Wills, L. J.; Wang-Heaton, H.; Polichnowski, A. J.; Thomas, K. L.; Jewett, B. E.; Jewett, S.; Aldridge, G.; Ordway, G. A.; Brown, R. W.; Chandley, M. J.

Background: Major depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling. Methods: We conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1{beta}, TNF-, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. Exploratory gut microbiome analyses were also conducted (see Supplemental Materials). Results: Saline-treated stressed rats demonstrated significantly elevated anhedonia and social avoidance compared to all other groups, while 3-AB treatment prevented these behavioral deficits. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented these hemodynamic changes. Neurobiological analyses showed that FLX-treated stressed rats unexpectedly exhibited elevated PARP-1 expression in prefrontal cortical gray matter. Microglial morphological analysis revealed significantly more prolate (activated) microglia in the saline-treated stressed rats compared to all other treatment groups. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically normalizing TNF- levels. Conclusion: PARP inhibition with 3-AB provides multi-system protection against chronic stress effects, preventing behavioral deficits, cardiovascular dysfunction, and neuroinflammation. These findings establish PARP-1 as a key mediator in the systemic pathophysiology of chronic stress and highlight PARP inhibition as a promising therapeutic approach for stress-related disorders with treatment-resistant features.