Graduation Date

Spring 5-7-2022

Document Type


Degree Name

Doctor of Philosophy (PhD)


Integrative Physiology & Molecular Medicine

First Advisor

Adam J. Case

Second Advisor

Kaushik P. Patel


Posttraumatic stress disorder (PTSD) is a devastating psychiatric disorder characterized by distinctive symptom clusters, including intrusive memories (i.e., flashbacks), avoidance of related stimuli, affective changes, and hyperarousal. Strikingly, patients with PTSD face a significantly increased risk for a number of inflammation-driven pathologies, ranging from cardiovascular to autoimmune disease. Yet, the exact etiology of this increased risk remains unknown. The immune system is known to be strongly influenced by the sympathetic nervous system, and sympathetic overactivity is a hallmark of PTSD. Lymphoid organs, such as the spleen, are richly innervated by sympathetic nerve fibers which terminate near adaptive immune cells, namely T-lymphocytes. Importantly, T-lymphocytes are able to receive and synthesize catecholamines (dopamine, norepinephrine, epinephrine; neurotransmitter effectors of the sympathetic nervous system), resulting in altered function. The work herein assesses the causal role of this neuroimmune connection in the inflammation seen following psychological trauma. Firstly, a murine model of PTSD known as repeated social defeat stress (RSDS) was adapted and validated. RSDS resulted in robust increases in systemic inflammation as measured by elevated pro-inflammatory cytokines, which were also strongly linked to anxiety-likebehavior. Within the spleen, measures of sympathetic tone were elevated, and splenic T-lymphocytes demonstrated increased mitochondrial superoxide specifically, which is a critical regulator of T-lymphocyte activation and inflammation. Within purified T-lymphocytes, RSDS increased expression of pro-inflammatory cytokines, which were strongly correlated with expression of tyrosine hydroxylase (TH; rate-limiting enzyme in catecholamine synthesis). In order to further deduce the role of catecholamines, a method for specific, sympathetic denervation (Dnx) of the spleen was developed. Dnx resulted in attenuation of T-lymphocyte-specific RSDS-induced cytokines, and reversal of mitochondrial superoxide and pro-inflammatory gene expression. Lastly, the effect of T-lymphocyte-generated catecholamines was assessed by generation of a T-lymphocyte-specific TH knockout (KO) mouse. T-lymphocyte TH KO resulted in decreased T-helper 17 (TH17) T-lymphocyte profiles after RSDS, however, the loss did not affect mitochondrial redox changes elicited by RSDS. Collectively, this work demonstrates psychological trauma works in part through sympathetic effectors—generated from both sympathetic nerves and T-lymphocytes—to regulate the T-lymphocyte redox environment and inflammation.

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