Date of Award

5-1-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Kim L Huhman

Second Advisor

H Elliott Albers

Third Advisor

Daniel Cox

Fourth Advisor

Katharine McCann

Fifth Advisor

Aaron Roseberry

Abstract

Social stress is a salient risk factor for the etiology and persistence of multiple neuropsychiatric diseases including schizophrenia, anxiety, and mood disorders and is often studied in rodents using social defeat models. A goal of understanding the neural substrates and molecular mechanisms underlying neurophysiological responses to social stress is to discover potential targets for novel, more effective treatments for these debilitating diseases. The overarching goal of this project was to evaluate two potential mechanisms underlying social stress-induced behavioral changes: brain derived neurotrophic factor (BDNF) and perineuronal nets (PNNs). In Aim 1, we tested the hypothesis that BDNF, a neurotrophic factor implicated in the function of anti-depressants, affects responses to social stress differentially in the light and the dark. Indeed, we found that manipulation of BDNF signaling has opposing effects on the response to social stress in the light versus the dark phase of the daily cycle. In Aim 1a, we examined cellular activation in key brain regions that are responsive to social defeat stress and BDNF-signaling but none were differentially affected by lighting. In Aim 1b, we tested the hypothesis that downstream effectors of BDNF-signaling are differentially expressed in the light and the dark. We found that the BDNF receptor tropomyosin kinase receptor B (TrkB) transcripts increase in the light in ACC and that gad1, a genetic marker for GABAergic cells, is lower in the light than in the dark in the BLA. In Aim 2, we investigated whether perineuronal nets (PNNs), an extracellular proteoglycan matrix protein involved in synaptic plasticity, were changing across the light:dark cycle or after social defeat stress. In hamsters, PNNs did not vary across the light:dark cycle, but they did change in a sex-specific manner after social defeat stress specifically in hippocampal area CA1. There were also sex differences in WFA expression in BLA and SSC. Collectively, these data revealed that both BDNF and PNNs are candidates in the modulations of behavioral responses to social defeat stress, and, in particular, the current data emphasize the importance of time-of-day as a critical variable when assessing potential therapeutic potential of novel interventions for stress-related neuropsychiatric disorders.

DOI

https://doi.org/10.57709/36969697

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