Distribution of orexin neurons in the adult rat brain

College of Medical Technology and Nursing, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Brain Research (Impact Factor: 2.83). 06/1999; 827(1-2):243-260. DOI: 10.1016/S0006-8993(99)01336-0

ABSTRACT Orexin (ORX)-A and -B are recently identified neuropeptides, which are specifically localized in neurons within and around the lateral hypothalamic area (LHA) and dorsomedial hypothalamic nucleus (DMH), the regions classically implicated in feeding behavior. Here, we report a further study of the distribution of ORX-containing neurons in the adult rat brain to provide a general overview of the ORX neuronal system. Immunohistochemical study using anti-ORX antiserum showed ORX-immunoreactive (ir) neurons specifically localized within the hypothalamus, including the perifornical nucleus, LHA, DMH, and posterior hypothalamic area. ORX-ir axons and their varicose terminals showed a widespread distribution throughout the adult rat brain. ORX-ir nerve terminals were observed throughout the hypothalamus, including the arcuate nucleus and paraventricular hypothalamic nucleus, regions implicated in the regulation of feeding behavior. We also observed strong staining of ORX-ir varicose terminals in areas outside the hypothalamus, including the cerebral cortex, medial groups of the thalamus, circumventricular organs (subfornical organ and area postrema), limbic system (hippocampus, amygdala, and indusium griseum), and brain stem (locus coeruleus and raphe nuclei). These results indicate that the ORX system provides a link between the hypothalamus and other brain regions, and that ORX-containing LHA and DMH neurons play important roles in integrating the complex physiology underlying feeding behavior.

