Thesis Seminars

Margaux C. Masten - PhD Candidate, Neuroscience Graduate Program

There is a growing body of epidemiological evidence linking air pollution (AP) exposure and increased risk for multiple childhood onset neurodevelopmental disorders (NDDs) including attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Exposure to AP in the third trimester of pregnancy has been linked with higher odds of ASD diagnosis, as well as, more symptoms of inattention and decreased corpus callosum (CC) volume associated with increased hyperactivity. Ultrafine particulate matter (UFP) is one of the most reactive components of AP, due to its large surface area to volume ratio. Furthermore, UFPs present a unique challenge as their small size allow them to penetrate deep into the lungs and traverse many of the body’s barrier mechanisms such as the placenta and the blood brain barrier, creating a unique challenge for the developing brain during gestation. Previous work from our lab in C57BL/6J mice shows that gestational and early postnatal exposures to ambient UFP from traffic related air pollution trigger unique sex-dependent neurobehavioral outcomes, with ventriculomegaly, alterations in myelination of the CC, persistent CC microglial activation, elevated glutamate in the brain, metal dyshomeostasis, and behavioral deficits including impulsivity, cognitive inflexibility, and altered social interaction. However, the sex-difference and directionality of these effects vary between gestational and post-natal exposures. Due to the altricial brain development at birth in traditional laboratory rodents, we do not know if the differences are due to critical windows of exposure or differential routes of exposure. Unlike C57BL/6J mice, the African Spiny mouse (genus Acomys) is born precocial with neural development more similar to humans at the time of birth. This unique model allows us to test the neurotoxicity of air pollution during late gestation with a more translational pattern of brain development. In addition to their precocial brain development at birth, spiny mice are highly social animals allowing for more expanded social behavioral evaluations. The central hypothesis of this thesis is that late gestational UFP exposure induces neurodevelopmental changes in spiny mice similar to the effects seen in postnatal C57BL/6J UFP exposures, including altered white matter development, cognitive inflexibility, and social behavioral deficits.

Experiments from Aim 1 will use transmission electron microscopy to characterize UFP metal contaminants and particle characteristics across maternal cranial nerves, maternal olfactory bulbs, placenta, and the periventricular region of the fetal brain. We hypothesize that inhaled UFP from the dam will translocate across the placenta and into the pup brain and will show differential bioprocessing in the maternal and fetal brains. In Aim 2 we will use electron microscopy and immunohistochemistry to identify changes in myelination and white matter tracts. We hypothesize that exposure in the spiny mice will lead to white matter damage with decreased corpus collosum size, altered myelin ultrastructure, and enlarged lateral ventricles in a male-biased manner. Experiments from Aim 3 will test social interaction and cognitive flexibility using behavioral paradigms including measures of social interaction and communication as well as the translationally relevant ID/ED shift operant task. We predict there will be sex-dependent deficits in social communication and cognitive flexibility in spiny mice exposed to UFP during the late gestational period in utero. Together these experiments will expand our understanding of how late gestational exposure to air pollution confers risk for multiple neurodevelopmental disorders that share sex-biased prevalence rates and behavioral presentations.

 Mar 07, 2025 @ 12:00 p.m.
 Medical Center | Adolph Lower Aud. (1-7619)