Date of Award

5-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Developmental and Brain Sciences

First Advisor

Richard G. Hunter

Second Advisor

Jin Ho Park

Third Advisor

Vivian Ciaramitaro

Abstract

Schizophrenia is a heterogenous disorder characterized by a myriad of perturbations including those related to brain physiology, learning, memory, attention, and sensorimotor processing. While the cause of schizophrenia has yet to be elucidated, the use of animals has been critical to teasing apart the individual and intersecting roles of genetic and environmental risk factors in schizophrenia etiology. One way to recreate certain behavioral impairments seen in people with schizophrenia is to disrupt the prenatal or neonatal environment of laboratory rodent offspring. This approach results in a phenotype that is congruent to humans with schizophrenia. While the use of animal models has propelled the mechanistic understanding of schizophrenia pathogenesis forward, there is still more to be uncovered. Recently, strong evidence has demonstrated a role of the non-coding genome, specifically transposable elements (TEs), in schizophrenia etiology. Yet, TEs have only received a fraction of the amount of research as the protein coding genome within animal models of schizophrenia. Therefore, the deep genome represents a novel frontier by which the mechanistic underpinnings and potential therapeutic targets for schizophrenia can be explored. In the present study, we investigated the prenatal disruption known as maternal immune activation (MIA), which is a leading risk factor for developing schizophrenia. We induced MIA in Sprague-Dawley rats to mimic a prenatal exposure to maternal infection and found a sex-specific rearrangement of the heterochromatin landscape of the placenta, as evidenced by an increase in histone-3 lysine-9 trimethylation (H3K9me3). Moreover, MIA was associated with long-term sensorimotor processing deficits as indicated by reduced prepulse inhibition of the acoustic startle reflex (PPI) and an increased mechanical allodynia threshold. Analyses of gene expression within the hypothalamus- chosen for its involvement in the sex-specific pathogenesis of schizophrenia and the stress response- revealed significantly higher levels of the stress-sensitive genes Gr and Fkbp5 and lower levels of Fkbp4. In addition, we found sex-specific increases in the expression of several TEs including IAP, B2 SINE, and LINE-1 ORF1. The data from this study warrant the future consideration of epigenetic regulation of the non-coding genome as a mechanism that drives changes in the development of the brain.

Comments

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