Orexin Neurons Research Articles

Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons.

Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons.

Short-term Fasting Induces Alternate Activation of Orexin and Melanin-concentrating Hormone Neurons in Rats

Orexin and melanin-concentrating hormone (MCH) neurons constitute the energy balance circuitry that coordinates the fasting response. Orexin neurons mediate food foraging at the expense of energy storage, while MCH neurons promote energy storage by reducing energy expenditure and increasing food intake. It is unknown if these cell groups undergo plastic changes as hunger and metabolic changes escalate over time during fasting. To address this, we performed in vitro electrophysiological recording on orexin and MCH neurons in the lateral hypothalamus and perifornical area from rats fasted for 12 or 24 h or fed ad-libitum. Orexin neurons showed a transient decrease in presynaptic glutamate release at 12 h. This turned to an increase at 24 h of fasting, while membrane potential depolarized and AMPA receptor conductance increased. In contrast, MCH neurons were transiently depolarized at 12 h fasting along with increased presynaptic glutamate release. These changes reversed at 24 h, while the number of AMPA receptors decreased. Our results indicate that MCH neurons are preferentially activated during the early phase of fasting (12 h), which would protect against weight loss. With a longer fast, orexin neurons become activated, which would promote arousal and exploratory activity required for foraging behaviors. This alternating activation of these cell groups may reflect a dynamic balance of energy conservation and foraging behaviors to optimize energy balance during ongoing fasting.

Orexin facilitates the ventilatory and behavioral responses of rats to hypoxia.

Orexin neurons are sensitive to CO2 and contribute to cardiorespiratory homeostasis as well as sensorimotor control. Whether orexin facilitates respiratory and behavioral responses to acute hypoxia is unclear. We hypothesized that orexin neurons are activated by acute hypoxia and that orexin facilitates the hypoxic ventilatory response (HVR), as well as the arterial blood pressure (ABP) and behavioral (movement) responses to acute hypoxia. We further hypothesized that orexin has greater effects in the active phase of the rat circadian cycle, when orexin neurons have high activity. Using whole body plethysmography with EEG, EMG, and the dual-orexin receptor (OxR) antagonist suvorexant (20 mg/kg ip), we determined the effect of OxR blockade on the respiratory, ABP, and behavioral responses of adult rats to acute, graded hypoxia ([Formula: see text]= 0.15, 0.13, 0.11, and 0.09) and hyperoxic hypercapnia ([Formula: see text]= 0.05; [Formula: see text]= 0.95). OxR blockade had no effect on eupnea. OxR blockade significantly reduced the HVR in both inactive and active phases, with a stronger effect in the active phase. OxR blockade reduced the behavioral response to acute hypoxia in the active phase. The central component of the ventilatory and the ABP responses to hypercapnia were reduced by OxR blockade solely in the inactive phase. In the inactive phase, hypoxia activated ∼10% of orexin neurons in the perifornical hypothalamus. These data suggest that orexin neurons participate in the peripheral chemoreflex to facilitate the ventilatory and behavioral responses to acute hypoxia in rats, particularly in the active phase. Orexin also facilitates central chemoreflex responses to CO2 in the inactive phase.

Association of fasting Orexin-A levels with energy intake at breakfast and subsequent snack in Chilean adolescents

Orexin-A, a hormone secreted by orexin neurons, is involved in caloric-intake regulation. Current understanding is based primarily on animal studies. Studies of orexin in humans are scarce, and to our knowledge there are no prior studies in adolescents. We studied fasting Orexin-A levels related to energy intake at breakfast and a subsequent snack in adolescents (n = 668) from a longitudinal study in Chile. Body-Mass Index (BMI), components of the metabolic syndrome and fasting blood levels of leptin, insulin, ghrelin, and orexin-A were measured. Energy intake was calculated based on food weights before and after the standardized breakfast and subsequent snack. High energy intake was defined as ≥ 75th percentile. We assessed the relationship between orexin-A and high energy intake, adjusting for confounders. Higher orexin levels were associated with high breakfast energy intake (OR: 1.21; 95%CI: 0.98–1.49). Conversely, those with higher orexin levels showed a non-significant trend for lower odds of high energy intake for the snack (OR: 0.87; 95%CI: 0.70–1.07). There was a significant interaction between high breakfast energy intake and orexin levels. Those who ate more calories at breakfast displayed a lower inhibitory effect of orexin on eating at the snack (p < 0.05). There was no significant interaction between weight status and orexin. In conclusion, orexin-A levels were associated with breakfast energy intake and inversely related with subsequent snack energy intake in participants whose caloric intake at breakfast was within the normal range. Based on these findings, it appears that the association of orexin-A with energy intake depends on eating behavior.

