New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

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Central nervous system control of food intake

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.

https://www.jneurosci.org/content/jneuro/18/23/9996.full.pdf

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

https://sites.oxy.edu/clint/physio/article/therewardcircuitlinkingprimateanatomyandhumanimaging.pdf

The reward circuit: linking primate anatomy and human imaging.

http://dept.wofford.edu/neuroscience/NeuroSeminar/pdfSpring2010/MolecularGenetics.pdf

Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

La narcolepsie de type 1 (NT1) est un trouble du sommeil dont les principaux symptômes sont causés par la perte des neurones à orexines/hypocrétines (ORX) de l’hypothalamus latéral. D’autres altérations hypothalamiques, telles qu’une augmentation des neurones à histamine (HIS) et une diminution des neurones de l’hormone de libération de la corticotropine (CRH), ont été trouvées. Nous nous sommes demandé si l’environnement neuro-inflammatoire, vraisemblablement présent dans l’hypothalamus au début de la maladie, pouvait engendrer des changements transcriptionnels dans les populations neuronales altérées dans la NT1, qui pourrait expliquer, au moins en partie, le devenir divergent des neurones à ORX, HIS et CRH dans la NT1. La neuro-inflammation a été induite chez des souris à l’âge de 42 jours par une injection périphérique de LPS (1 mg/kg). Des séquençages d’ARN à cellule unique et à noyau unique ont été utilisés pour découvrir les changements transcriptionnels des populations cellulaires de l’hypothalamus 24 h et 48 h après injection de LPS. Les neurones ont montré un changement transcriptionnel significatif 48 h après injection de LPS. Nous avons détecté l’activation de processus pro-apoptotiques dans les neurones à ORX et HIS, mais pas dans les neurones à CRH. Les neurones à ORX et HIS ont montré une sensibilité aux enjeux neuro-inflammatoires. En plus de l’attaque auto-immune ciblée, une fragilité accrue des neurones à ORX, due à la condition neuro-inflammatoire, pourrait contribuer à leur dégénérescence au début de la NT1. 

Analyses transcriptomiques à cellule unique et à noyau unique de l’hypothalamus dans un état neuro-inflammatoire induit par le LPS

Narcolepsy is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations including cataplexy (sudden loss of muscle tone triggered by strong emotions), sleep paralysis, hypnagogic hallucinations, and sleep-onset REM (SOREM) periods [1]. It is generally admitted that narcolepsy with cataplexy is caused by the loss of hypothalamic hypocretin/orexin neurons [2]. Patients with narcolepsy–cataplexy have been shown to lack hypocretin-1 in their cerebrospinal fluid (CSF). This allows distinguishing narcolepsy with cataplexy from other forms of central hypersomnia, that is, narcolepsy without cataplexy and idiopathic hypersomnia, which show normal CSF hypocretin-1 level [3] and is sufficient to define narcolepsy type 1 based on the last classification (ICSD-3). However, because of a possible continuum in terms of clinical manifestations and physiopathological mechanisms between these sleep disorders [4,5], differential diagnosis remains often tricky and difficult. Developing an easy, reliable, sensitive, and specific diagnostic tool has always been a major requirement in sleep medicine. Since the nineties, genotyping for HLA DR2 is extensively used as an index to confirm diagnosis because 85–95% of patients with narcolepsy–cataplexy carry the DQB1*0602 haplotype. However, it is unspecific to narcolepsy with cataplexy because it is also found in 20% of the general population. A striking decrease in CSF hypocretin-1 has been noted in patients with narcolepsy–cataplexy with a high (94%) positive predictive value for the diagnosis [3]. Unfortunately, such measurements require invasive lumbar puncture and it is of no use for differentiating narcolepsy without cataplexy from idiopathic or other hypersomnia. A few studies measured plasmatic hypocretin-1 levels, but the reliability of this approach remains a matter of debate. Finally, other tryouts have also been attempted without clear success [6,7]. In a recent letter to the editor of CNS Neurosci Therap., Chen and colleagues [8] using HPLC and mass spectrometry have analyzed serum proteins in 35 patients with narcolepsy (25 with cataplexy), compared with 49 patients with other sleep disorders and 35 healthy controls. They found a protein fragment peak in 65.7% of patients with narcolepsy, 72%when considering patients with cataplexy only. The authors further sequenced the extracted protein fragment and identified it as RBM4/Lark protein [8]. This is clearly an interesting attempt and original observation, worth to be pursued in further investigations in order to assess whether such RBM4/Lark protein may constitute a specific marker of narcolepsy and therefore a useful diagnostic tool. On the one hand, the protein fragment peak was also seen in 15% of other patients with sleep disorder and 16% of healthy controls [8]. Quantitative analysis on patients with narcolepsy and the two control groups is therefore necessary to determine to which extent the RBM4/Lark protein could be specific to narcolepsy. On the other hand, only three patients with idiopathic hypersomnia and 10 with narcolepsy without cataplexy were included in this study [8]. A much larger group size of patients in a matched case–control study is required to confirm whether or not the RBM4/Lark protein could serve as marker to differentiate narcolepsy from other forms of hypersomnia. In addition, the authors also report that the protein peak was not correlated with excessive daytime sleepiness assessed using Epworth scale, but was correlated positively with cataplexy and negatively with sleep latency and the number of SOREM during the multiple sleep latency tests [8]. If one considers short sleep latency as an index of sleepiness, and SOREM and cataplexy as signs of REM sleep dysregulation, the significance of these correlations with narcoleptic phenotypes is of interest although it remains to be determined. Finally, detection, quantification, and other further studies of the RBM4/Lark protein in currently available narcoleptic animal models, such as those in murine, will certainly promote its characterization as marker of narcolepsy. Another major question raised from this study is the biological significance of the presence of such a Lark protein in the serum of patients with narcolepsy. Is it a consequence of the pathology in the CNS or periphery or is it a reflection of adaptive mechanisms?

