Abstract
Animal studies using chronic social defeat stress (CSDS) in mice showed that brain-derived neurotrophic factor (BDNF) signaling in the mesolimbic dopamine (DA) circuit is important for the development of social aversion. However, the downstream molecular targets after BDNF release from ventral tegmental area (VTA) DA terminals are unknown. Here, we show that depressive-like behaviors induced by CSDS are mediated in part by Gadd45b downstream of BDNF signaling in the nucleus accumbens (NAc). We show that Gadd45b mRNA levels are increased in susceptible but not resilient mice. Intra-NAc infusion of BDNF or optical stimulation of VTA DA terminals in NAc enhanced Gadd45b expression levels in the NAc. Importantly, Gadd45b downregulation reversed social avoidance in susceptible mice. Together, these data suggest that Gadd45b in NAc contributes to susceptibility to social stress. In addition, we investigated the function of Gadd45b in demethylating CpG islands of representative gene targets, which have been associated with a depressive phenotype in humans and animal models. We found that Gadd45b downregulation changes DNA methylation levels in a phenotype-, gene-, and locus-specific fashion. Together, these results highlight the contribution of Gadd45b and changes in DNA methylation in mediating the effects of social stress in the mesolimbic DA circuit.
Highlights
Animal studies using chronic social defeat stress (CSDS) in mice, an ethologically validated model of aspects of depression in mice[1,2], previously showed that the mesolimbic dopamine (DA) circuit is critically involved in the development of social aversion and other behavioral abnormalities[3,4]
As chronic social stress is known to alter transcriptional profiles in several brain regions including the NAc23, we first tested whether Gadd45b expression is altered following chronic social stress
This is in accordance with previous findings showing the involvement of Gadd45b in hippocampus in fear conditioning and memory consolidation in mice[21] and in parietal cortex of humans with psychosis[22], expanding the involvement of Gadd45b in nucleus accumbens (NAc) in the context of chronic social stress
Summary
Animal studies using chronic social defeat stress (CSDS) in mice, an ethologically validated model of aspects of depression in mice[1,2], previously showed that the mesolimbic dopamine (DA) circuit is critically involved in the development of social aversion and other behavioral abnormalities[3,4]. Genome-wide assessments of DNA methylation changes in human brain previously revealed global reorganization of DNA methylation profiles, associated with psychiatric disorders including major depression, psychosis, bipolar disorder, post-traumatic stress disorder (PTSD), and child abuse[13,14,15,16,17]. Analyses of human post-mortem tissue revealed increased Gadd45b mRNA and protein expression in the parietal cortex of psychotic patients[22]. Together, these findings raise the possibility that, by changing DNA methylation levels at specific gene loci, Gadd45b might modulate the molecular cascades regulating stress susceptibility
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
