Sex Differences in Glial Function

Many neuropsychiatric disorders exhibit marked sex differences in prevalence and age of onset.  Males are more likely to have disorders that arise in early childhood, including autism and learning disabilities.  Females more often have disorders that arise during puberty, including anxiety and depression.  This epidemiology suggests that there are sex-based neurobiological differences, which are likely to arise during development, that either directly promote specific neuropsychiatric disorders or increase the susceptibility to environmental factors that lead to such disorders. We have reported that male neonatal (postnatal day (P) 4) mice and rats display a markedly increased number of microglia in brain regions important for emotion and cognition. More recently, we used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer’s and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer’s Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. 

Representative Publications:

  1. Schwarz, JM, Sholar, P, & Bilbo SD.  (2012) Sex differences in microglial colonization of the developing rat brain. Journal of Neurochemistry, 120(6): 948-63. PMCID: PMC3296888
  2. Hanamsagar, R, Alter, MD, Block, CS, Sullivan, H, Bolton, JL, Bilbo SD. (2017) Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. GLIA, 65(9): 1504-1520. PMCID: PMC5540146
  3. Smith, CJ, Kingsbury, MA, Dziabis, JE, Hanamsagar, R, Malacon, KE, Tran, JN, Norris, HA, Guilino, M, Bordt, EA, Bilbo, SD. (2020) Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number. Brain, Beh, Immunity, 90:332-345.