Orexinergic Neurons Research Articles

The olfactory bulb: A link between environmental agents and narcolepsy

Narcolepsy with cataplexy is a lifelong sleep disorder associated with orexin/hypocretin deficiency in the central nervous system. In addition to a genetic predisposition, a variety of environmental factors, such as influenza viruses, have been implicated in the pathogenesis of the disease. In this article, a hypothesis is proposed that environmental agents access the olfactory bulb and trigger neuroinflammation, which in turn induces neurodegeneration of orexinergic neurons in the lateral hypothalamus and other neuronal subpopulations regulating the sleep-wake cycle, which triggers the development of narcolepsy.

Serotonergic neurons in the dorsal raphe nucleus mediate the arousal-promoting effect of orexin during isoflurane anesthesia in male rats

Previous studies have demonstrated that the activation of orexinergic neurons facilitates the recovery of animals from general anesthesia. Moreover, serotonergic neurons that receive projections from orexin neurons have also been shown to participate in sleep-wakefulness regulation. In the present study, we aimed to explore whether orexinergic neurons facilitate emergence from isoflurane anesthesia in rats by activating serotonergic neurons. Orexin A (30 or 100 pmol), orexin B (30 or 100 pmol), and their respective antagonists SB-334867 and TCS-OX2–29 (5 or 20 μg) were microinjected into the dorsal raphe nucleus (DRN) of rats, and their effects on induction and emergence times were analyzed. Electroencephalogram (EEG) changes were also recorded and analyzed to illuminate the effect of orexin injection into the DRN on cortical excitability under isoflurane anesthesia. Activation of serotonergic neurons was detected via immunohistochemical analysis of c-Fos expression following orexin administration. Our results indicated that injection of neither orexins nor orexin antagonists into the rat DRN exerted an impact on induction time, whereas orexin-A injection (100 pmol) enhanced arousal when compared with the saline group. In contrast, administration of orexin receptor type 1 antagonist SB-334867 (20 μg) prolonged emergence time from isoflurane anesthesia. Microinjection of orexin-A induced an arousal pattern on EEG, and decreased the burst suppression ratio under isoflurane anesthesia. Isoflurane anesthesia inhibited the activity of serotonergic neurons, as shown by decrease in the number of c-Fos-immunoreactive serotonergic neurons when compared with the sham group. This inhibitory effect was partially reversed by administration of orexin-A. Taken together, our findings suggest that orexinergic signals facilitate emergence from isoflurane anesthesia, at least partially, by reversing the effects of isoflurane on serotonergic neurons of the DRN.

On the Abilities of Unconscious Freudian Motivational Drives to Evoke Conscious Emotions.

Human beings use conscious emotions to direct their behaviors. There is some agreement in the scientific community that unconscious motivations are able to evoke conscious emotions. This manuscript focuses on Freudian motivational drives as inductors for unconscious motivation, and also on Panksepp’s framework of affective neuroscience for describing the generation of emotions. Recently, it has been suggested that imperative motor factors of Freudian drives (i.e., the hormones ghrelin, testosterone, angiotensin II and adenosine) have the ability to activate both a drive-specific brain area and brain areas of the SEEKING command system. In fact, this manuscript contends that all imperative motor factors have typical SEEKING targets (i.e., so-called receptors) in the brain areas of both nucleus accumbens and lateral hypothalamus. In addition, all imperative motor factors are able to target the central amygdala directly, a brain area classified by Panksepp as the instinctual part of the FEAR command system. Another point of interest may be the evaluation that imperative motor factors of the sexual drive, hunger and thirst can directly activate the RAGE command system by targeting the medial amygdala. Surprisingly, all imperative motor factors are able to modulate Panksepp’s granddaddy mechanism, i.e., to stimulate all seven command systems via the lateral hypothalamus. Orexinergic neurons exclusively located in the lateral hypothalamus have targets for imperative motor factors and project axons to characteristic brain areas of all seven command systems. From the fact that the imperative motor factors of the sexual drive and hunger act in an excitatory manner on orexinergic neurons whereas those of thirst and sleep inhibit such neurons, temporary termination of hunger by thirst may be understood as a very simple example of a co-regulation of Freudian drives. The author wishes to note that there are motivational drives other than the ones described by Freud. Bowlby was obviously the first in describing such drives, and Bowlbyian drive activities cannot be explained with the intermediacy of imperative motor factors. Nevertheless, the ignorance of the magnificent importance of imperative motor factors must be discarded.

