Cell type- and pathway-specific synaptic regulation of orexin neurocircuitry

Orexin-expressing neurons are located exclusively in the lateral hypothalamic and perifornical areas and exhibit complex connectivity. The intricate wiring pattern is evident from a diverse function for orexin neurons in regulating many physiological processes and behaviors including sleep, metabolism, circadian cycles, anxiety, and reward. Nevertheless, the precise synaptic and circuitry-level mechanisms mediating these processes remain enigmatic, partially due to the wide spread connectivity of the orexin system, complex neurochemistry of orexin neurons, and previous lack of suitable tools to address its complexity. Here we summarize recent advances, focusing on synaptic regulatory mechanisms in the orexin neurocircuitry, including both the synaptic inputs to orexin neurons as well as their downstream targets in the brain. A clear and detailed elucidation of these mechanisms will likely provide novel insight into how dysfunction in orexin-mediated signaling leads to human disease and may ultimately be treated with more precise strategies.