Abstract

Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.

Highlights

  • Major depressive disorder (MDD) is an important social issue that can potentially lead to suicide, and lifetime prevalence estimates are usually high in the general population [1, 2]

  • One-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison analyses showed that our results were consistent with those of previous studies [29] in that both susceptible (P < 0:001) and resilient (P < 0:001) mice showed significantly less time spent in the open arm of the Elevated Plus Maze Test (EPM) compared with controls (F2,30 = 14:66, P < 0:001; Figure 1(f))

  • The Social Interaction Test (SIT) showed that nonstressed controls with intact Atg7 expression (Cre-; white circle; P < 0:01) and nonstressed microglial Atg7knockout mice (Cre+; pink circle; P < 0:05) exhibited increased time in the interaction zone when exposed to CD1 mice (F7,56 = 19:55, P < 0:0001; Figure 5(a))

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Summary

Introduction

Major depressive disorder (MDD) is an important social issue that can potentially lead to suicide, and lifetime prevalence estimates are usually high in the general population [1, 2]. Repeated environmental stress is w5idely accepted to be involved in the pathogenesis of MDD, promoting its onset or recurrence [3]. Social activity is avoided by patients with MDD. Social contacts provoke anxiety and depression, making minor stressors overwhelming [4]. Animals exposed to repeated stress have been used to understand the pathophysiology of MDD. Repeated social defeat (RSD) stress causes a robust depression-like phenotype marked by anhedonia, anxiety, and social avoidance behaviors, and these behaviors are helpful for elucidating individual differences [5]. The PFC circuits are involved in stress responses in mice and patients [7, 8]

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