Activity of putative orexin neurons during cataplexy

It is unclear why orexin-deficient animals, but not wild-type mice, show cataplexy. The current hypothesis predicts simultaneous excitation of cataplexy-inhibiting orexin neurons and cataplexy-inducing amygdala neurons. To test this hypothesis, we measured the activity of putative orexin neurons in orexin-knockout mice during cataplexy episodes using fiber photometry. We created two animal models of orexin-knockout mice with a GCaMP6 fluorescent indicator expressed in putative orexin neurons. We first prepared orexin-knockout mice crossed with transgenic mice carrying a tetracycline-controlled transactivator transgene under the control of the orexin promoter. TetO-GCaMP6 was then introduced into mice via an adeno-associated virus injection or natural crossing. The resulting two models showed restricted expression of GCaMP6 in the hypothalamus, where orexin neurons should be located, and showed excitation to an intruder stress that was similar to that observed in orexin-intact mice in our previous study. The activity of these putative orexin neurons increased immediately before the onset of cataplexy-like behavior but decreased (approximately − 20% of the baseline) during the cataplexy-like episode. We propose that the activity of orexin neurons during cataplexy is moderately inhibited by an unknown mechanism. The absence of cataplexy in wild-type mice may be explained by basal or residual activity-induced orexin release, and emotional stimulus-induced counter activation of orexin neurons may not be necessary. This study will serve as a basis for better treatment of cataplexy in narcolepsy patients.

Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats.

PurposeIntraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures.MethodsSprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI).ResultsAdministration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8–40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4–16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015).ConclusionsDORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.

Lateral Hypothalamic Orexin Neurons Mediate the Reward Effects of Pain Relief Induced by Electroacupuncture.

The reward of pain relief caused by acupuncture has been found to be clinically significant. However, the molecular mechanisms underlying acupuncture-induced reward of pain relief in chronic pain remain unclear and have not been analyzed in suitable preclinical models. Here, we investigated whether acupuncture could potentially induce the reward of pain relief and orexin neuronal signaling in the lateral hypothalamus (LH) and exhibit a possible role in electroacupuncture (EA)-induced reward in spared nerve injury (SNI) rats. Therefore, by using conditioned place preference (CPP) paradigm, we noticed that EA induced the preference for cues associated with EA-induced pain relief in the early, but not late, phase of chronic pain. These observations were different from the immediate antihyperalgesic effects of EA. c-Fos/orexin double labeling revealed that EA stimulation on 14 days but not on 28 days after SNI modeling activated greater numbers of c-Fos positive orexin neurons in the LH after the CPP test. Moreover, the administration of an orexin-A antagonist in the LH significantly blocked the reward effects of pain relief induced by EA. Furthermore, by using cholera toxin b subunit combined with c-Fos detection, we found that the orexin circuit from the LH to the nucleus accumbens (NAc) shell was significantly activated after EA induced CPP. Microinjection of the orexin antagonist into the NAc shell substantially attenuated the CPP induced by EA. Intravenous injection of low-dose orexin-A together with EA resulted in significantly greater antihyperalgesia effects and CPP scores. Together, these findings clearly demonstrated that LH orexin signaling could potentially play a critical role in the reward effects of pain relief induced by acupuncture. The observations of the present study extended our understanding of orexin signaling in the LH and its role in EA-induced reward, providing new insights into the mechanisms of acupuncture analgesia.

Early-life Stress Modifies the Reactivity of Neurons in the Ventral Tegmental Area and Lateral Hypothalamus to Acute Stress in Female Rats

Early-life stress (ELS) has long-term consequences, including an increased risk for drug abuse and psychiatric disorders later in life, which is higher in women than in men. The consequences of ELS include heightened sensitivity to stressful events. Here, we hypothesized that ELS changes the stress sensitivity of dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) and orexin (OXA) neurons in the lateral hypothalamus (LH), that are crucial for the control of motivated behaviors. We combined morphological and immunohistochemical approaches to investigate the effect of maternal separation (MS), a rodent model of the ELS, on the expression of c-Fos protein in putative DAergic and non-DAergic VTA and LH OXA neurons, as well as on dendritic spine density and morphology in the VTA of adult female rats. We showed that MS increased basal and acute restraint stress-induced c-Fos expression in putative DAergic neurons, specifically in the dorsomedial VTA, an area implicated in responsiveness to aversive stimuli. Conversely, restraint-induced increase in c-Fos expression in non-DAergic dorsolateral VTA neurons was dampened by MS. Furthermore, an increase in spine head diameter of VTA neurons and a concurrent decrease in dendritic spine density in dorsal VTA were observed. We also showed that MS changed the stress sensitivity of OXA neurons selectively in the dorsomedial hypothalamus (DMH), which is implicated in arousal and the stress response. These findings show the long-lasting consequences of ELS and indicate the selective, regional sensitivity of structures involved in the control of arousal, motivational behaviors and the stress response to ELS.

