Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group


First Advisor

Tracy L. Bale


Neuropsychiatric diseases represent a major public health burden worldwide; due to gaps in our understanding of the pathogenic mechanisms of disease, approximately 30% of patients are refractory to treatment. Activation of neuroinflammatory signaling cascades has shown promise as a contributing factor for disease development. This hypothesis is driven in part by an intriguing overlap of symptoms in patients with neuropsychiatric and immunological disorders. Patients with depression, bipolar disorder, schizophrenia, and autism commonly present with immune dysfunction, while patients with multiple sclerosis, lupus, and rheumatoid arthritis often experience severe mood disturbances. Diversity in presentation of symptoms, however, has posed a research challenge to our mechanistic understanding of this link. In contrast to the complexity of modeling specific diseases, altered sensitivity to stress is a well-documented vulnerability marker across neuropsychiatric disorders. Of relevance to clinical advancement, aspects of stress behavior and physiology can be modeled and measured in animals, where core components of the stress axis are conserved in humans and rodents. Thus, we performed an examination of the neuroinflammatory regulation of stress behavior and physiology. Using a genetic model of stress sensitivity, we report the discovery that anti-inflammatory treatment ameliorates hypothalamic-pituitary-adrenal axis dysregulation, identifying the dorsal raphe (DR) as a locus of heightened responsivity. We then demonstrated sex differences in this brain region in response to the stress neuropeptide, corticotropin-releasing factor, suggesting that differences in its responsivity may underlie sex differences in vulnerability to stress-related disorders. Finally, we used a transgenic approach to show that neuroinflammation localized specifically to the DR results in dysregulated stress behavior and physiology through interactions with the serotonergic neurotransmitter system. Overall, this work demonstrates that hyper- or hypo-function of the DR, based on genetic susceptibility, sex, or neuroinflammatory insult, can result in altered stress physiology and behavior. Though the DR has previously been identified as a potential locus of dysregulation, here we establish the specific, mechanistic link between risk factors for stress-related disorders. We present evidence of quantitative changes to this brain region and its functional output, and demonstrate that differences in responsivity of the DR may underlie vulnerability to stress-related disorders.

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