lastly, ultrastructural analysis showed that microglia in WT animals make overall more contacts with pre- and post-synaptic elements than in FCG animals. Moreover, microglial markers of cellular stress, including mitochondrion elongation, dilation of the endoplasmic reticulum and Golgi apparatus were mostly chromosomally driven. Overall, we characterized different aspects of microglial properties during normal physiological conditions that were found to be shaped by sex chromosomes and sex hormones, shading more light onto how sex differences affect brain immunity at steady-state.