Wednesday, February 5, 2025
2/5/2025
Project Summary/Abstract Alcohol’s effects on the body are complex, altering behaviors, emotions and physiology. These effects all contribute to the cycle of alcohol use and abuse that leads to alcohol use disorders (AUDs). They also contribute to the development of comorbid psychiatric disorders, like panic disorder (PD), which are common. Comorbidity is associated with worse patient outcomes, yet little is known regarding the pathophysiology regulating comorbidity. Emerging evidence supports dysregulated acid-base homeostasis may be a shared mechanism in AUD and PD. Maintaining physiological homeostasis (e.g. neutral pH) is critical for survival, and threats to homeostasis elicit behavioral, emotional and physiological responses directed toward this goal. Alcohol use induces acidosis which is positively correlated with withdrawal severity. Strong evidence supports dysregulated acid-sensing in PD, but its role in AUDs is not well understood. Our lab recently found a role for a novel microglial acid-sensor T-cell death associated gene 8 (TDAG8) in panic-relevant behavior and physiology. Interestingly, preliminary data show ethanol increases TDAG8-promoter driven GFP expression and neuroinflammation in a TDAG8 dependent manner. Thus, TDAG8 and associated neuroimmune effectors may provide a unique and novel shared mechanism for AUD and PD. The purpose of this K99-R00 proposal is to determine if TDAG8 regulates AUD-associated outcomes (K99 phase) and contributes to development of comorbid AUD-PD (R00 phase). My published and preliminary data support the hypothesis that microglial TDAG8 regulates behaviors (ethanol consumption) and physiological (respiratory/cardiovascular) responses associated with alcohol use (K99), and that ethanol-evoked upregulation of TDAG8 increases susceptibility to develop comorbid AUD-PD (R00 phase). Aim1 (K99 phase) will test the hypothesis that microglial acid-sensor TDAG8 regulates ethanol consumption in the “drinking in the dark” (DID) voluntary binge drinking model. Aim 2 (K99 phase) will test the hypothesis that TDAG8 mediates cardiovascular (blood pressure, heart rate, heart rate variability) and respiratory effects of alcohol use and withdrawal (acute and protracted abstinence). Aim 3 (R00 Phase) will test the hypothesis that alcohol dependence will increase panic-relevant behavioral and physiological responses to CO2 inhalation (PD-relevant homeostatic stress) in a TDAG8-dependent manner. Each aim will also investigate neuroinflammation. These aims will elucidate mechanisms of AUDs and comorbidity with PD. Investigating the intersection of AUD and PD by focusing on shared physiological and neuroimmune mechanisms will further our understanding of each disorder and lead to novel treatments. This K99/R00 proposal will provide training in mouse models of AUDs, methods for quantifying neuroinflammation, and collection/analysis of physiological outcomes. Additionally, it will provide professional development that will facilitate my transition to an independent academic research position. These aims will provide a foundation for a successful independent career investigating pathophysiology of AUD and comorbid disorders like PD.
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