Neuroscience Seminar Series

Profile & Research

Abstract: TBA

Profile & Research

Title: “Dynamic Resilience: How Stress Phenotypes Shape Opioid-Taking, Brain Activity, and Gene Expression”

Abstract: Stress and stressful environments often lead to maladaptive behaviors that can increase vulnerability to substance use disorders and the development of affective disorders. While the relationship between stress and substance use disorders is well documented, there exists a significant gap in knowledge regarding the role of individual differences in stress susceptibility in mediating opioid taking. When presented with a stressor some individuals respond with resilience, but the majority are susceptible to the detrimental effects of stress. Social defeat is a type of chronic stress used in preclinical rodent models to investigate the molecular mechanisms underlying maladaptive behaviors. This paradigm is one of the few tests used to reliably distinguish animals resilient to stress from animals susceptible to stress, with approximately 40% showing a resilient phenotype and 60% showing a susceptible phenotype. However, regardless of phenotype, all stressed mice exhibited increased drug intake at 1 week, but by 3 weeks, resilient mice returned to baseline responding, whereas susceptible mice maintained elevated intake. To investigate neural correlates of these behavioral changes, we assessed activity in stress- and reward-related brain regions using cFOS. These findings highlight resilience as a dynamic process, with both behavioral and neural responses evolving over time. By incorporating multiple time points, we provide insight into how stress phenotypes influence opioid use trajectories and identify candidate brain regions underlying these differences. One region showing phenotype-dependent differences in activity was the paraventricular nucleus of the thalamus (PVT), suggesting a potential role for the PVT in stress-response variability. Interestingly, the PVT exhibits some of the highest mu-opioid receptor (MOR) expression in the brain and MORs play a major role in modulating stress responses. We therefore examined MOR-expressing neurons in the PVT (PVT-MOR+ neurons). Chemogenetic inhibition of PVT-MOR+ neurons during CSDS shifted behavioral outcomes toward resilience. Projection-specific analyses further revealed that PVT-MOR+ neurons projecting to the amygdala play a key role in promoting resilience. Future studies will examine additional PVT-MOR+ projections, test the effects of PVT-MOR+ neuron stimulation during CSDS, and use spatial transcriptomics to characterize phenotype-specific gene expression in the PVT and its projections.