Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress–Induced Depressive Behaviors

Abstract

Background Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical since increased dopamine (DA) signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress remains unknown. Methods We used CSDS with repeated optogenetic activation and pharmacological manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. BDNF protein expression and DA release were measured in this model. Results Pharmacological blockade of BDNF-TrkB signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were also blocked by local knockdown of BDNF in VTA. Conclusions These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS, and establish such BDNF-TrkB signaling as a pathological mechanism during periods of chronic stress.

Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice

“…As the first step of this study, the CSDS model of depression was established. The C57BL/6J mice subjected to CSDS showed significantly less sucrose preference and social interaction than those of control mice (Figure A), showing depressive‐like behaviours, as reported earlier (Wook Koo et al ., ; Bondar et al ., ). We then used Western blotting to evaluate the effects of CSDS on PPARα expression in hippocampus, mPFC, amygdala, NAc, VTA and hypothalamus, which are all related with depression.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Activation of TrkB is necessary for these behavioral actions [291, 292]. It should be noted though that the effects on BDNF-TrkB signaling are region-specific since there is evidence showing that enhanced BDNF-TrkB signaling in the mesolimbic dopaminergic system results in a depressive phenotype in rodents [293, 294]. …”

Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression

“…First, phasic firing changes in VTA DA neurons are inconsistent across stress models (66, 69). Furthermore, a recent paper using DA voltammetry in the NAc discovered VTA dopamine release was unaltered following CSDS and blockade of dopamine receptors had no effect on depression-like outcomes (67). Rather, BDNF was responsible for stress susceptibility and antagonism of the BDNF receptor TrkB, prevented susceptibility (37, 38, 54, 65, 67, 68).…”