Stress while lacking of control induces ventral hippocampal autophagic flux hyperactivity and a depression-like behavior

Abstract

Background: Stressed animals may perform depression-like behavior insomuch as stress-provoking blood–brain barrier (BBB) disruption, central immune activation, and autophagic flux changes. This study was undertaken to assess whether adult mice having (executive) vs. lacking (yoke) of behavioral control in otherwise equivalent stress magnitude condition, may display differences in their BBB integrity, ventral hippocampal (VH) interleukin-6 (IL-6) and autophagic flux level and VH-related depression-like behavior. To further understand the causative relation of enhanced autophagic flux and stress-primed depression-like behavior, we assessed the effects of bilateral intra-VH 3-methyladenine (3-MA), an autophagic flux inhibitor, infusion in stressed mice. Methods: Adult mice used had comparable genetic background and housing condition. Executive/yoke pairs of mice received a 10-day (1 h/day) footshock stressor regimen. Throughout the regimen, the ongoing footshock was terminated immediately contingent on the executive mouse’, while irrelevant to the respective yoke mouse’ voluntary behavior, or lasting for 7 s. Each dyad's cage-mate receiving no such regimen served as no stressor controls. Results: Yoke mice displayed disrupted BBB integrity (escalated Evans blue extravasation and decreased VH ZO-1, claudin-5 expression), increases in VH autophagic flux (increased LC3II/LC3I and decreased p62) and immobility duration in forced swimming test. Most of these indices remained unaltered in executive mice. Administration of 3-MA did not affect immobility duration in control mice, while prevented the increases in immobility duration in yoke mice. Conclusions: (1) stress susceptibility may be determined by their differences in stress-coping results; (2) VH autophagic flux increase plays a permissive role in priming the stressed animals susceptible to exhibit depression-like behavior.

Keywords

• Executive
• Yoke
• Hippocampus
• Forced swimming
• Autophagy
• Blood–brain barrier