Sparkes, Kerri M. (2024) Investigating the role of neural and immune androgen signaling in male vulnerability to neurodevelopmental disorders. Masters thesis, Memorial University of Newfoundland.
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Abstract
There is a prevalent sex bias in neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), such that males are 3 to 4 times more likely to be diagnosed than females. A potential reason for this sex bias is the prenatal androgen surge in male offspring that serves to masculinize some areas of the fetal brain while defeminizing others. The neuroimmune system is also quite important during development as microglial cells (innate immune cells of the brain) are some of the first cells to differentiate, and these cells are responsible for guiding critical processes during neurodevelopment such as synapse pruning and apoptosis. Microglia are also important in the sexual differentiation of the brain and are themselves sexually differentiated. As both of these factors are important for neurodevelopment, it is possible they interact to increase risk of NDD in males. I investigated whether microglial androgen receptors (AR) contribute to neonatal and juvenile behaviours often disrupted in NDDs using a knockout approach: 1) microglia/macrophage androgen receptor knockout (mARKO), and 2) neural progenitor/neuron androgen receptor knockout (nARKO). I hypothesized that reducing AR in microglia may be more effective compared to neural AR in decreasing ASD-like behaviours. Ultimately, I found no social behaviour differences among the genetic groups with the exception of early (neonatal) communication disruptions in the nARKO genotype. Contrary to my hypothesis that ARKO would reduce the likelihood of NDD-like behaviours in the juvenile period, mARKO showed consistent and persistent hyperactivity reminiscent of ADHD as well as a downregulation in dopamine transporter (DAT), a serotonin receptor (Htr1a) and brain derived neurotrophic factor (BDNF), also consistent with ADHD, compared to the wildtype controls. As such, these findings suggest that microglial AR may ANDROGEN EXPOSURE AND MIA ON SOCIAL BEHAVIOUR contribute to the development of ADHD-like behaviours and should be investigated further as a potential model for this disorder.
| Item Type: | Thesis (Masters) |
|---|---|
| URI: | http://research.library.mun.ca/id/eprint/16649 |
| Item ID: | 16649 |
| Additional Information: | Includes bibliographical references (pages 73-94) -- Restricted until September 1, 2025 |
| Keywords: | androgen signaling, neurodevelopmental disorder, microglia, neurons, sex differences |
| Department(s): | Humanities and Social Sciences, Faculty of > Psychology Science, Faculty of > Psychology |
| Date: | July 2024 |
| Date Type: | Submission |
| Library of Congress Subject Heading: | Microglia--Physiology; Sex differences (Psychology); Prenatal influences; Androgens--Physiological effect; Developmental disabilities; Developmental neurobiology |
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