Date of Degree

5-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Probal Banerjee

Committee Members

Greg Phillips

Dan McCloskey

Lorenz S. Neuwirth

Sara R. Guariglia

Jeffrey S. Goodman

Kathryn Chadman

Subject Categories

Behavioral Neurobiology | Biology | Cell and Developmental Biology | Cell Biology | Cognitive Neuroscience | Computational Neuroscience | Developmental Biology | Developmental Neuroscience | Molecular and Cellular Neuroscience | Nervous System Diseases | Neuroscience and Neurobiology

Keywords

neurodevelopment, serotonin, brain, neuroscience, anxiety, depression

Abstract

Anxiety affects nearly twice as many women as it affects men across all cultures and economic groups. Importantly, girls have a higher chance of inheriting anxiety disorders than boys, and many anxiety disorders appear at a very young age. However, little is known about sex differences in brain and behavioral development and how they relate to anxiety in adulthood. Serotonin 1A receptor (5-HT1A-R) mediated signaling has been implicated in depression and anxiety, however most studies that focus on the involvement of the 5-HT1A-R have been conducted in adults. Little is known about how the 5-HT1A-R might be linked to behavioral and brain development and if sex differences play an important role in this process. A possible time window during which brain development might be vulnerable to aberrant signaling is during the first few weeks of life in the mouse, which may correspond to the first 3-6 months in human infants. This critical period is characterized by a peak in neurogenesis at around postnatal day 8 (P8) in mice, and the beginning of synaptogenesis thereafter. Although neurogenesis has been found to be decreased in the brains of depressed patients, and sex differences have been recorded, the link between postnatal neurogenesis and adult anxiety has not been investigated until now. In addition, the first few weeks of life in the mouse are also characterized by a series of behavioral milestones including ultrasonic vocalizations, righting, grasping and startle reflexes. The 5-HT1A-R knockout (KO) mouse model of anxiety has been used extensively to investigate anxiety and depressive behaviors, but not in the context of brain and behavioral development. In this project, postnatal behavioral milestones were evaluated in relation to anxiety, and neurogenesis and synaptogenesis were also investigated. We observed sex differences in the production of ultrasonic vocalizations on P8, adult behavior, and postnatal neuroproliferation. KO female mice produced more vocalizations on P8 and, in adulthood, displayed elevated anxiety on the elevated plus maze, open field, and light dark chamber tests. In general, we observed a significant linear relationship between the number of calls at P8 and anxiety behavior in adulthood. The KO female mice also had lower levels of neuroproliferation, but higher amounts of post-mitotic cells in the dentate gyrus at P8. No significant differences were observed in synaptogenesis in the CA1 region of the hippocampus at P10. Together these results showed that the female mice were more prone to anxiety. Female-specific aberrances did appear postnatally in both behavioral features as well as brain development. These predictive phenotypes of anxiety can be used in future rescue studies to investigate early sex-specific interventions.

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