Date of Award

Spring 1-1-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Christopher A. Lowry

Second Advisor

Kenneth P. Wright

Third Advisor

Monika Fleshner

Fourth Advisor

Pei-San Tsai

Fifth Advisor

Robert L. Spencer

Abstract

Adverse experiences, whether early in life or in adulthood, alter behavioral, neuroendocrine, and neurochemical responses to future stressors and confer vulnerability to developing stress-related psychiatric disorders including anxiety and mood disorders. One potential hypothesis for how prior stress modifies behavioral and physiologic responses to future stress is through stress-induced adaptations in serotonergic systems. To test this hypothesis, we investigated the effects of daily maternal separation, during a critical period of development, on behavioral coping strategies during social defeat stress in adulthood and serotonergic gene expression using in situ hybridization histochemistry. We also compared early life stress to a model of acute and repeated social defeat in adulthood to investigate whether prior stress in adulthood is sufficient to change behavior as well as functional cellular responses, as measured by the immunohistochemical staining of the neuronal activation marker, c-Fos, in brainstem serotonergic neurons and their afferent neuropeptidergic circuits originating in the forebrain. Maternal separation shifted the coping response during social defeat in adulthood to a more reactive coping strategy, characterized by increased anxiety- and fear-like behaviors, and away from proactive coping, characterized by decreased confrontational and escape behaviors. This behavioral shift was accompanied by stress-induced alterations in tryptophan hydroxylase 2 (tph2) mRNA, encoding the neuronal isoform of the rate-limiting enzyme of serotonin synthesis, specifically in serotonergic neurons in the ventrolateral dorsal raphe nucleus and ventrolateral periaqueductal gray, a subregion implicated in inhibiting fight-or-flight responses, and the dorsal part of the dorsal raphe nucleus (DRD), a subregion that facilitates conflict anxiety. Likewise, exposure to repeated, but not acute, social defeat in adulthood shifted the coping style towards reactive coping and away from proactive coping, and altered the cellular responses of tryptophan hydroxylase-expressing neurons specifically in the DRD. Social defeat also altered forebrain neuropeptidergic systems implicated in control of serotonergic neuronal activity, including orexin/hypocretin, melanin-concentrating hormone and corticotropin-releasing hormone systems. Together, these data identify functionally distinct subpopulations of serotonergic neurons and associated neuropeptidergic circuits that coordinate responses to stress. Dysfunction of these subpopulations and circuits may be involved in the adoption of reactive coping, which may be relevant for vulnerability to stress-related psychiatric disorders.

Share

COinS