Distinct neuromodulatory effects of endogenous orexin and dynorphin corelease on projection-defined ventral tegmental dopamine neurons.

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues and circuit-specific signaling drives different aspects of motivated behavior. Orexins (ox; also known as hypocretin) and dynorphin (dyn) are co-expressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors, respectively. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the co-released peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LH neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregates based on VTADA 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 orexincre mice we showed a diverse response of LH optical stimulation on VTADA neuronal firing, that are not mediated by fast transmitter release and are blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA projecting VTADA neurons, optical stimulation of LH inputs in the VTA bidirectionally affects firing of either lAcbSh or mAchSh projecting VTADA neurons. These findings indicate that LHox/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. Significance StatementThe mesolimbic dopamine (DA) system is known to play a crucial role in motivation and reward-learning and receives neuromodulatory input from the lateral hypothalamus (LH). We show that optical stimulation of the orexin-containing LH input in the VTA releases both orexin and dynorphin to bidirectionally alter VTADA firing. Furthermore, orexin and dynorphin differentially modulate firing of DA inputs to the basolateral amygdala, whereby dynorphin predominates, or to the nucleus accumbens which is sensitive to both neuromodulators. Our findings contribute to a more comprehensive understanding of the neuromodulatory effects of coreleased LH orexin and dynorphin on the VTADA system.