Sustained stress-induced changes in mice as a model for chronic depression

Major depression is a chronic disabling disorder, often preceded by stress. Despite emerging clinical interest in mechanisms perpetuating episodes of depression and/or establishing increased vulnerability for relapse, little attention has been paid to address these aspects in experimental models. Here, we studied the long-term neuroadaptive effects of chronic mild stress (CMS) as well as the effectiveness of a course of an antidepressant treatment. CMS was applied for 6 weeks, and paroxetine was administered from the third week and continued for 2 weeks thereafter. In order to validate our CMS procedure, we first studied short-term (24 h after CMS) hippocampal cell proliferation and neurogenesis, along with anhedonic-like behaviour. Subsequently, we examined the long-term (one month after CMS) anhedonia, hippocampal neurogenesis, the regulation of c-Fos immunoreactivity and neurotransmitter levels in different areas as well as cortical spine density and hippocampal expression of synaptic proteins. CMS induced a decrease in short-term neurogenesis that was fully recovered in the long term. In addition, CMS-induced lasting anhedonia and region-specific changes in neuronal activity (c-Fos immunoreactivity) and neurotransmitter (glutamate and GABA) levels. Repeated paroxetine reverted these effects with the exception of decreased neuronal activity in the dentate gyrus (DG) and GABA levels in the ventral hippocampus. Moreover, CMS downregulated the GAD65 and VGLUT1 expressions. This study shows region-specific long-term neurobiological adaptations induced by CMS and residual hippocampal signs after paroxetine treatment. We propose the use of this model to study molecular mechanisms involved in chronic depression and vulnerability for relapse.