Date of Award

Spring 1-1-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Pei-San Tsai

Second Advisor

Christopher Lowry

Third Advisor

Sondra Bland

Fourth Advisor

Benjamin Greenwood

Fifth Advisor

Robert Spencer

Abstract

Anxiety disorders are some of the most commonly diagnosed psychopathologies in both pediatric and adult populations and have been linked to disrupted brain serotonergic systems. The risk for adult anxiety disorders increases in people with a history of childhood or adolescent anxiety, and the average age of onset for anxiety is eleven years old. These data suggest that anxiety has neurodevelopmental origins, yet our understanding of how anxiety-related serotonergic neurocircuits are formed and how their malformation contributes to the etiology of anxiety disorders is far from complete. This dissertation examined the role of fibroblast growth factor 8 (Fgf8) signaling in the development of midbrain serotonergic neurons and anxiety-like behavior. Fgf8 is a signaling molecule that coordinates the genesis of the putative midbrain region. My hypothesis is that moderately reduced Fgf8 signaling during development impacts the structure and function of anxiety-related serotonergic neuronal subpopulations, thereby leading to anxiety-related behavior. Using adult male mice genetically altered to produce one-third less Fgf8, we observed defects specifically in anxiety- and panic-related serotonergic subpopulations. These defects included 1) fewer serotonergic neurons, 2) abnormal activation and functional responses of serotonergic neurons following a stressful stimulus, and 3) increased baseline anxiety-like behaviors. The results from this dissertation expand our knowledge on how developmental disruption of specific subpopulations of serotonergic neurons can affect their structural and functional integrity, thereby contributing to the persistent manifestation of anxiety behaviors. Overall, this dissertation suggests a role of Fgf signaling in the neurodevelopment of circuits that are disrupted in anxiety and affective disorders.

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