Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

Abstract

The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep-waking cycle.

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

“…Renewed interest in the hypothalamus has emerged due to the discovery of the hypocretinergic system which has been suggested to be involved in the control of motor activity, sleep and wakefulness (reviewed by (Siegel, 2004, Sutcliffe and de Lecea, 2002, Taheri, et al, 2002). MCHergic neurons are intermingled with the hypocretinergic neurons in the hypothalamus and their projections are strikingly similar (Bayer, et al, 2002, Bittencourt, et al, 1992, Guan, et al, 2002, Peyron, et al, 1998, Skofitsch, et al, 1985; this anatomical data suggest that the MCHergic neurons may also contribute to the regulation of motor activity, sleep and waking functions. However, very few reports examined the role of MCH in relation to these functions.…”

“…In hamsters and rats, MCHergic neurons are intermingled with hypocretinergic neurons and make numerous synaptic contacts with these cells (Bayer, et al, 2002, Guan, et al, 2002, Khorooshi and Klingenspor, 2005. The hypocretinergic system has an anatomical organization similar to the MCHergic system (Peyron, et al, 1998), and it has been proposed to be involved in the regulation of behavioral states; deficits in this system have been associated with narcolepsy/cataplexy (Siegel, 2004, Sutcliffe and de Lecea, 2002, Taheri, et al, 2002. In the present report, as a foundation for furthering understanding of the function of the MCHergic system and its interactions with the hypocretinergic system, we determined the location of the neuronal somata of MCH-containing neurons and their anatomical relationship with the hypocretinergic system in the cat.…”

Normal Sleep and Circadian Rhythms: Neurobiologic Mechanisms Underlying Sleep and Wakefulness

“…The hypocretin-producing neurons in the hypothalamus receive direct input from the SCN (the circadian rhythm clock) and project to the posterior hypothalamus (tuberomammillary nucleus [TMN]-histamine), basal forebrain (cholinergic vigilancewake area), thalamus, locus caeruleus and dorsal raphe neucleus (norepinephrine and serotonin REM off cells), LDT, and PRF (cholinergic REM-on cells and muscle atonia) [30], [31] . In accordance with circadian rhythm control of hypocretin levels (through SCN input), their concentration is highest during the waking period.…”

Requirement of Intact Disulfide Bonds in Orexin-A-Induced Stimulation of Gastric Acid Secretion That Is Mediated by OX1 Receptor Activation

“…In addition to the locus coeruleus, the lateroanterior hypothalamic nucleus, ventromedial hypothalamic nucleus, amygdalohippocampal area, and dorsal and median raphe highly express OX1R. Immunohistochemical studies have shown that orexinimmunoreactive fibers and terminals are richly distributed in these brain sites (15,16,17). It is therefore speculated that the site of action of orexin-A to stimulate gastric acid secretion should be in the brain nuclei that express OX1R because the orexin-A-induced stimulation of gastric acid should be mediated through the action of OX1R as shown in this study.…”