Concurrent chronic stress and cocaine self-administration: Understanding effects on mPFC microglia and drug choice behavior - Project Summary: Substance use disorder (SUD) is a devastating psychiatric condition that exhibits robust comorbidity with other mental health disorders. In 2021, approximately 1.4 million people faced cocaine use disorder in the United States. There are no FDA approved treatments for cocaine use disorder, which presents a major unmet medical need. Stress exposure can precipitate or worsen many mental health conditions and is a barrier to recovery for individuals with SUD. Thus, addressing the negative consequences of stress exposure is a critical target for therapeutic intervention in SUD. Stress acts in medial prefrontal cortex (mPFC), a corticolimbic node involved in motivation and reward, to influence neuronal activity and changes in dendritic architecture. Microglia are innate immune cells in the brain whose actions contribute to stress-induced dendritic remodeling in rodents following chronic unpredictable stress (CUS). Alterations in dendritic spine morphology are implicated in the behavioral sequelae of chronic stress exposure. Interestingly, chronic cocaine use results in similar dendritic remodeling and prefrontal cortex deficits. The role of microglia in this process is largely unknown. In this proposal, I will use a rat model of CUS concurrent with cocaine self-administration (SA) to recapitulate a clinical presentation of cocaine addiction complicated by ongoing stress exposure. Our preliminary data demonstrate that when cocaine SA is paired concurrently with CUS, rodents display increased drug seeking in an extinction-reinstatement model. I hypothesize that cocaine SA in the context of CUS produces robust activation of microglial machinery involved neuronal remodeling, leading to prefrontal cortex dysfunction and facilitation of drug seeking behavior. In Aim 1, I will use flow cytometry, qRT-PCR, and advanced spine morphometry to study microglial activity profiles and dendritic spine architecture after CUS, chronic cocaine SA, and concurrent CUS/chronic cocaine SA. Existing literature and preliminary data demonstrate that CUS alone causes marked changes in microglial profiles, dendritic spine morphology, and mPFC function. However, little is known about how chronic cocaine SA or chronic cocaine SA complicated by CUS affects microglia and spine morphology. In Aim 2, I will use a novel drug vs. non-drug choice paradigm to elucidate changes in motivation after CUS exposure, while additionally employing a pharmacological approach to inhibit microglial contributions to stress. During this fellowship period, I will relish the opportunity to gain technical expertise and develop investigative acuity, to facilitate my future success as an academic physician-neuroscientist. My sponsors and I have assembled a diverse mentorship team with a wide range of expertise. As a vital part of my professional development, I will interact with this group of highly talented scientists, as they push my scientific capabilities and foster my excitement for discovery. MCW offers the infrastructure and, more importantly, the people that will offer growth opportunities and outlets for creative collaboration, as evidenced by my desire to explore the intersectional field of neuroimmunology.
