Dissertation
LATERAL HABENULA AND ENDOCANNABINOID REGULATION OF STRESS-RELATED BEHAVIOR
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2024
DOI:
https://doi.org/10.7273/000006522
Abstract
Major depressive disorder (MDD) affects over 300 million people and is the largest contributor to disability worldwide. Strategies used to cope with stress impact the onset and maintenance of MDD and other stress-related disorders. Clinical and preclinical data indicate that individuals with stress-related disorders and rodents exposed to chronic stress exhibit impaired flexible decision-making and coping behaviors. The lateral habenula (LHb) is a key brain region that contributes to stress and cognitive performance via indirect projections that effectively inhibit the activity of downstream monoaminergic nuclei orchestrating behavioral responses to stress. We have shown that endocannabinoid (ECB) signaling is recruited in the LHb during stress. However, ECB contribution to stress-induced alterations in LHb activity, the impact of chronic stress on LHb recruitment during task performance, and whether the ECB system can be targeted to reverse the effects of stress remain largely unknown.
This dissertation details my investigation of the impact of stress on the ECB system within the LHb and its contribution to stress-induced behavior. I addressed these questions using fiber photometry, site-specific pharmacology, deep learning behavioral classifiers, and ex vivo patch clamp electrophysiology, I found that chronic stress did not disrupt operant-based behavioral flexibility but did alter LHb calcium dynamics in a sex- and stress-dependent manner, which may underlie increased task engagement. Additionally, augmentation of the cannabinoid type 1 receptor signaling within the LHb did not disrupt flexible decision-making. When I site-specifically augmented the ECB 2-arachidonoylglycerol within the LHb under conditions of acute or chronic stress, I found that it did not affect coping behavior but did reduce the activation of the medial ventral tegmental area, a major downstream dopaminergic center. Lastly, I assessed ECB regulation of inhibitory inputs to LHb neurons that project to the rostromedial tegmental nucleus (LHbRMTg) in stress-naïve and chronically stressed rats. I found that chronic stress exposure recruits ECB tone in the LHb to reduce inhibitory events in LHbRMTg neurons. However, I did not observe an effect of CUS exposure on baseline inhibitory transmission. My dissertation provides insight into the interaction between stress and ECBs to shape LHb involvement in flexible decision-making, stress coping behavior, and circuit-dependent LHb activity. My results underscore the complex nature of LHb contributions to goal-directed behavior.
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Details
- Title
- LATERAL HABENULA AND ENDOCANNABINOID REGULATION OF STRESS-RELATED BEHAVIOR
- Creators
- Hayden Russell Wright
- Contributors
- Ryan J McLaughlin (Chair)Rita A Fuchs Lokensgard (Committee Member) - Washington State University, Integrative Physiology and Neuroscience, Department ofJames H Peters (Committee Member)Ilia N Karatsoreos (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 151
- Identifiers
- 99901120940901842
- Language
- English
- Resource Type
- Dissertation