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.
Recommended Citation
Nam, Hyungwoo, "Norepinephrine Circuits in Mediating Stress-Elicited Behavior" (2015). All ETDs from UAB. 2559.
https://digitalcommons.library.uab.edu/etd-collection/2559