Functional Organization of the Sympathetic Pathways Controlling the Pupil: Light-Inhibited and Light-Stimulated Pathways

Pupil dilation is mediated by a sympathetic output acting in opposition to parasympathetically mediated pupil constriction. While light stimulates the parasympathetic output, giving rise to the light reflex, it can both inhibit and stimulate the sympathetic output. Light-inhibited sympathetic pathways originate in retina-receptive neurones of the pretectum and the suprachiasmatic nucleus (SCN): by attenuating sympathetic activity, they allow unimpeded operation of the light reflex. Light stimulates the noradrenergic and serotonergic pathways. The hub of the noradrenergic pathway is the locus coeruleus (LC) containing both excitatory sympathetic premotor neurones (SympPN) projecting to preganglionic neurones in the spinal cord, and inhibitory parasympathetic premotor neurones (ParaPN) projecting to preganglionic neurones in the Edinger-Westphal nucleus (EWN). SympPN receive inputs from the SCN via the dorsomedial hypothalamus, orexinergic neurones of the latero-posterior hypothalamus, wake- and sleep-promoting neurones of the hypothalamus and brain stem, nociceptive collaterals of the spinothalamic tract, whereas ParaPN receive inputs from the amygdala, sleep/arousal network, nociceptive spinothalamic collaterals. The activity of LC neurones is regulated by inhibitory α2-adrenoceptors. There is a species difference in the function of the preautonomic LC. In diurnal animals, the α2-adrenoceptor agonist clonidine stimulates mainly autoreceptors on SymPN, causing miosis, whereas in nocturnal animals it stimulates postsynaptic α2-arenoceptors in the EWN, causing mydriasis. Noxious stimulation activates SympPN in diurnal animals and ParaPN in nocturnal animals, leading to pupil dilation via sympathoexcitation and parasympathetic inhibition, respectively. These differences may be attributed to increased activity of excitatory LC neurones due to stimulation by light in diurnal animals. This may also underlie the wake-promoting effect of light in diurnal animals, in contrast to its sleep-promoting effect in nocturnal species. The hub of the serotonergic pathway is the dorsal raphe nucleus that is light-sensitive, both directly and indirectly (via an orexinergic input). The light-stimulated pathways mediate a latent mydriatic effect of light on the pupil that can be unmasked by drugs that either inhibit or stimulate SympPN in these pathways. The noradrenergic pathway has widespread connections to neural networks controlling a variety of functions, such as sleep/arousal, pain, and fear/anxiety. Many physiological and psychological variables modulate pupil function via this pathway.

Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep–wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep–wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep–wake cycle.

Orexins increase the firing activity of nigral dopaminergic neurons and participate in motor control in rats.

Orexin is a member of neuropeptides which is involved in the central motor control. The substantia nigra pars compacta (SNc) is an important nucleus participating in motor control under both physiological and pathological conditions. Morphological studies reveal that orexinergic neurons located in lateral hypothalamus innervate the SNc. Both orexin-1 receptors (OX1 R) and orexin-2 receptors (OX2 R) are expressed in the SNc. To investigate the effects of orexins on SNc, single unit invivo extracellular recordings and behavioral tests were performed in this study. Micro-pressure administration of orexin A and orexin B significantly increased the spontaneous firing rate of nigral DAergic neurons by 65.87±7.73% and 90.49±17.83%, respectively. The excitatory effects of orexin A on nigral DAergic neurons were mainly mediated by OX1 R, while OX2 R were involved in the increase in firing rate induced by orexin B. Selectively blocking OX1 R and OX2 R significantly decreased the firing rate of nigral DAergic neurons by 36.77±6.26% and 32.04±6.12%, respectively, which suggested that endogenous orexins modulated the spontaneous firing activity of nigral DAergic neurons. Finally, both elevated body swing test and haloperidol-induced postural behavioral test showed that unilateral microinjection of orexin A and orexin B induced significantly contralateral-biased swing and deflection behavior. Meanwhile, the specific OX1 R and OX2 R antagonists produced opposite effects. The present electrophysiological and behavioral studies suggested that orexins increased the firing activity of nigral DAergic neurons and participated in central motor control. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson's disease model

