Hypocretin/orexin signaling at the interface of arousal and motivation : from need for feed to craving for drug

The development of survival skills requires the evolutionary emergence of coherent and coordinated innate behaviors that adapt behavioral strategies in function of basic need priorities. These behaviors have evolved from the most basic instinct expression to the elaboration of complex goal-oriented behaviors and subtle decision-making processes. Compelling evidence has established over the last 50 years that a complex network of intermingled hypothalamic nuclei, which are anatomically and functionally distinct, mediates the integration and processing of basic needs. The current consensus acknowledges the hypothalamus as a brain orchestrator composed of heterogeneous, widely-projecting neurons whose activity is essential for coordinating vital functions including energy balance, sleep and body temperature, stress response and reproduction. However, how these intricate networks are organized to produce coordinated behavior, and further, how alteration of this complex circuitry may lead to a pathological state, remains largely unknown. Therefore, elucidating circuits, neurotransmitters, intracellular signaling molecules, and genes that underlie the complex coordination of basic needs is invaluable for the treatment of sleep impairments, eating disorders, drug addiction and other stress-related psychiatric disorders. In this perspective, the role of the hypocretin/orexin system in the control of sleep and wakefulness through multiple interactions with brain structures involved in the regulation of emotion, reward, stress and energy homeostasis has been evolving over the past 15 years. It is now quite accepted that hypocretin/orexin neuropeptides elicit appropriate levels of arousal to engage exploratory and goal-oriented behaviors depending on physiological needs (hunger, thirst), and orchestrates the stress response that drives motivation for food and liquid seeking. Increasing evidence also suggests that chronic drug intoxication may compromise basic need priorities, and that “high jacking” of the orexin/hypocretin system may serve for triggering drug-oriented behaviors at the expense of former basic need priorities. Our goal is to assemble, in a special topic, the most contemporary research depicting the role of the hypocretin/orexin system in arousal, stress and motivation.
Sakurai and Yanagisawa will present the overview on the anatomy, physiology and pharmacology of the hypocretin/orexin system. Contributions from Adamantidis et al. and Burdakov et al. will focus on the development of optogenetic tools which offer new ways of probing this neural circuit in arousal maintenance and food intake. Concomitantly, de Lecea and colleagues will present the most recent evidence on the role played by the hypocretin/orexin system in the orchestration of the stress response, whereas articles by Borgland et al. and Espana et al. will present how this system interact with other neurotransmitters within the mesocorticolimbic system to strengthen the dopaminergic neurotransmission and ultimately to reinforce motivation for reward seeking. Contributions from Aston-Jones et al., Boutrel et al., Kenny et al., Lawrence et al., and Martin-Fardon et al. will present evidence on the emerging role for hypocretin/orexin in abuse liability of several different classes of addictive drugs.
Collectively, this Research Topic aims at summarizing the most current knowledge in the field, and hopefully will inspire additional research given the real therapeutic potential of hypocretin/orexin blockers for treating addiction and stress-related psychopathologies.