Distinct Neuromodulatory Effects of Endogenous Orexin and Dynorphin Corelease on Projection-Defined Ventral Tegmental Dopamine Neurons.

Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues, and circuit-specific signaling drives different aspects of motivated behavior. Orexin (ox; also known as hypocretin) and dynorphin (dyn) are coexpressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors. Given that Ox1R activation increases VTA firing, and KOR decreases firing, it is unclear how the coreleased peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LH neuromodulates VTA neuronal activity via peptide release and if the effects of optically driven LH release segregate based on VTA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch-clamp electrophysiology in male and female orexin mice, we showed a diverse response of LH optical stimulation on VTA neuronal firing, which is not mediated by fast transmitter release and is blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LH inputs in the VTA inhibited firing of the majority of BLA-projecting VTA neurons, optical stimulation of LH inputs in the VTA bidirectionally affects firing of either lAcbSh- or mAchSh-projecting VTA neurons. These findings indicate that LH corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.