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Commentary: A Quest for a Novel Peripheral Biomarker for Narcolepsy.

Young Neurons Tickle Memory during REM Sleep.

An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with narcolepsy type 1 (NT1). In quest for enlightenment, we evaluate whether an increase in HDC cell number and expression level would be detected in mouse models of the disease, in order to provide proof of concepts reveling possible mechanisms of compensation for the loss of orexin neurons, and/or of induced expression as a consequence of local neuroinflammation, a state that likely accompanies NT1. To further explore the compensatory hypothesis, we also study the noradrenergic wake-promoting system. Immunohistochemistry for HDC, orexin, and melanin-concentrating hormone (MCH) was used to count neurons. Quantitative-PCR of HDC, orexin, MCH, and tyrosine-hydroxylase was performed to evaluate levels of mRNA expression in the hypothalamus or the dorsal pons. Both quantifications were achieved in genetic and neuroinflammatory models of narcolepsy with major orexin impairment, namely the orexin-deficient (Orex-KO) and orexin-hemagglutinin (Orex-HA) mice respectively. The number of HDC neurons and mRNA expression level were unchanged in Orex-KO mice compared to controls. Similarly, we found no change in tyrosine-hydroxylase mRNA expression in the dorsal pons between groups. Further, despite the presence of protracted local neuroinflammation as witnessed by the presence of reactive microglia, we found no change in the number of neurons nor the expression of HDC in Orex-HA mice compared to controls. Importantly, no correlation was found in all conditions between HDC and orexin. Our findings indicate that, in mice, the expression of histamine and noradrenalin, two wake-promoting systems, are not modulated by orexin level whether the lack of orexin is constitutive or induced at adult age, showing thus no compensation. They also show no recruitment of histamine by local neuroinflammation. Further studies will be needed to further define the role of histamine in the pathophysiology of NT1.

Christelle Peyron

Papers

Analyses transcriptomiques à cellule unique et à noyau unique de l’hypothalamus dans un état neuro-inflammatoire induit par le LPS

Commentary: A Quest for a Novel Peripheral Biomarker for Narcolepsy.

Young Neurons Tickle Memory during REM Sleep.

Histamine in murine narcolepsy: What do genetic and immune models tell us?