Neural control of pancreatic peptide hormone secretion

Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.

Conditional Knockout of Bmal1 in Corticotropin-Releasing Factor Neurons Does Not Alter Sleep-Wake Rhythm in Mice.

Sleep and wakefulness are regulated by both the homeostatic mechanism and circadian clock. In mammals, the central circadian clock, the suprachiasmatic nucleus, in the hypothalamus plays a crucial role in the timing of physiology and behavior. Recently, we found that the circadian regulation of wakefulness was transmitted via corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus to orexin neurons in the lateral hypothalamus. However, it is still unclear how the molecular clock in the CRF neurons contributes to the regulation of sleep and wakefulness. In the present study, we established CRF neuron-specific Bmal1-deficient mice and measured locomotor activity or electroencephalography and electromyography. We found that these mice showed normal circadian locomotor activity rhythms in both light–dark cycle and constant darkness. Furthermore, they showed normal daily patterns of sleep and wakefulness. These results suggest that Bmal1 in CRF neurons has no effect on either circadian locomotor activity or sleep and wakefulness.

Association of fasting orexin-A levels with energy intake at breakfast and subsequent snack in Chilean adolescents

Orexin-A, a hormone secreted by orexin neurons, is involved in caloric-intake regulation. Current understanding is based primarily on animal studies. Studies of orexin in humans are scarce, and to our knowledge there are no prior studies in adolescents. We studied fasting Orexin-A levels related to energy intake at breakfast and a subsequent snack in adolescents (n = 668) from a longitudinal study in Chile. Body-Mass Index (BMI), components of the metabolic syndrome and fasting blood levels of leptin, insulin, ghrelin, and orexin-A were measured. Energy intake was calculated based on food weights before and after the standardized breakfast and subsequent snack. High energy intake was defined as ≥ 75th percentile. We assessed the relationship between orexin-A and high energy intake, adjusting for confounders. Higher orexin levels were associated with high breakfast energy intake (OR: 1.21; 95%CI: 0.98–1.49). Conversely, those with higher orexin levels showed a non-significant trend for lower odds of high energy intake for the snack (OR: 0.87; 95%CI: 0.70–1.07). There was a significant interaction between high breakfast energy intake and orexin levels. Those who ate more calories at breakfast displayed a lower inhibitory effect of orexin on eating at the snack (p < 0.05). There was no significant interaction between weight status and orexin. In conclusion, orexin-A levels were associated with breakfast energy intake and inversely related with subsequent snack energy intake in participants whose caloric intake at breakfast was within the normal range. Based on these findings, it appears that the association of orexin-A with energy intake depends on eating behavior.

Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons

Maladaptive coping behaviors are probably involved in post-traumatic stress disorders (PTSD), but underlying mechanisms are incompletely understood. We now report that mice lacking functional insulin-like growth factor I (IGF-I) receptors in orexin neurons of the lateral hypothalamus (Firoc mice) are unresponsive to the anxiolytic actions of IGF-I and develop PTSD-like behavior that is ameliorated by inhibition of orexin neurons. Conversely, systemic IGF-I treatment ameliorated PTSD-like behavior in a wild-type mouse model of PTSD (PTSD mice). Further, systemic IGF-I modified the GABA/Glutamate synaptic structure in orexin neurons of naïve wild-type mice by increasing the dephosphorylation of GABA(B) receptor subunit through inhibition of AMP-kinase (AMPK). Significantly, pharmacological inhibition of AMPK mimicked IGF-I, normalizing fear behavior in PTSD mice. Thus, we suggest that IGF-I enables coping behaviors by balancing E/I input onto orexin neurons in a context-dependent manner. These observations provide a novel therapeutic approach to PTSD through modulation of AMPK.

Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone.

