Defense Date

9-10-2021

Graduation Date

Fall 12-17-2021

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Biological Sciences

Committee Chair

Benedict J Kolber

Committee Member

Sarah K Woodley

Committee Member

John A Pollock

Committee Member

Allyson F O'Donnell

Committee Member

Sarah E Ross

Keywords

pain, lateralization, central amygdala, parabrachial nucleus, bladder

Abstract

The central amygdala (CeA) is a bilateral, mid limbic brain region involved in the processing of pain and emotion. Interestingly, the left and right CeA are functionally lateralized in the context of bladder pain, with the left and right CeA having opposing effects on bladder pain-like behavior. However, the specific mechanisms driving these divergent functions are unknown. Nociceptive signals from the bladder are relayed to the CeA via projection neurons in the parabrachial nucleus (PBN) that express high levels of calcitonin gene-related peptide (CGRP). In these studies, we investigated the influence of PBN CGRP signaling in the left and right CeA on the lateralized modulation of bladder pain. We found that both optogenetic and pharmacological manipulation of left versus right PBN-to-CeA terminals resulted in opposing effect on bladder pain-like behaviors. Use of AMPA and NMDA receptor antagonists and CGRP knockout animals confirmed that the effects of optogenetic activation are driven by CGRP signaling. Molecular analysis revealed no basic anatomical differences in expression of CGRP input or CGRP receptor across hemispheres that could contribute to observed functional lateralization. Finally, we explored the role of CGRP in the CeA in rodent models of neuropathic and inflammatory pain to see if CGRP-mediated CeA lateralization extends beyond bladder pain. We found no evidence of CeA lateralization in either model but discovered a novel role for CeA CGRP in the modulation of neuropathic pain-induced cold allodynia. Overall, these studies have expanded our understanding of CeA lateralization in the context of bladder pain by revealing that the contrasting functions of the left and right CeA are ultimately due to the activity of the same neuropeptide in opposite sides of the brain.

Language

English

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