Hypocretin as a Hub for Arousal and Motivation

Abstract

The lateral hypothalamus is comprised of a heterogeneous mix of neurons that serve to integrate and regulate sleep, feeding, stress, energy balance, reward, and motivated behavior. Within these populations, the hypocretin/orexin neurons are among the most well studied. Here, we provide an overview on how these neurons act as a central hub integrating sensory and physiological information to tune arousal and motivated behavior accordingly. We give special attention to their role in sleep-wake states and conditions of hyper-arousal, as is the case with stress-induced anxiety. We further discuss their roles in feeding, drug-seeking, and sexual behavior, which are all dependent on the motivational state of the animal. We further emphasize the application of powerful techniques, such as optogenetics, chemogenetics, and fiber photometry, to delineate the role these neurons play in lateral hypothalamic functions.

Rapid sensory integration in orexin neurons governs probability of future movements

“…To our knowledge, this is the first hypothalamic neuronal population shown to mediate a rapid sensorimotor transformation, similar to those seen in the neocortex (Ferezou et al, 2007;Svoboda and Li, 2018). The broad stimulus receptivity ( Figure 5) and robust activation during mobile behaviours ( Figure 1) indicate that orexin neurons have a broader and more immediate influence on awake behaviour than previous literature suggests (Mahler et al, 2014;Tyree et al, 2018).…”

“…It should also assess whether orexin cell movement-subtypes correlate with known electrophysiological, molecular or anatomical subtypes (Apergis-Schoute et al, 2015;Iyer et al, 2018;Mickelsen et al, 2019Mickelsen et al, , 2017Schöne et al, 2011). It has been hypothesized that orexin neurons promote exploratory activity, hunger-driven food-seeking or any motivated behaviour (Mahler et al, 2014;Tyree et al, 2018;Yamanaka et al, 2003). Future work should therefore also inspect whether orexin activation is specifically associated with movement toward a particular goal, given the option for an animal to move in order to achieve different outcomes.…”

“…A key genetically-distinct population of LH neurons that responds to external stimuli are the orexin (hypocretin) neurons, which are evolutionarily conserved and project throughout the brain (Tyree et al, 2018). Orexin neurons are critical regulators of arousal and whole body metabolism (Adamantidis et al, 2007;Yamanaka et al, 2003), that are commonly thought to act on a slow timescale.…”

Characterization ofmWakeexpression in the murine brain

“…In particular, the dorsolateral quadrant of the LH contains dense mWake + processes, as well as a population of cell bodies which are intermingled with the orexinergic cell bodies which classically occupy this region (Bell et al, 2020). The LH contains a variety of arousal-promoting circuits and cell types in addition to orexin, including wake-promoting populations of both glutamatergic and GABAergic neurons (Heiss, Yamanaka, & Kilduff, 2018;Herrera et al, 2016;Tyree, Borniger, & de Lecea, 2018;Venner, Anaclet, Broadhurst, Saper, & Fuller, 2016).…”

Central regulation of breast cancer growth and metastasis

“…The lateral hypothalamus (LH) is a highly heterogeneous structure that serves a primary role in arousal, metabolism, and motivated behavior [24] . A neural population that has been intensely studied in this area are those that express the excitatory neuromodulators hypocretin-1 and hypocretin-2 (aka orexin-A and -B; HO) [26,27] . Discovered by two groups at essentially the same time [28,29] , these neurons are critical for maintaining wakefulness, as their destruction results in the sleep disorder narcolepsy [30][31][32][33] .…”