When Stress Becomes Instructive: Paradoxical CRF Neuronal Activity Promotes Resiliency via Stress-History-Dependent Modulation in the BNST 公开
Haynes, Sherod (Spring 2022)
Published
Abstract
While most individuals have the capacity to handle stress for a short time, cumulative stressors can emotionally overwhelm and precipitate neuropsychiatric conditions such as Major Depressive Disorder (MDD). Despite extensive research examining the relationship between stress and MDD, the substrates responsible for setting psychological tipping points remain elusive. Using repeated social defeat stress in tandem with electrophysiology, we uncovered a discrete stress window during which neuroadaptation in Corticotropin-Releasing Factor (CRF) neurons of the Bed Nucleus of the Stria Terminalis (BNST) demarcated the divergence of susceptible and resilient mice. In chapter one, I survey the literature surrounding the BNST and its role in adaptive responses to stress, with particular emphasis on mechanisms underlying resiliency. Chapter two details the research methods used to conduct the work herein described. Chapter three explores how CRF’s paradoxical role as a resiliency modulator depends heavily on the stress-history context where resiliency is established between 7 and 10 episodes of social defeat. Much of the stress literature has shown CRF in the BNST to serve as a potent transducer of pro-stress and anxiety responses (via HPA axis regulation). Therefore, it was unexpected to find that CRF neuronal activation was necessary and sufficient for mice to develop resiliency. I used combinatorial cell-type selective chemogenetics with fiber photometry to simultaneously track and bidirectionally manipulate CRF neural dynamics essential to establishing resiliency. Further, I employed opsin-expressing transgenic CRF mice for cell-type selective optogenetics combined with RNAScope to correlate neural activity with genetic changes in critical targets of CRF transmission with behavior. Chapter four investigates whether developing resiliency to cumulative stress impacts the affective experience of stressful stimuli. Using a suite of behavioral assays, we uncover that resilience has state and trait dimensions associated with a blunting of aversion. Specifically, we observed that CRF activation positively biases social motivation, switches contexts of negative valence from aversive to appetitive, and promotes persistence in the face of ongoing stress. Chapter five offers concluding remarks and future directions. This work highlights an overlooked dimension to stress regulation in which resiliency processes are dynamically fine-tuned to one’s stress history.
Table of Contents
Abstract……………………………………………………………………………………………………..i
Dedication………………………………………………………………………………………………….ii
Acknowledgements………………………………………………………………………………………iii
List of Figures……………………………………………………………………………………………..v
List of Abbreviations…………………………………………………………………………………..…vii
Table of Contents……………………………………………………………………………………….viii
1. CHAPTER 1: Literature Review
1.1. Major Depressive Disorder (MDD)…………………………………………………………….1
1.1.1. Structural changes implicated in the development of MDD………………………...2
1.1.2. Molecular biomarkers implicated in the development of MDD……………………..3
1.1.3. Genetic/Epigenetic factors in MDD development……………………………………3
1.1.4. Neural Circuits implicated in MDD…………………………………………………….5
1.1.5. Stress as a causative agent in MDD development………………………………….6
1.1.5.1. Rodent models of MDD………………………………………………………..7
1.1.5.2. Treatment failures of CRF antagonists………………………………………9
1.2. Bed Nucleus of the Stria Terminalis (BNST)……………………………………………….10
1.2.1. Stress in the BNST…………………………………………………………………….11
1.2.2. BNST CRFR1…………………………………………………………………………..14
1.2.3. The role of the BNST in MDD………………………………………………………...15
1.2.4. BNST CRF involvement in social behavior…………………………………………18
1.2.5. DBS for MDD in the BNST……………………………………………………………19
1.3. Neural circuits implicated in resiliency………………………………………………………19
1.4. Figure…………………………………………………………………………………………...22
2. CHAPTER 2: Experimental Methods…………………...………………………………………...24
3. CHAPTER 3: Results of CRF Neurons Establish Resilience via Stress-History Dependent Modulation………………………………………………………………………………………...…35
3.1. Introduction to chapter 3………………………………………………………………………36
3.2. Results………………………………………………………………………………………….39
3.3. Discussion…………………………………………………………………………………...…46
3.4. Figures………………………………………………………………………………………….51
4. CHAPTER 4: Results of CRF neurons of the BNST promote resilience by blunting the internal experience of aversion…………………………………………………………………....76
4.1. Introduction to chapter 4………………………………………………………………………77
4.2. Results………………………………………………………………………………………….78
4.3. Discussion………………………………………………………………………………...……85
4.4. Figures……………………………………………………………………………………...…..91
5. CHAPTER 5: Conclusion and Future Directions……………………………………………….107
5.1. Conclusion…………………………………………………………………..………………..108
5.2. Future Directions……………………………………………………………………………..115
6. CHAPTER 6: References,,………………………………………………...……………………..124
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