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra compacta (SNpc) and the only risk factor is aging. We showed that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the neuronal profile within the brainstem ventral respiratory column with a decrease in the hypercapnic ventilatory response. Here we tested the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing in a 6-OHDA PD model. In this model of PD, there is a reduction in the total number of orexinergic neurons and in the number of orexinergic neurons that project to the RTN, without changing the number of CO2-activated orexinergic neurons during the dark phase. The ventilation at rest and in response to hypercapnia (7% CO2) was assessed in animals that received 6-OHDA or vehicle injections into the striatum and saporin anti-Orexin-B or IgG saporin into the LH/PeF during the sleep and awake states. The experiments showed a reduction of respiratory frequency (fR) at rest during the light phase in PD animals only during sleep. During the dark phase, there was an impaired fR response to hypercapnia in PD animals with depletion of orexinergic neurons in awake and sleeping rats. In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

Ablation of Central Serotonergic Neurons Decreased REM Sleep and Attenuated Arousal Response.

Sleep/wake behavior is regulated by distinct groups of neurons, such as dopaminergic, noradrenergic, and orexinergic neurons. Although monoaminergic neurons are usually considered to be wake-promoting, the role of serotonergic neurons in sleep/wake behavior remains inconclusive because of the effect of serotonin (5-HT)-deficiency on brain development and the compensation for inborn 5-HT deficiency by other sleep/wake-regulating neurons. Here, we performed selective ablation of central 5-HT neurons in the newly developed Rosa-diphtheria toxin receptor (DTR)-tdTomato mouse line that was crossed with Pet1Cre/+ mice to examine the role of 5-HT neurons in the sleep/wake behavior of adult mice. Intracerebroventricular administration of diphtheria toxin completely ablated tdTomato-positive cells in Pet1Cre/+; Rosa-DTR-tdTomato mice. Electroencephalogram/electromyogram-based sleep/wake analysis demonstrated that central 5-HT neuron ablation in adult mice decreased the time spent in rapid eye movement (REM) sleep, which was associated with fewer transitions from non-REM (NREM) sleep to REM sleep than in control mice. Central 5-HT neuron-ablated mice showed attenuated wake response to a novel environment and increased theta power during wakefulness compared to control mice. The current findings indicated that adult 5-HT neurons work to support wakefulness and regulate REM sleep time through a biased transition from NREM sleep to REM sleep.

Orexin prevents depressive-like behavior by promoting stress resilience

Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatric disorders and accumulating clinical evidence indicates a potential link between orexin and depression. However, the exact role of orexin in depression, particularly the underlying neural substrates and mechanisms, remains unknown. In this study, we reveal a direct projection from the hypothalamic orexinergic neurons to the ventral pallidum (VP), a structure that receives an increasing attention for its critical position in rewarding processing, stress responses, and depression. We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors, OX1R and OX2R, and their downstream Na+–Ca2+ exchanger and L-type Ca2+ channel co-mediate the effect of orexin. Furthermore, pharmacological blockade or genetic knockdown of orexin receptors in VP increases depressive-like behaviors in forced swim test and sucrose preference test. Intriguingly, blockage of orexinergic inputs in VP has no impact on social proximity in social interaction test between novel partners, but remarkably strengthens social avoidance under an acute psychosocial stress triggered by social rank. Notably, a significantly increased orexin level in VP is accompanied by an increase in serum corticosterone in animals exposed to acute stresses, including forced swimming, food/water deprivation and social rank stress, rather than non-stress situations. These results suggest that endogenous orexinergic modulation on VP is especially critical for protecting against depressive reactions to stressful events. The findings define an indispensable role for the central orexinergic system in preventing depression by promoting stress resilience.

Orexin neurons couple neural systems mediating fluid balance with motivation-related circuits.

