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

Many neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA projections originating from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DA ^VTA neurons arises from the dense axonal projections emanating 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 (OX ₁ R and OX ₂ R) in DA cells is poorly characterized. We thus genetically engineered mice whose DA neurons are selectively unresponsive to OX input via OX ₁ R (DA ^Ox1R-KO mice) or OX ₂ R (DA ^Ox2R-KO mice) and compared their behavior and DA cell electrophysiology to genetic controls. We previously showed a profound functional divergence between OX ₁ R-and OX ₂ R-mediated modulation of DA neurons in controlling vigilance states, brain oscillations and cognitive behavior. Inactivation of OX ₂ R, but not OX ₁ R, in DA neurons dramatically increased time spent in EEG theta-rich wakefulness, improved reward-driven learning and attentional skills, while it impaired inhibitory control. Here, we interrogate DA ^Ox1R-KO and DA ^Ox2R-KO mice in further behavioral domains. We show that mice with DA-specific OX ₁ R loss exhibit hyperactivity, or anxiety-like responding, in context-dependent manners. OX ₂ R loss in contrast decreases sociability and aversion-driven learning. We next investigate the underlying electrophysiological substrates and uncover previously unrecognized effects of OX peptides on DA ^VTA cell responses. In WT and control mice, we show that while OXA enhances, OXB diminishes DA ^VTA neuronal excitability. OX ₁ R-deficient DA cells lose OXA responding and OX ₂ R-deficient DA cells lose OXB responding. We altogether evidence strikingly distinct functions of OX ₁ vs OX ₂ R signaling in modulating the intrinsic excitability of DA ^VTA neurons and influencing DA-related behaviors. Our data position OX→DA neurotransmission via OX ₁ or OX ₂ R as relevant to endophenotypes observed in the context of disorders such as obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders.