Functional Plasticity of Orexin/Hypocretin Neurons Balances Stress States

Orexin/hypocretin (Orx) peptides critically contribute to stress and arousal circuits' flexibility and equilibrium. New discoveries highlight plasticity of orexin neurons themselves, as well as plasticity-inducing properties of orexin peptides within projection circuits, as an integral part of this function. Specifically, orexin peptide release in response to stress alters the microcircuitry and gene expression profile of downstream stress regions. Here, we propose that orexin-mediated plasticity within stress circuitry is constructed across a lifetime in response to a myriad of variable challenges, ultimately enhancing neural flexibility and future adaptive behavioral responses. This provides a framework through which exposure to unusually salient stressors, either acutely or over extended periods, can result in altered engagement of stress circuitry and maladaptive affective behavioral outcomes (as in general anxiety disorder and posttraumatic stress disorder). Furthermore, we posit that the diversity of plastic orexin functions is regulated, at least in part, by unique signaling roles for Orx 1 and 2 receptors in distinct brain regions. By extension, therapeutics with selective actions at these receptors may offer viable treatments designed to override pathological rewiring of stress circuits and restore adaptive stress responsivity.