Prenatal Environmental Stressors Impair Postnatal Microglia Function and Adult Behavior in Males

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2020

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Autism is one of the most common neurodevelopmental disorders and is characterized by deficits in social and communication behavior along with repetitive interests. Large scale genetic studies implicate synaptic dysfunction as a mechanism for disease pathogenesis, and increasingly is accompanied by immune dysfunction. Microglia are the primary immune cells in the CNS. They are important in immune host defense and are involved in normal brain development including refinement of synapses. Previous research has demonstrated that microglia are abnormal in several neurodevelopmental disorders including autism, and in rodent models, transgenic manipulation of microglia function results in brain dysfunction. However, it is unclear whether environmentally relevant immune activation, such as maternal immune activation during pregnancy produces a similar phenotype. Here I used a mouse model where pregnant females are exposed to a combination of two environmental toxins to investigate the cellular mechanisms by which these combined stressors alter the developing brain of offspring. In this model, pregnant mouse dams are intermittently exposed to diesel exhaust particles throughout gestation, as a model of air pollution exposure. This exposure is combined with nest material restriction during the last trimester of gestation to induce stress. I found that combined prenatal exposure to air pollution and maternal stress induced maternal immune activation in pregnant dams primarily via TNF-. I found that offspring born to mothers prenatally exposed to environmental toxins had altered communication as neonates, and interestingly, only male offspring had alterations in social and communication behavior as adults. Developing offspring exhibited sexually dimorphic changes in the transcriptome of the prefrontal cortex, including a male specific downregulation of synaptic genes. In the ACC, a brain region critical for regulating social and communication behavior, male offspring displayed persistent abnormal thalamocortical connectivity. When we performed in vivo functional recordings from brain networks important for social behavior, we found that only males engaging in a social preference task, had impaired activation of this network. Microglia development and microglia-synapse interactions were also altered in the anterior cingulate cortex of male offspring, specifically I discovered a unique type of functional heterogeneity in microglia early in development and found that this functional heterogeneity could be modulated by prenatal exposure to environmental toxins. Finally, this heterogeneity was associated with a loss of normal pruning function, which was accompanied by enduring changes in brain wiring. I found that elimination of microglia early in development could mimic some of the behavioral phenotypes observed in our combined stress males. These data suggest that the brain abnormalities which were found in male’s is not due to a toxic gain of function in microglia, but instead a loss of normal microglia function. While the prevailing hypothesis in the field has been that immune activation induces chronic inflammation and a toxic gain of function in microglia, my research demonstrates that a loss of normal microglia can also profoundly alter brain wiring and function.

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Block, Carina Lea (2020). Prenatal Environmental Stressors Impair Postnatal Microglia Function and Adult Behavior in Males. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/22198.

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