Continuous psychosocial stress stimulates BMP signaling in dorsal hippocampus concomitant with anxiety-like behavior associated with differential modulation of cell proliferation and neurogenesis

Abstract

Bone morphogenetic protein (BMP) signaling in the hippocampus regulates psychiatric behaviors and hippocampal neurogenesis in non-stress conditions; however, stress-induced changes in hippocampal BMP signaling have not yet been reported. Therefore, we sought to examine whether psychosocial stress, which induces psychiatric symptoms, affects hippocampal BMP signaling. A total of 32 male Sprague-Dawley rats were exposed to a psychosocial stress using a Resident/Intruder paradigm for ten consecutive days. Subsequently, rats were subjected to a battery of behavioral tests (novelty-suppressed feeding test, sucrose preference test, and forced swimming test) for the evaluation of adult neurogenesis and activity of BMP signaling in the dorsal and ventral hippocampus. Repeated social defeat promoted anxiety-like behaviors, but neither anhedonia nor behavioral despair. Socially defeated rats exhibited an increase in the number of Ki-67-positive cells, decrease in the number of doublecortin (DCX)-positive cells, and decrease only in the dorsal hippocampus of the ratio of DCX-positive to Ki-67-positive cells, a proxy for newly-born cell maturation speed and survival. In contrast, no differences were observed in the number of 5-Bromo-2′-deoxyuridine (BrdU)-positive cells, indicating survival of newly-born cells both in the dorsal and ventral hippocampus. Furthermore, psychosocial stress significantly increased the BMP-4 and phosphorylated Smad1/5/9 expression levels specifically in the dorsal hippocampus. Our findings suggest that repeated psychosocial stress activates BMP signaling and differently affects cell proliferation and neurogenesis exclusively in the dorsal hippocampus, potentially exacerbating anxiety-related symptoms. Targeting BMP signaling is a potential therapeutic strategy for psychiatric disorders.