Fig. 1.

Stress alters ventral tegmental area dopamine neurons to generate depressive behavior. Top: Simplified schematic of ventral tegmental area (VTA) projections associated with stress susceptibility. Inhibition of the VTA to prefrontal cortex (PFC) projection is pro-depressant. Stimulation of the VTA to nucleus accumbens (NAc) projection is pro-depressant. Noradrenergic neurons from the locus coeruleus (LC) project to the VTA where they modulate excitability and stress-susceptibility. Middle: VTA dopamine neuron firing is increased in mice susceptible to social defeat (CSDS) and decreased after chronic unpredictable stress (CUS). Excitability of VTA dopamine neurons is modulated by norepinephrine through α₁ and β₃ receptors (brown), acetylcholine through muscarinic receptors (pink), and a balancing of I_h and K⁺ currents through HCN (orange) and KCNQ channels (purple). Inset box details genes associated with stress susceptibility in the VTA. Bottom: Dopamine varicosity (green) releasing dopamine in the NAc. Stress is associated with greater phasic dopamine release, upregulation of dopamine transporters (DAT), dopamine receptors, and BDNF-TrkB signaling