A new approach to an old problem: investigating the molecular blueprints underlying the social defeat stress-induced resilient and susceptible phenotypes using engram-multiomics sequencing techniques
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Abstract
Resilience and susceptibility are two plausible outcomes following stress exposure. Those individuals that can successfully cope with daily stressors and maintain normal daily functions are known to exhibit resilience, while those that succumb to the stressors are known to be susceptible to the stressor. Susceptibility to a stressor is a major precedent towards the development of mental health disorders. Unfortunately, mental health disorders not only compromise an individual’s quality of life but also exert a huge burden on the global economy. Therefore, with the anticipated surge in mental health disorders following the recent COVID lockdowns, a more comprehensive understanding of resilience and susceptibility molecular mechanisms is crucial for facilitating early interventions.
As mechanistic studies on humans face certain limitations, we employ the chronic social defeat (CSD) paradigm for rodents - known for its high face validity, construct validity as well as predictive validity, mirroring the social stressors that humans experience. However, current molecular studies investigating the CSD stress impacts embody at least two limitations. First, most studies use bulk tissues rather than isolating engram cells/nuclei. As engrams play pivotal roles in the onset of diseased pathways, the use of bulk tissues limits the potential to identify rare but crucial signals. Second, the majority of the current literature investigates only one omics level at a stationary time point. Such an approach curtails the ability to delineate causative factors, which are potent therapeutic targets. Therefore, to circumvent these limitations, the thesis employs a study design centered around the implementation of transgenic mouse lines to facilitate the capture of specific engram nuclei. These nuclei will then be subjected to multiomics investigations to access different layers of molecular machineries at a single time point. This approach will facilitate the generation of a higher resolution picture of the ongoing alterations, thereby enhancing the potential to delineate plausible causal pathways.
Thus, within the framework of the study, I highlight the importance of employing optimal stressors for the transgenic mouse lines and engram nuclei isolation techniques to increase the confidence of the results from the engram-multiomics data. From such systematically curated multiomics data, I identified significant roles of the GTPase signaling and endocytic pathways behind the divergence and persistence of the susceptibility-resilience patterns post-stress. Further analysis of the results led to the identification of endocytosis-related Arf6 GTPase as a potential therapeutic target, wherein I hypothesize that reducing Arf6 expression in the ventral hippocampus within a defined window period, will enhance resilience outcomes.