During extracellular dehydration, neural systems that sense deficits in body fluid homeostasis operate in tandem with those that mediate motivation and reward in order to promote ingestive behaviors that restore fluid balance. We hypothesized that hypothalamic orexin (Ox) neurons act as an interface to couple brain regions sensing and processing information about body fluid status with central nervous system motivation and reward systems. An initial set of anterograde and retrograde tracing experiments suggested that structures along the lamina terminalis (LT), a region of the forebrain that serves to monitor and integrate information reflecting body fluid balance, project to hypothalamic Ox neurons that, in turn, project to dopamine neurons in the ventral tegmental area (VTA). A second set of experiments determined whether Ox neuron activation is associated with extracellular dehydration and the seeking out and consumption of water and saline. An elevation of Fos-like immunoreactivity in Ox neurons was observed in fluid-depleted rats that were allowed to ingest water and sodium. A final experiment was conducted to determine whether Ox release in the VTA promotes thirst and salt appetite. Bilateral microinjection of the Ox Type I receptor antagonist SB-408124 into the VTA prior to acute extracellular dehydration attenuated fluid intake. Together, these studies support the hypothesis that structures along the LT modulate activity in the VTA through actions of orexinergic neurons that have cell bodies in the hypothalamus. This pathway may function to facilitate sustained consumption of fluids necessary for restoration of fluid balance. (PsycINFO Database Record

Orexin-1 receptor is involved in ageing-related delayed emergence from general anaesthesia in rats

BackgroundPrevious clinical studies have shown that emergence from isoflurane anaesthesia takes longer in elderly patients compared with middle-aged patients. The current study investigated whether delayed emergence from anaesthesia in older age is associated with the age-related decrease in orexin receptors by using a rat model. MethodsAdult and aged Sprague–Dawley rats were used to assess the time to emergence after 30 min isoflurane anaesthesia (1.4 vol%), and differences in the orexinergic systems, including the number of orexinergic neurones, plasma orexin concentrations, and expression of orexin-1 (OX1R) and orexin-2 receptors, compared using immunofluorescence, radioimmunoassay, western blot, and real-time polymerase chain reaction. The effects of OX1R expression on emergence time were determined by virus-mediated overexpression of OX1R using intra-cerebroventricular injection. ResultsThe median (range) emergence time of aged rats was longer than that in adult rats [1082 (1010–1130) compared with 848 (829–938) s; P=0.0009]. Plasma orexin concentrations were higher in the aged group than the adult group [34 (33–37) and 25 (22–31) pg ml−1, respectively; P=0.04], but the number of orexinergic neurones was similar in both groups. Protein expression of OX1R was lower in the aged group compared with the adult group [0.47 (0.35–0.58) compared with 0.97 (0.86–1.32), respectively; P=0.002]. Overexpression of OX1R significantly shortened the emergence time in aged rats from [1120 (1040–1190) s] to [769 (576–928) s; P=0.03]. ConclusionsAge-related decrease in OX1R expression is associated with delayed emergence from isoflurane anaesthesia in aged rats.

Monoamines Inhibit GABAergic Neurons in Ventrolateral Preoptic Area That Make Direct Synaptic Connections to Hypothalamic Arousal Neurons.

The hypothalamus plays an important role in the regulation of sleep/wakefulness states. While the ventrolateral preoptic nucleus (VLPO) plays a critical role in the initiation and maintenance of sleep, the lateral posterior part of the hypothalamus contains neuronal populations implicated in maintenance of arousal, including orexin-producing neurons (orexin neurons) in the lateral hypothalamic area (LHA) and histaminergic neurons in the tuberomammillary nucleus (TMN). During a search for neurons that make direct synaptic contact with histidine decarboxylase-positive (HDC+), histaminergic neurons (HDC neurons) in the TMN and orexin neurons in the LHA of male mice, we found that these arousal-related neurons are heavily innervated by GABAergic neurons in the preoptic area including the VLPO. We further characterized GABAergic neurons electrophysiologically in the VLPO (GABAVLPO neurons) that make direct synaptic contact with these hypothalamic arousal-related neurons. These neurons (GABAVLPO→HDC or GABAVLPO→orexin neurons) were both potently inhibited by noradrenaline and serotonin, showing typical electrophysiological characteristics of sleep-promoting neurons in the VLPO. This work provides direct evidence of monosynaptic connectivity between GABAVLPO neurons and hypothalamic arousal neurons and identifies the effects of monoamines on these neuronal pathways.SIGNIFICANCE STATEMENT Rabies-virus-mediated tracing of input neurons of two hypothalamic arousal-related neuron populations, histaminergic and orexinergic neurons, showed that they receive similar distributions of input neurons in a variety of brain areas, with rich innervation by GABAergic neurons in the preoptic area, including the ventrolateral preoptic area (VLPO), a region known to play an important role in the initiation and maintenance of sleep. Electrophysiological experiments found that GABAergic neurons in the VLPO (GABAVLPO neurons) that make direct input to orexin or histaminergic neurons are potently inhibited by noradrenaline and serotonin, suggesting that these monoamines disinhibit histamine and orexin neurons. This work demonstrated functional and structural interactions between GABAVLPO neurons and hypothalamic arousal-related neurons.

