Reactive and predictive homeostasis: Roles of orexin/hypocretin neurons

Homeostasis is the maintenance of a healthy physiological equilibrium in a changing world. Reactive (feedback, counter-regulatory) and predictive (feedforward, anticipatory) homeostatic control strategies are both important for survival. For example, in energy homeostasis, the pancreas reacts to ingested glucose by releasing insulin, whereas the brain prepares the body for ingestion through anticipatory salivation based on food-associated cues. Reactive control is largely innate, whereas predictive control is often acquired or modified through associative learning, though some important predictive control strategies are innate, e.g. avoidance of fox scent in mice that never met a fox. Traditionally, the hypothalamus has been viewed as a reactive controller, sensing deviations from homeostasis to elicit counter-regulatory responses, while higher areas such as the cortex have been viewed as predictive controllers. However, experimental evidence argues against such neuroanatomical segregation: for example, receptors for internal homeostatic indicators are found throughout the brain, while key interoceptive hypothalamic cells also rapidly sense external cues. Here a model is proposed where the brain-wide-projecting, non-neuroendocrine, neurons of the hypothalamus, exemplified by orexin/hypocretin neurons, function as brain government systems that convert integrated internal and external information into reactive and predictive autonomic, cognitive, and behavioural adaptations that ensure homeostasis. Like regions of a country without a government, individual brain regions can function normally without hypothalamic guidance, but these functions are uncoordinated, producing mismatch between supply and demand of arousal, and derailing decision-making as seen in orexin-deficient narcolepsy. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'.