Effects of stress and alcohol on E-I balance in the mPFC

About This Grant

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) and Post-Traumatic Stress Disorder (PTSD) frequently co-occur, exacerbating symptom severity and complicating treatment outcomes. AUD impairs stress regulation and heightens vulnerability to PTSD, while PTSD promotes maladaptive alcohol consumption as a coping mechanism. Both disorders involve GABAergic and glutamatergic signaling disruptions, resulting in hyperexcitability within the medial prefrontal cortex (mPFC). Acute alcohol exposure enhances inhibitory tone through GABAergic mechanisms, but chronic use reduces inhibition and amplifies excitation, paralleling the elevated excitatory activity seen in PTSD. The dysfunction of somatostatin-expressing interneurons, which maintain inhibitory tone, contributes to this shared pathophysiology. This proposal hypothesizes that stress exposure disrupts excitation-inhibition (E-I) balance in the mPFC driving increased alcohol consumption and heightened motivation for alcohol use, and that targeting metabotropic glutamate receptor 7 (mGluR7), a presynaptic regulator of glutamatergic transmission, can restore this balance. Using single prolonged stress (SPS) to model stress alongside alcohol exposure paradigms such as drinking- in-the-dark (DID) and operant self-administration, I will employ electrophysiology, dual-color fiber photometry, and behavioral assays to quantify E-I balance changes and evaluate the efficacy of AMN082, a mGluR7 allosteric agonist, in reducing pathological alcohol use and PTSD-like behaviors. In Aim 1, I will assess the impact of stress on alcohol consumption in binge drinking. Aim 2 will examine the effects of stress on motivation for alcohol use in mice with prolonged alcohol exposure. Despite known sex differences in AUD neurobiology, the interaction between sex and altered synaptic transmission in comorbid AUD/PTSD remains poorly understood and will be explicitly investigated. Through these aims, I will explore the shared circuit mechanisms between AUD and PTSD and distinct E-I balance differences associated with binge drinking versus long-term alcohol use. This study seeks to identify novel intervention strategies targeting E-I balance, offering dual-benefit approaches to mitigate alcohol use and PTSD symptoms and ultimately improve treatment outcomes. This proposed project will be conducted in the labs of Drs. Jane Taylor and Alicia Che, within Yale University's Departments of Psychiatry and Psychology, and provide me with expertise in electrophysiology, fiber photometry, and behavior, essential for successfully achieving the project's aims. Yale University and the Interdepartmental Neuroscience Program offer a robust scientific community that fosters opportunities for professional development in scientific communication and mentoring. The training and mentorship provided through this fellowship will equip me to become a successful independent researcher focused on understanding the interactions between AUD and PTSD.