Salience attributed to stimuli predicting rewarding or aversive outcomes is critical for adaptive behavior. Dopamine DA -neurons play a central role in this process by modulating responses to both rewarding and aversive cues. DA-neurons are tightly and readily modulated by DA D2 autoreceptors autoD2Rs , but their role in regulating responses to aversive stimuli remains unclear. In this study, we investigated the role of autoD2R in regulating the activity of VTA DA-neurons in response to salient aversive stimuli.
Using Drd2 Slc6a3 mice, in which Drd2 is selectively deleted in DA-neurons, we observed enhanced excitatory and inhibitory responses of VTA DA-neurons to aversive stimuli, suggesting that autoD2R acts as a critical regulatory brake.
Importantly, this modulation occurred independently of either the pacemaker activity of DA-neurons or their coupling to the non-selective sodium leak channel NALCN. Behaviorally, Drd2 Slc6a3 male mice showed enhanced discrimination between threat-predicting and non-predicting cues that persisted during extinction learning, highlighting a sex-biased role of autoD2R in threat processing.
Our results provide new mechanistic insights through which autoD2R influence behavioral responses to aversive stimuli, with implications for understanding neuropsychiatric disorders characterized by maladaptive threat processing. The ability to attribute motivational salience to stimuli that predict rewarding or aversive outcomes is essential for survival. This process relies on associative learning, which enables salient cues to recruit attentional resources and assists animals to prioritize actions in response to significant events Bromberg-Martin et al.
These alterations are frequently associated with core symptoms of neuropsychiatric disorders, such as generalized anxiety and high-risk taking behaviors.
