Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression

Brain-derived neurotrophic factor (BDNF) is widely accepted as being critical for neural and synaptic plasticity throughout the nervous system. Recent work has shown that BDNF in the mesolimbic dopamine (DA) circuit, originating in ventral tegmental area DA neurons that project to the nucleus accumbens, is crucial in the development of depressive-like behaviors following exposure to chronic social defeat stress in mice. Whereas BDNF modulates DA signaling in encoding responses to acute defeat stress, BDNF signaling alone appears to be responsible for the behavioral effects after chronic social defeat stress. Very different patterns are seen with another widely used chronic stress paradigm in mice, chronic mild stress (also known as chronic variable or unpredictable stress), where DA signaling, but not BDNF signaling, is primarily responsible for the behavioral effects observed. This review discusses the molecular, cellular, and circuit basis of this dramatic discrepancy, which appears to involve the nature of the stress, its severity and duration, and its effects on distinct cell types within the ventral tegmental area–to–nucleus accumbens mesolimbic circuit.