Author ORCID Identifier

https://orcid.org/0000-0001-6254-3391

Date of Award

1-7-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Kim L. Huhman

Second Advisor

H. Elliott Albers

Third Advisor

Nancy G. Forger

Fourth Advisor

Erin B. Tone

Abstract

Social stress is implicated in the etiology and persistence of neuropsychiatric disorders in humans and is investigated using social defeat models in animals. Multiple factors influence how social stress impacts the brain and behavior, either reducing or enhancing susceptibility to maladaptive responses. The overarching goal of this project was to identify factors that promote resiliency to social defeat stress throughout the lifespan. In Aim 1, we investigated the effects of social defeat during development and found that a brief, pubertal social defeat increases susceptibility to adult social stress. In Aim 2, we tested whether epigenetic changes, namely histone deacetylation (HDAC), underlie either the short- or long-term effects of this brief, pubertal defeat; however, systemic HDAC inhibitors did not alter behavioral responses to pubertal social defeat. Shifting focus to potential treatment options and resiliency factors in adults, Aim 3 explored whether brain-derived neurotrophic factor (BDNF) prevents or promotes responses to social defeat stress. In Aim 3a, we determined that increasing BDNF activity either systemically or within the basolateral amygdala reduced responses to social defeat in both hamsters and mice. This is consistent with significant evidence that BDNF/tropomyosin receptor kinase B (TrkB) signaling provides anti-depressant effects but is contrary to research showing that BDNF/TrkB signaling enhances responses to chronic social defeat stress in mice. Thus, in Aim 3b, we investigated a possible explanation for these seemingly contradictory results, testing whether BDNF/TrkB activates different neural circuits after acute versus repeated social defeat. Unfortunately, these results were inconclusive. Finally, in Aim 3c, we tested the hypothesis that circadian phase underlies the contrasting BDNF/TrkB results and found that systemic TrkB agonism interacts with circadian phase to alter responses to acute social defeat in hamsters, reducing responses to social defeat during the dark phase but enhancing responses during the light phase. This interaction effect was not found in mice, wherein BDNF/TrkB signaling reduced responses to acute social defeat regardless of circadian phase. Collectively, these data demonstrate several factors that significantly impact resiliency to social stress including developmental period, stressor repetition, BDNF signaling and, lastly, circadian phase, a critical factor that is often overlooked in stress research.

DOI

https://doi.org/10.57709/24353740

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