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    • "Despite their relatively small number (estimates of 1000e7000 neurons in rat (Peyron et al., 1998; Modirrousta et al., 2005), and 70,000 neurons in human brain (Thannickal et al., 2000), orexin neurons innervate many brain areas. Prepro-orexin mRNA is present in the zona incerta, dorsomedial, anterior, lateral and perifornical hypothalamus (Sakurai et al., 1998), and the precise distribution of orexinsynthesising neurons has been independently confirmed by immunohistochemical staining in rat, mouse and human brain (Chen et al., 1999; Date et al., 1999; Gonzalez et al., 2012; Nambu et al., 1999; Sakurai et al., 1998). "
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    ABSTRACT: Orexin/hypocretin peptides play a central role in the integrated control of feeding/reward and behavioural activation, principally via interactions with other neural systems. A brainstem area involved in behavioural activation is the nucleus incertus (NI), located in the posterior ventromedial central grey. Several studies have implicated NI in control of arousal/stress and reward/feeding responses. Orexin receptor mRNA expression identifies NI as a putative target of orexin modulation. Therefore, in this study we performed neural tract-tracing and immunofluorescence staining to characterise the orexinergic innervation of NI. Our results indicate a convergent innervation of the NI area by different orexin neurons populations, along with an abundance of orexin-A-containing axons making putative synaptic contacts with relaxin-3-positive NI neurons. The influence of orexin-A on NI neuron activity was investigated using patch-clamp recordings. Orexin-A depolarised the majority (64%) of recorded neurons and this effect was maintained in the presence of tetrodotoxin and glutamate and GABA receptor antagonists, indicating a likely postsynaptic action. Voltage-clamp experiments revealed that in 'type I' NI neurons comprising relaxin-3-positive cells, orexin-A acted via L-type calcium channels, whereas in 'type II' relaxin-3-negative neurons, activation of a sodium/calcium exchanger was involved. A majority of the orexin-A sensitive neurons tested for the presence of orexin receptor mRNA, were OX2 mRNA-positive. Immunohistochemical staining for putative orexin receptors on NI neurons, confirmed stronger expression of OX2 than OX1 receptors. Our data demonstrate a strong influence of orexin-A on NI neurons, consistent with an important role for this hypothalamic/tegmental circuit in the regulation of arousal/vigilance and motivated behaviours. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 08/2015; DOI:10.1016/j.neuropharm.2015.08.014 · 4.82 Impact Factor
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    • "In the hypothalamus orexin projections are mainly found in the paraventricular (PVH), ventromedial (VMH) and arcuate (ARC) nuclei (Horvath et al., 1999). Outside the hypothalamus orexin neurons project to the olfactory bulb, cerebral cortex, thalamus, the brainstem and all levels of the spinal cord (Broberger et al., 1998; Elias et al., 1998; Peyron et al., 1998; Date et al., 1999; Nambu et al., 1999). The projections with the highest density are found at the level of the locus coeruleus (LC) within the brainstem, where catecholaminergic neurons are innervated by orexin containing fibers, which suggested a potential role of these peptides in the regulation of the sleepewake cycle (Peyron et al., 1998). "
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    ABSTRACT: Initially implicated in the regulation of feeding, orexins/hypocretins are now acknowledged to play a major role in the control of a wide variety of biological processes, such as sleep, energy expenditure, pain, cardiovascular function and neuroendocrine regulation, a feature that make them one of the most pleiotropic families of hypothalamic neuropeptides. While the orexigenic effect of orexins is well described, their central effects on energy expenditure and particularly on brown adipose tissue (BAT) thermogenesis are not totally unraveled. Better understanding of these actions and their possible interrelationship with other hypothalamic systems controlling thermogenesis, such as AMP-activated protein kinase (AMPK) and endoplasmic reticulum (ER) stress, will help to clarify the exact role and pathophysiological relevance of these neuropeptides have on energy balance. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 07/2015; DOI:10.1016/j.mce.2015.07.022 · 4.24 Impact Factor
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    • "Neuroscience 298 (2015) 190–199 studies have shown that the release of hypocretin in the hypothalamus is greater during AS compared to quiet sleep (QS; i.e., non-REM sleep) (Kiyashchenko et al., 2002). These studies are complemented by anatomical explorations that demonstrate that hypocretinergic neurons project directly to the NPO (Peyron et al., 1998; Nambu et al., 1999; Zhang et al., 2004). The preceding findings support the hypothesis that hypocretinergic projections are capable of directly activating neurons that comprise the AS-generator in the NPO which results in the generation of AS in a manner that is separate from cholinergic AS-inducing inputs, such as those from the LDT/PPT. "
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    ABSTRACT: Anatomical studies have demonstrated that hypocretinergic and GABAergic neurons innervate cells in the nucleus pontis oralis (NPO), a nucleus responsible for the generation of active (REM) sleep (AS) and wakefulness (W). Behavioral and electrophysiological studies have shown that hypocretinergic and GABAergic processes in the NPO are involved in the generation of AS as well as W. An increase in hypocretin in the NPO is associated with both AS and W, whereas GABA levels in the NPO are elevated during W. We therefore examined the manner in which GABA modulates NPO neuronal responses to hypocretin. We hypothesized that interactions between the hypocretinergic and GABAergic systems in the NPO play an important role in determining the occurrence of AS or W. To determine the veracity of this hypothesis, we examined the effects of the juxtacellular application of hypocretin-1 and GABA on the activity of NPO neurons, which were recorded intracellularly, in chloralose-anesthetized cats. The juxtacellular application of hypocretin-1 significantly increased the mean amplitude of spontaneous EPSPs and the frequency of discharge of NPO neurons; in contrast, the juxtacellular microinjection of GABA produced the opposite effects, i.e., there was a significant reduction in the mean amplitude of spontaneous EPSPs and a decrease in the discharge of these cells. When hypocretin-1 and GABA were applied simultaneously, the inhibitory effect of GABA on the activity of NPO neurons was reduced or completely blocked. In addition, hypocretin-1 also blocked GABAergic inhibition of EPSPs evoked by stimulation of the laterodorsal tegmental nucleus. These data indicate that hypocretin and GABA function within the context of a neuronal gate that controls the activity of AS-on neurons. Therefore, we suggest that the occurrence of either AS or W depends upon interactions between hypocretinergic and GABAergic processes as well as inputs from other sites that project to AS-on neurons in the NPO.
    Neuroscience 04/2015; 298. DOI:10.1016/j.neuroscience.2015.04.022 · 3.33 Impact Factor
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