The hypocretin (orexin) system: from a neural circuitry perspective

Hypocretin/orexin neurons are distributed restrictively in the hypothalamus, a brain region known to orchestrate diverse functions including sleep, reward processing, food intake, thermogenesis, and mood. Since the hypocretins/orexins were discovered more than two decades ago, extensive studies have accumulated concrete evidence showing the pivotal role of hypocretin/orexin in diverse neural modulation. New method of viral-mediated tracing system offers the possibility to map the monosynaptic inputs and detailed anatomical connectivity of Hcrt neurons. With the development of powerful research techniques including optogenetics, fiber-photometry, cell-type/pathway specific manipulation and neuronal activity monitoring, as well as single-cell RNA sequencing, the details of how hypocretinergic system execute functional modulation of various behaviors are coming to light. In this review, we focus on the function of neural pathways from hypocretin neurons to target brain regions. Anatomical and functional inputs to hypocretin neurons are also discussed. We further briefly summarize the development of pharmaceutical compounds targeting hypocretin signaling. This article is part of the special issue on Neuropeptides.