Increasing evidence suggests that the mesolimbic reward system plays critical roles in the regulation of depression and nociception; however, its circuitry and cellular mechanisms remain unclear. In this study, we investigated the output-specific regulatory roles of dopaminergic (DA) neurons within the ventral tegmental area (VTA) in depressive-like and nociceptive behaviors in mice subjected to unpredictable chronic mild stress (CMS), using the projection-specific electrophysiological recording, pharmacological manipulation, behavioral test, and molecular biology technologies. We demonstrated that CMS decreased the firing activity in VTA projecting to medial prefrontal cortex (VTA → mPFC), but not in VTA to nucleus accumbens (VTA → NAc), DA neurons. However, both VTA → mPFC and VTA → NAc DA neurons showed increased firing activity in response to morphine perfusion in CMS mice. Behavioral results showed that intra-VTA microinjection of morphine (25.5 ng/0.15 μL) relieved depressive-like behaviors, intriguingly, accompanied by a thermal hyperalgesia. Furthermore, the relief of depressive-like behaviors induced by intra-VTA injection of morphine in CMS mice could be prevented by blocking brain-derived neurotrophic factor (BDNF) signaling and mimicked by the administration of exogenous BDNF in mPFC rather than in NAc shell. Nociceptive responses induced by the activation of VTA DA neurons with morphine in CMS mice could be prevented by blocking BDNF signaling or mimicked by administration of exogenous BDNF in NAc shell, but not in mPFC. These results reveal projection-specific regulatory mechanisms of depression and nociception in the mesolimbic reward circuitry and provide new insights into the neural circuits involved in the processing of depressive and nociceptive information.

Robust sex difference among humans regarding psychiatry- and pain-related behaviors is being researched; however, the use of female mice in preclinical research is relatively rare due to an unchecked potential behavioral variation over the estrous cycle. In the present study, a battery of psychiatry- and pain-related behaviors are examined under physiological condition in female C57BL/6J mice over different estrous cycle phases: proestrus, estrous, metestrous, diestrous. Our behavioral results reveal that there is no significant difference over different phases of the estrous cycle in social interaction test, sucrose preference test, tail suspension test, open field test, marble burying test, novelty-suppressed feeding test, Hargreaves thermal pain test, and Von Frey mechanical pain test. These findings implicate those psychiatry- and pain-related behaviors in normal female C57BL/6J mice appear to be relatively consistent throughout the estrous cycle; the estrous cycle might not be a main contributor to female C57BL/6J mice’s variability of behaviors.