Abstract
In the heterogeneous hub represented by the lateral hypothalamus, neurons containing the orexin/hypocretin peptides play a key role in vigilance state transitions and wakefulness stability, energy homeostasis, and other functions relevant for motivated behaviors. Orexin neurons, which project widely to the neuraxis, are innervated by multiple extra- and intra-hypothalamic sources. A key property of the adaptive capacity of orexin neurons is represented by daily variations of activity, which is highest in the period of the animal’s activity and wakefulness. These sets of data are here reviewed. They concern the discharge profile during the sleep/wake cycle, spontaneous Fos induction, peptide synthesis and release reflected by immunostaining intensity and peptide levels in the cerebrospinal fluid as well as postsynaptic effects. At the synaptic level, adaptive capacity of orexin neurons subserved by remodeling of excitatory and inhibitory inputs has been shown in response to changes in the nutritional status and prolonged wakefulness. The present review wishes to highlight that synaptic plasticity in the wiring of orexin neurons also occurs in unperturbed conditions and could account for diurnal variations of orexin neuron activity. Data in zebrafish larvae have shown rhythmic changes in the density of inhibitory innervation of orexin dendrites in relation to vigilance states. Recent findings in mice have indicated a diurnal reorganization of the excitatory/inhibitory balance in the perisomatic innervation of orexin neurons. Taken together these sets of data point to “chronoconnectivity,” i.e., a synaptic rearrangement of inputs to orexin neurons over the course of the day in relation to sleep and wake states. This opens questions on the underlying circadian and homeostatic regulation and on the involved players at synaptic level, which could implicate dual transmitters, cytoskeletal rearrangements, hormonal regulation, as well as surrounding glial cells and extracellular matrix. Furthermore, the question arises of a “chronoconnectivity” in the wiring of other neuronal cell groups of the sleep-wake-regulatory network, many of which are characterized by variations of their firing rate during vigilance states.
Highlights
A wealth of studies has been stimulated by the discovery, two decades ago, of neurons of the lateral hypothalamus (LH) which synthesize the orexin/hypocretin peptides
This study was based on electrophysiological approaches, ultrastructure, fluorescence immunostaining of presynaptic components using vesicular glutamate transporter-2 (VGluT2) to label excitatory axon terminals and GAD to label GABAergic ones
Possibly because ob/ob mice lack endogenous leptin when weaned but receive leptin from their heterozygous mothers during lactation, synapse remodeling at orexin neurons only occurred after weaning and was reversed by exogenous leptin injection (Cristino et al, 2013; Becker et al, 2017). Consistent with these findings and with data indicating that experimental exposure to high-fat diet (HFD) induces various forms of functional and structural plasticity within the reward circuitry (Sharma et al, 2013), a recent report in rats has pointed out plastic changes in orexin neurons following exposure to HFD (Linehan et al, 2018)
Summary
A wealth of studies has been stimulated by the discovery, two decades ago, of neurons of the lateral hypothalamus (LH) which synthesize the orexin/hypocretin peptides (de Lecea et al, 1998; Sakurai et al, 1998) Interest in these neurons has been boosted by findings that rapidly accumulated on their role in food intake, in the promotion and consolidation of wakefulness, as well as in a wide range of other physiological functions relevant for motivated behaviors. Seminal investigations have shown plastic synaptic changes in the excitatory wiring of orexin neurons after changes in food intake or prolonged wakefulness (Horvath and Gao, 2005; Rao et al, 2007) Such findings have focused attention on the response of these neurons to perturbations of physiological functions. The findings point to daily variations in the excitatory/inhibitory wiring of orexin neurons as operational mode of these neurons inserted in a network that should meet daily demands
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
