Reactivating a positive feedback loop VTA-BLA-NAc circuit associated with positive experience ameliorates the attenuated reward sensitivity induced by chronic stress

Abstract

Both genetic predisposition and life events, particularly life stress, are thought to increase the risk for depression. Reward sensitivity appears to be attenuated in major depressive disorder (MDD), suggesting deficits in reward processing in these patients. We identified the VTA-BLA-NAc circuit as being activated by sex reward, and the VTA neurons that respond to sex reward are mostly dopaminergic. Acute or chronic reactivation of this circuit ameliorates the reward insensitivity induced by chronic restraint stress. Our histological and electrophysiological results show that the VTA neuron subpopulation responding to restraint stress, predominantly GABAergic neurons, inhibits the responsiveness of VTA dopaminergic neurons to reward stimuli, which is probably the mechanism by which stress modulates the reward processing neural circuits and subsequently disrupts reward-related behaviours. Furthermore, we found that the VTA-BLA-NAc circuit is a positive feedback loop. Blocking the projections from the BLA to the NAc associated with sex reward increases the excitability of VTA GABAergic neurons and decreases the excitability of VTA dopaminergic neurons, while activating this pathway decreases the excitability of VTA GABAergic neurons and increases the excitability of VTA dopaminergic neurons, which may be the cellular mechanism by which the VTA-BLA-NAc circuit associated with sex reward ameliorates the attenuated reward sensitivity induced by chronic stress.