Drugs affecting sleep and wakefulness: a review

It was in the second half of the twentieth century that Sleep Medicine was recognized as an immensely respected field of clinical research. As a result, past few decades have seen this field making some giant strides towards a better understanding of the neurochemical mechanisms that regulate the state of sleep and wakefulness. This involves a complex interplay of neuronal systems, neurotransmitters and some special nuclei located in the brain. Major wakefulness promoting nuclei being the orexinergic neurons in the lateral hypothalamic region and the tuberomammillary nucleus (TMN) while the sleep-promoting nucleus being ventrolateral preoptic nucleus (VLPO). Sleep-related complaints are one of the common complaints encountered by the physicians and the psychiatrists. As, long-standing sleep disturbances can have far-reaching implications on an individual’s physical, mental and social wellbeing, the importance of drugs affecting sleep and wakefulness could not be stressed upon anymore. Broadly, the sleep disorders are classified as insomnia, hypersomnia, and parasomnia and the presently available drugs work either by acting on the sleep-promoting GABAergic system like benzodiazepines, barbiturates etc. or by interacting with wakefulness promoting system like histaminergic system, 5- hydroxtryptaminergic system, orexinergic system etc. There are drugs which interact with other mechanisms which modulate arousal, like melatonin receptor agonists which promote sleep and adenosine receptor antagonists which promote wakefulness. This review article tries to have an overview of the available drugs for use in pathological states of sleep and wakefulness with a special emphasis on the commonly prescribed drugs and the recently approved one’s.

Central and peripheral chemoreceptors in sudden infant death syndrome.

The pathogenesis of sudden infant death syndrome (SIDS) has been ascribed to an underlying biological vulnerability to stressors during a critical period of development. This paper reviews the main data in the literature supporting the role of central (e.g. retrotrapezoid nucleus, serotoninergic raphe nuclei, locus coeruleus, orexinergic neurons, ventral medullary surface, solitary tract nucleus) and peripheral (e.g. carotid body) chemoreceptors in the pathogenesis of SIDS. Clinical and experimental studies indicate that central and peripheral chemoreceptors undergo critical development during the initial postnatal period, consistent with the age range of SIDS (<1year). Most of the risk factors for SIDS (gender, genetic factors, prematurity, hypoxic/hyperoxic stimuli, inflammation, perinatal exposure to cigarette smoke and/or substance abuse) may structurally and functionally affect the developmental plasticity of central and peripheral chemoreceptors, strongly suggesting the involvement of these structures in the pathogenesis of SIDS. Morphometric and neurochemical changes have been found in the carotid body and brainstem respiratory chemoreceptors of SIDS victims, together with functional signs of chemoreception impairment in some clinical studies. However, the methodological problems of SIDS research will have to be addressed in the future, requiring large and highly standardized case series. Up-to-date autopsy protocols should be produced, involving substantial, and exhaustive sampling of all potentially involved structures (including peripheral arterial chemoreceptors). Morphometric approaches should include unbiased stereological methods with three-dimensional probes. Prospective clinical studies addressing functional tests and risk factors (including genetic traits) would probably be the gold standard, allowing markers of intrinsic or acquired vulnerability to be properly identified.

Functional brown adipose tissue and sympathetic activity after cold exposure in humans with type 1 narcolepsy.

