Divergent modulation of dopaminergic neurons by hypocretin/orexin receptors-1 and -2 shapes dopaminergic cell activity and socio-emotional behavior

BACKGROUNDMany neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA projections stemming from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DAVTA neurons arises from lateral hypothalamic area hypocretin/orexin (OX) neurons. Despite being a major input, the differential action of orexin peptides A and B (OXA and OXB) on orexin receptors 1 and 2 in DA cells is poorly understood. We recently identified profoundly divergent functions of OX1R vs OX2R in DA cells in regulating sleep/wake architecture, brain oscillations and cognitive behaviors. OX2R, but not OX1R, loss dramatically increased time in EEG theta-rich (alert) wakefulness, reward-driven learning and attentional skills, but impaired inhibitory control. METHODSUsing genetically engineered mice whose DA cells selectively lack OX input via Hcrtr1 (DAOx1R-KO) or Hcrtr2 (DAOx2R-KO), we assessed intrinsic excitability and electrophysiological responses of DAVTA neurons and evaluated behavioral phenotypes across multiple domains. RESULTSWe uncover previously unrecognized effects of OX peptides on DAVTA cell response. In WT and control mice, we show that while OXA enhances, OXB diminishes DAVTA neuronal excitability. OX1R-deficient DA cells lose OXA responding and OX2R-deficient DA cells lose OXB responding. DA Ox1R loss generates anxiety-like behavior and context-dependent hyperactivity. In contrast, OX2R loss decreases sociability and, despite exhibiting enhanced reward-driven learning, mice show highly compromised aversion-driven learning. CONCLUSIONSWe evidence strikingly distinct functions of OX1R vs OX2R signaling in modulating the intrinsic excitability of DAVTA neurons and influencing DA-related behaviors. These data implicate OX[->]DA signaling pathways in neuropsychiatric endophenotypes relevant to obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders, and raise important considerations for the development of OXR-targeted therapeutics.