Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats.

Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by a range of symptoms that often lead to reduced quality of life. Although chronic stress is a major risk factor for the development of MDD, only a subset of individuals exposed to stress develop depressive symptoms, while others remain resilient. Emerging evidence suggests that autophagy and mitophagy, key cellular processes involved in maintaining homeostasis and energy balance, may play a critical role in the response to stress. In this study, we investigated the impact of 6 weeks of chronic mild stress (CMS) on autophagy and mitophagy pathways in adult male rats, aiming to explore their potential association with vulnerability or resilience to stress-induced anhedonic-like behavior. By analyzing key autophagy and mitophagy markers in the dorsal (dHip) and ventral hippocampus (vHip), we describe region- and phenotype-specific alterations that may reflect distinct neurobiological adaptations to stress. In particular, we observed enhanced mitophagy alongside an overall impairment of autophagy in the vHip of vulnerable rats, while resilient animals showed preserved activity. These findings provide new insights into the molecular mechanisms associated with stress susceptibility and may inform future studies aimed at identifying novel therapeutic targets for MDD.