To investigate the activity of brown adipose tissue (BAT) in patients with type 1 narcolepsy during cold exposure using two separate scans of sympathetic and metabolic activity of BAT to evaluate whether orexin deficiency leads to altered nonshivering thermoregulation in narcolepsy. Seven patients with type 1 narcolepsy and seven healthy controls underwent two consecutive scans after 2 hr cold exposure: 123I-meta-iodo-benzyl-guanidine (123I-MIBG) single photon emission computed tomography and18F-2-deoxy-glucose (18F-FDG) positron emission tomography and computed tomography to visualize sympathetic innervation and metabolic activity of BAT, respectively. Plasma levels of eight hormones regulating BAT activity were measured before and after 2 hr in the cold. 18F-FDG-uptake and uptake of 123I-MIBG in BAT after 2 hr cold exposure were observed in all individuals, but the activity of BAT was not significantly different between patients with type 1 narcolepsy and healthy controls (p > 0.05). Plasma levels of GLP-1 were higher in patients with type 1 narcolepsy compared with controls (p < 0.05), but not altered by cold adaptation in patients and controls (p > 0.05). FGF21 concentrations decreased after 2 hr cold exposure in both patients with type 1 narcolepsy and healthy participants (p < 0.05). Sympathetic and metabolic activity of BAT was observed after cold exposure in patients with type 1 narcolepsy. Increased GLP-1 in narcolepsy may suggest autonomic dysfunction with metabolic changes. We conclude that BAT is functional after cold exposure in spite of the loss of orexinergic neurons in narcolepsy.

Orexin A in the ventral tegmental area enhances saccharin-induced conditioned flavor preference: The role of D1 receptors in central nucleus of amygdala

In industrialized societies, food intake is largely determined by its hedonic characteristics, which can be modified by our experience via taste learning. In this learning, the hedonic value of a neutral flavor changes after its association with a motivationally significant stimulus. Experiment 1 analyzes the effect of orexin administration (53 and 107 ng) in the ventral tegmental area (VTA) on hedonic intake through acquisition of a flavor-taste preference and a flavor-taste aversion. Accordingly, animals underwent four one-bottle acquisition sessions with unilateral application of orexin-A or saline in the VTA at 10 min before a 15-min flavor intake period. Preference and aversion were tested by a two-bottle test containing the flavors used for CS+ and CS−. Results indicate that intra-VTA orexin strengthens flavor-taste conditioned flavor preference (CFP) by saccharin but does not facilitate flavor-taste aversion induced by association of a neutral flavor with the unpalatable taste of quinine. Experiment 2 examines the acquisition of a flavor-taste preference after co-administration of an effective dose of orexin-A in the VTA and of D1-like dopamine receptor antagonist SCH23390 (6 and 12 nmol) in the central nucleus of the amygdala (CeA). SCH23390 impedes the CFP strengthening observed after intra-VTA orexin administration, indicating that this effect may be mediated by dopaminergic receptors in the CeA. These data suggest that the simultaneous presentation of a flavor and a hedonically positive taste may be detected by orexinergic neurons that activate dopamine-releasing neurons of the VTA, thereby reinforcing the positive signals required to develop a taste preference.

Non-Rapid Eye Movement Sleep Parasomnias and Migraine: A Role of Orexinergic Projections.

