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^DA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors. Given that Ox1R activation increases VTA^DA 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_ox/dyn neuromodulates VTA^DA neuronal activity via peptide release and if the effects of optically driven LH_ox/dyn release segregate based on VTA^DA 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^cre mice, we showed a diverse response of LH_ox/dyn optical stimulation on VTA^DA 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_ox/dyn inputs in the VTA inhibited firing of the majority of BLA-projecting VTA^DA neurons, optical stimulation of LH_ox/dyn inputs in the VTA bidirectionally affects firing of either lAcbSh- or mAchSh-projecting VTA^DA neurons. These findings indicate that LH_ox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.