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A “personality test” for rats reveals subtle but distinct effects of sex and early life inflammation on brain and behavior

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2024
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dissertation
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Brain development is a supremely complex process that begins early in gestation, extends beyond birth and involves a precise sequence of processes that work in concert to ultimately allow for the expression of behaviors an organism will need to navigate life. Perturbation of these processes—for example by gestational inflammation, a well-studied risk factor for neuropsychiatric disorders (NDDs) in humans—can shift the trajectory of brain development at the molecular, cellular and circuit levels, resulting in behavioral alterations that persist beyond the initial insult. Despite converging lines of evidence implicating the immune system in NDD etiology combined with known sex differences in NDD diagnosis rates and the increasingly appreciated role of traditionally immune-associated factors in the sexual differentiation of the brain, a direct link between these three processes remains elusive. The overarching goal of this project is to characterize the enduring effects of early life inflammation on brain and behavior in male and female rats exposed to the viral mimic polyinosinic:polycytidylic acid (poly(I:C), 5 mg/kg) in the first ten days of postnatal life, which roughly correlates to late third trimester pregnancy in humans. Chapter 3 assesses a variety of behaviors—ranging from juvenile social play to adult reward-guided decision-making—following neonatal inflammation, with a focus on behaviors commonly associated with NDDs in humans and rodent models. In Chapter 4, I record from single neurons in nucleus accumbens as rats performed a task commonly used across species to assess cognitive control. I then leverage the fact that all assessments were performed in the same animals by employing factor analysis in Chapter 5, which identified five factors that together reveal novel connections between behavioral measures and neural activity patterns across a condensed set of 48 variables. Collectively, this work suggests that viral-mediated inflammation at this developmental timepoint is not a robust risk factor for an NDD-associated phenotype in rats and, surprisingly, imparted subtle behavioral alterations that could be considered beneficial. Factor analysis further revealed that sex and early life inflammation shifted two distinct modalities of rat “personality”, highlighting the utility of combining modern neuroscience approaches with the study of complex, naturalistic behaviors.

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University of Maryland, Baltimore, School of Medicine, Ph.D. 2024.
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