Hippocampal overexpression of tissue-type plasminogen activator “tPA” attenuates social defeat-induced depression and ethanol related behavior in mice

Depression and anxiety disorders are often exacerbated by social stress, necessitating the exploration of molecular mechanisms underlying stress resilience. Tissue plasminogen activator (tPA), a serine protease with pleiotropic effects in the brain, plays a critical role in modulating neuroplasticity and stress responses. This study investigates the behavioral and molecular effects of tPA gain-of-function in a social stress paradigm in male C57BL/6 mice using lentiviral vectors. Behaviorally, hippocampal tPA gain-of-function mitigated depression-like responses in the novelty-suppressed feeding, sucrose splash, tail suspension, and forced swim tests following exposure to chronic social stress. Additionally, in a two-bottle choice drinking paradigm, tPA overexpression reduced social stress-induced ethanol intake and preference, suggesting a role in dampening maladaptive coping behaviors. However, analysis of tastants’ intake and preference revealed no significant effects of tPA overexpression, indicating that it does not influence hedonic responses under stress conditions. Molecularly, tPA overexpression preserved hippocampal tPA mRNA expression and maintained levels of mature brain-derived neurotrophic factor in the hippocampus despite chronic stress exposure. These findings highlight the potential neuroprotective effects of tPA in maintaining hippocampal plasticity and mitigating stress-induced dysregulation of critical neurotrophic pathways. Collectively, this study underscores the potential of tPA as a therapeutic target for stress-induced mood and substance use disorders by modulating behavioral and neurobiological responses to chronic social stress.