Date of Award

8-13-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Geert J. de Vries

Second Advisor

Nancy G. Forger

Third Advisor

Aras Petrulis

Fourth Advisor

Andrew T. Gewirtz

Abstract

The gut microbiota is a complex ecosystem of microorganisms that form a bidirectional communication pathway with the brain, called the gut-brain axis. In addition to their roles in mediating host metabolism and digestion, a wealth of research is identifying roles for the gut microbiota in neural development and function, immune modulation, and behavioral expression. Many neural targets of gut-brain axis signaling have been identified, but little attention has been paid to vasopressin and oxytocin. Vasopressin and oxytocin are neuropeptides that are targets of immune signaling and are implicated in the control of anxiety-like, depressive-like, and social behaviors, making them likely mediators in the communication between the gut and the brain. As the immune system is a main signaling pathway in the gut-brain axis, it is possible that vasopressin and oxytocin would be affected through immune system activation to result in behavioral alterations seen in microbiota dysbiosis. To test these predictions, we used pro-inflammatory and anti-inflammatory microbiota manipulation mouse models to identify the roles of vasopressin and oxytocin in the gut-brain axis. First, we demonstrated that microbiota is needed for proper vasopressin and oxytocin system development by using a germ-free mouse model. Second, we explored the impacts that chronic intestinal inflammation has on behavior and neuropeptide expression in Toll-like receptor 5 knockout (T5KO) mice. Third, we investigated whether the behavioral phenotype in T5KO mice is microbiota dependent. Collectively, these experiments provide support to the hypothesis that microbiota alter the vasopressin and oxytocin systems through an immune-mediated pathway to alter the behavior of both mouse models. They also support the use of T5KO mice in investigating the interplay between chronic, low-grade inflammation and psychiatric disorders. Future experiments are needed to uncover the exact mechanisms underlying the microbiota-gut-brain-behavior axis and understanding this axis will provide a basis for developing microbiota-based therapeutics to treat CNS disorders.

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