Sleep and migraine share a common pathophysiological substrate, although the underlying mechanisms are unknown. The serotonergic and orexinergic systems are both involved in the regulation of sleep/wake cycle, and numerous studies show that both are involved in the migraine etiopathogenesis. These two systems are anatomically and functionally interconnected. Our hypothesis is that in migraine a dysfunction of orexinergic projections on the median raphe (MR) nuclei, interfering with serotonergic regulation, may cause Non-Rapid Eye Movement parasomnias, such as somnambulism. Acting on the serotonergic neurons of the raphe nuclei, the dysfunction of orexinergic neurons would lead to a higher release of serotonin. The activation of serotonergic receptors located on the walls of large cerebral vessels would lead to abnormal vasodilatation and consequently increase transmural pressure. This process could activate the trigeminal nerve terminals that innervate vascular walls. As a consequence, there is activation of sensory nerve endings at the level of hard vessels in the meninges, with release of pro-inflammatory peptides (e.g., substance P and CGRP). Within this hypothetical frame, the released serotonin could also interact with trigeminovascular afferents to activate and/or facilitate the release of the neuropeptide at the level of the trigeminal ganglion. The dysregulation of the physiological negative feedback of serotonin on the orexinergic neurons, in turn, would contribute to an alteration of the whole system, altering the sleep-wake cycle. Serotonergic neurons of the MR nuclei receive an excitatory input from hypothalamic orexin/hypocretin neurons and reciprocally inhibit orexin/hypocretin neurons through the serotonin 1A receptor (or 5-HT1A receptor). Considering this complex system, if there is an alteration it may facilitate the pathophysiological mechanisms involved in the migraine, while it may produce at the same time an alteration of the sleep-wake rhythm, causing sleep disorders such as sleepwalking. Understanding the complex mechanisms underlying migraine and sleep disorders and how these mechanisms can interact with each other, it would be crucial to pave the way for new therapeutic strategies.

ИММУНОГИСТОХИМИЧЕСКОЕ ИССЛЕДОВАНИЕ ПУТЕЙ ВЛИЯНИЯ ДОФАМИНА НА ОРЕКСИНЕРГИЧЕСКИЕ НЕЙРОНЫ ПЕРИФОРНИКАЛЬНОЙ ОБЛАСТИ ГИПОТАЛАМУСА КРЫСЫ, "Российский физиологический журнал им. И.М. Сеченова"

Analysis of double immunostaining using confocal microscopy indicates the localization of a large number of tyrosine hydroxylase-immunopositive processes around the bodies of orexinergic neurons in the perifornical area of the hypothalamus in rats. In the bodies of orexynergic neurons the dopamine D1-receptors have been identified. A high degree of colocalization of D1- and D2-dopamine receptors was detected in the perifornical area, which indicates the formation of heterodimeric D1/ D2-complexes. After intraperitoneal administration of a selective D1-receptor antagonist (SCH 39166) the optical density of the cFos-protein was increased in orexinergic neurons and in adjacent GABA-neurons in perifornical area. The obtained data indicate the possibility of dopamine influence on orexinergic neurons as directly through the D1- and D2-dependent signaling pathways, and through the effect on GABA-neurons

Orexinergic neurons hyperfunction causes sleep disorders and hypertension in SHR

Orexinergic neurons hyperfunction causes sleep disorders and hypertension in SHR

A Neurochemical Approach to the Search for Drugs for the Treatment of Symptoms of Alzheimer’s Disease

We performed an analysis of the reciprocal influences of neurons involved in the rapid-eye-movement phase of sleep (REM sleep) under the conditions of changes in the concentrations of various neuromodulators that are characteristic of Alzheimer’s disease. Several approaches to the search for drugs for the weakening of disease symptoms have been proposed taking the results of this analysis into account. The antagonists of orexin receptors were recently suggested for the treatment of Alzheimer’s disease because the anomalously high concentration of orexin, which is specific for this pathology, results in impairment of REM sleep. However, our analysis shows that the treatment with the antagonists of orexin receptors is not appropriate because it may lead to depression of the excitation of cholinergic cells, an additional decrease in the cholinergic deficit, and aggravation of symptoms of the disease. For the same reason it is unlikely that one should apply the antagonists of histamine H1 receptors and the agonists of adenosine A1 receptors. Substances that can lead to reduced activity of orexinergic neurons may be helpful instead. These substances include melatonin and the agonists of melatonin M1 receptors. Administration of these substances should improve REM sleep because it decreases the efficacy of excitation of orexinergic and histaminergic cells. Melanin-concentrating hormone also should decrease the efficacy of excitation of orexinergic cells. Additionally, the antagonists of histamine H3 receptors may be used because they promote the increased efficacy of excitation of neurons that secrete the melanin-concentrating hormone. Experimental evidence exists that indicates the benefits of these substances for improvement of REM sleep and attenuation of cognitive impairments in Alzheimer’s disease. These drugs must be applied before nightfall and their action should not be prolonged because orexinergic cells must be active in the daytime.