Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Susan K. Wood

Abstract

Social stress is a significant risk factor for the emergence of psychiatric disorders including depression and anxiety. While there are a number of commercially available therapeutic options for the treatment of these disorders, these treatments require weeks of continuous use to produce behavioral efficacy. It has also been suggested that these traditional therapies are only marginally effective in producing complete remission, suggesting that our understanding as it pertains to the mechanisms underlying stressinduced behavioral dysfunction is still in its infancy. In the last few years, inflammation has become a major focus in the field of stress and depression as clinical and pre-clinical models have shown that stress results in an enhancement of inflammation in the periphery and the brain. While the field of stress-induced inflammation is rapidly growing, there is still a vast amount that remains unknown. Therefore, the primary goal of the work described in this dissertation was to elucidate mechanisms underlying stress-induced depressive like behaviors as it pertains to inflammation. Using the resident-intruder paradigm of social defeat, the following studies demonstrate that repeated stress exposure results not only in the enhancement of inflammation but also sensitizes inflammatory responses in the periphery and the brain. While these inflammatory responses are largely indiscriminate as evidenced by enhancement of both pro- and anti-inflammatory cytokines, expression profiles in the brain demonstrated significant regional specificity. Strikingly, these inflammatory responses differed greatly between animals that demonstrated resilience or susceptibility to the behavioral consequences of stress. Rats that exhibited active coping defensive behaviors during the stress exposure demonstrated resilience to the behavioral and inflammatory effects of social defeat. In contrast, rats demonstrating passive coping behaviors during the stress exposure and subsequent susceptibility to the depressogenic effects of social defeat exhibited robust neuroinflammation within the locus coeruleus (LC). Peripheral administration of resveratrol, a natural anti-inflammatory, seven days prior to and during the 5-day social defeat period was able to dose dependently inhibit these behavioral and inflammatory effects in susceptible rats. Importantly, only the highest dose which achieved complete inhibition of stress-induced inflammation was associated with complete inhibition of depressive-like behaviors. A follow-up study demonstrated that stress-induced inflammatory effects in the periphery and the brain were directly dependent upon norepinephrine (NE) derived from the LC. In the periphery LC-derived NE was found to potentiate and sensitize stress-induced inflammation as evidenced by enhanced cytokine concentrations in the plasma. While the effects of LC derived NE in the plasma were clear, the effects of LC-NE on the brain were highly dependent upon the brain region analyzed. For example, loss of NE in the central amygdala (CeA) in response to stress or pharmacological NE lesion of the LC, resulted in a significant enhancement of inflammation within this region. In contrast, inflammatory responses in the dorsal raphe were largely independent of LC-NE. Inflammation in the brain is known to result in significant shift in neuronal function and with respect to the CeA has been shown to engage signaling cascades associated with tyrosine receptor kinase (Trk)B, which has been suggested to underlie the emergence of anxiety-like behaviors and cardiovascular abnormalities. To elucidate the specific involvement of this receptor in stress-induced behavioral and cardiovascular responses, a small molecule TrkB inhibitor was injected directly into the CeA 30-minutes prior to social defeat on days 1, 3, and 5. Notably, CeA TrkB signaling was directly associated with the expression of defensive behaviors and cardiovascular reactivity during defeat. These effects were associated with enhanced TrkB phosphorylation and were accompanied by preferential activation of the extracellular signal-regulated kinase (ERK) pathway. Surprisingly, these effects in cellular signaling occurred independently of the TrkB ligand brain derived neurotrophic factor (BDNF). While CeA TrkB signaling was critical for the expression of behavior and cardiovascular responses during stress, behaviors and cardiovascular measurements obtained after stress exposure were largely independent of the CeA and TrkB. Taken together, the studies outlined in this particular document function to (1) directly implicate inflammatory processes in the emergence of stress-induced behavioral dysfunction, (2) suggest that these responses are driven by LC derived NE, and (3) begin to probe inflammatory sensitive mechanisms that may be involved in the expression of adverse behaviors.

Rights

© 2019, Julie Elaine Finnell

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