All ETDs from UAB

Advisory Committee Chair

Ilan A Kerman

Advisory Committee Members

Sarah M Clinton

Lori L McMahon

Linda S Overstreet-Wadiche

Lucas Pozzo-Miller

Michael Wyss

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Norepinephrine in the central nervous system (CNS) is a key mediator of stress-elicited behavioral and physiological adaptations. However, our understanding of central noradrenergic circuitry that regulates specific stress-elicited adaptations is incomplete. The working model for the studies described in this dissertation is that disruptions of specific noradrenergic circuits are responsible for the manifestation of distinct stress-elicited behaviors. Initially the organization of descending noradrenergic neurons with poly-synaptic collaterals to the adrenal gland and skeletal muscle was defined. These noradrenergic presympathetic-premotor neurons (PSPMNs) were distributed within the ventral locus coeruleus (LC), nucleus subcoeruleus (SubC), and the A7 cell group. Then behavioral characterization was performed in the Wistar-Kyoto (WKY) rat, a strain that exhibits dysregulated noradrenergic signaling. These rats exhibit: 1) high baseline levels of immobility, and 2) increasing immobility upon re-exposure to the forced swim test (FST), a model of behavioral despair. Using immunocytochemical staining for c-Fos, a marker of neuronal activation, this study then demonstrated hypoactivation within the A2 noradrenergic cell group and hyperactivation within the LC in the WKYs in response to FST. In follow-up studies, an anti-dopamine beta-hydroxylase antibody conjugated to saporin was used to selectively lesion the A2 noradrenergic neurons in Wistar rats. These lesioned animals manifested increased baseline FST immobility, similar to the behavior of WKY rats, implicating A2 neurons in mediating behavioral despair. Taken together, these results extend our understanding of the role of the norepinephrine system in the CNS by assigning function and connectivity to a novel descending and a novel ascending noradrenergic circuit. The descending circuitry is made up of noradrenergic PSPMNs within the A7, SubC, and ventral LC. These neurons do not appear to be engaged by emotional stressors such as FST, but may be involved in mediating adaptations to homeostatic perturbations. The A2 noradrenergic neurons are part of the ascending circuitry, which mediates motor responses to emotional stress, a heretofore unrecognized role for this cell group. These descending and ascending circuits may be targets for future interventions to ameliorate specific homeostatic and behavioral disturbances of stress-related disorders.

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