Orexin peptides comprise two neuropeptides, orexin A and orexin B, that bind two G-protein coupled receptors (GPCRs), orexin receptor 1 (OXR1) and orexin receptor 2 (OXR2). Although cell bodies that produce orexin peptides are localized in a small area comprising the lateral hypothalamus and adjacent regions, orexin-containing fibres project throughout the neuraxis. Although orexins were initially described as peptides that regulate feeding behaviour, research has shown that orexins are involved in diverse functions that range from the modulation of autonomic functions to higher cognitive functions, including reward-seeking, behaviour, attention, cognition, and mood. Furthermore, disruption in orexin signalling has been shown in mood disorders that are associated with low hedonic tone or anhedonia, including depression, anxiety, attention deficit hyperactivity disorder, and addiction. Notably, projections of orexin neurons overlap circuits involved in the modulation of hedonic tone. Evidence shows that orexins may potentiate hedonic behaviours by increasing the feeling of pleasure or reward to various signalling, whereas dysregulation of orexin signalling may underlie low hedonic tone or anhedonia. Further, orexin appears to play a key role in regulating behaviours in motivationally charged situations, such as food-seeking during hunger, or drug-seeking during withdrawal. Therefore, it would be expected that dysregulation of orexin expression or signalling is associated with changes in hedonic tone. Further studies investigating this association are warranted.

Plasma orexin A does not reflect severity of illness in the intensive care units patients with systemic inflammation

BackgroundSystemic inflammatory response occurs by sepsis and invasive surgery. Recent articles suggest that not only CRP but also procalcitonin, presepsin, and neutrophil gelatinase-associated lipocalin may reflect the severity of systemic inflammation. In addition, as systemic inflammation could degenerate orexin neurons, plasma orexin A might also be a good biomarker to predict the severity. Thus, we have determined relation between plasma biomarker and severity of illness score in patients with systemic inflammation.MethodsPrevious database (UMIN000018427) was used to secondly determine which plasma biomarkers may predict the severity of illness in the ICU patients with systemic inflammation (n = 57, 31 non-sepsis surgical patients and 26 sepsis patients). We measured plasma levels of orexin A, CRP, procalcitonin, presepsin, and neutrophil gelatinase-associated lipocalin were measured, and APACHE II score was assessed in these patients at their admission to the ICU. Data are shown as mean ± SD. Statistical analyses were done with unpaired t test. The correlation between APACHE II score and plasma biomarkers were examined using Pearson’s correlation coefficient and a least squares linear regression line.ResultsDemographic data did not differ between sepsis and non-sepsis groups. However, APACHE-II score was significantly higher in sepsis group than those in non-sepsis group (20.9 ± 6.6 vs 15.8 ± 3.2, p < 0.01). There were significant correlations between APACHE II score and plasma CRP (r = 0.532, p < 0.01), procalcitonin (r = 0.551, p < 0.01), presepsin (r = 0.510, p < 0.01), and neutrophil gelatinase-associated lipocalin (r = 0.466, P < 0.01) except orexin A.ConclusionAll plasma biomarkers tested except orexin A may reflect the severity of illness in patients with systemic inflammation.

Multifaceted roles of orexin neurons in mediating methamphetamine-induced changes in body temperature and heart rate.

Methamphetamine (METH), which is used to improve the alertness of narcoleptic patients, elicits autonomic physiological responses such as increases in body temperature, blood pressure and heart rate. We have shown that orexin synthesizing neurons, which have an important role in maintaining wakefulness, greatly contribute to the regulation of cardiovascular and thermoregulatory function. This regulation is partly mediated by glutamatergic as well as orexinergic signalling from the orexin neurons. These signals may also be involved in the autonomic response elicited by METH. This study aimed to determine if loss of either orexin or glutamate in orexin neurons would affect METH-induced changes in heart rate and body temperature. We used transgenic mice in which the vesicular glutamate transporter 2 gene was disrupted selectively in orexin-producing neurons (ORX;vGT2-KO), prepro-orexin knockout mice (ORX-KO), and control wild type mice (WT). We measured body temperature, heart rate and locomotor activity with a pre-implanted telemetry probe and compared the effect of METH (0.5, 2 and 5 mg/kg i.p.) on these parameters between these three groups. A low dose of METH induced hyperthermia and tachycardia responses in ORX;vGT2-KO mice, which were significant compared to ORX-KO and WT mice. The highest dose of METH induced hypothermia and bradycardia in ORX-KO mice, however, it induced hyperthermia in both WT and ORX;vGT2-KO mice. These results suggest that glutamate and orexin from orexin neurons have differential roles in mediating METH-induced changes in body temperature and heart rate.

Characterization of orexin input to dopamine neurons of the ventral tegmental area projecting to the medial prefrontal cortex and shell of nucleus accumbens

Orexin neurons are involved in homeostatic regulatory processes, including arousal and feeding, and provide a major input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. VTA neurons are a central hub processing reward and motivation and target the medial prefrontal cortex (mPFC) and the shell part of nucleus accumbens (NAcs). We investigated whether subpopulations of dopamine (DA) neurons in the VTA projecting either to the mPFC or the medial division of shell part of nucleus accumbens (mNAcs) receive differential input from orexin neurons and whether orexin exerts differential electrophysiological effects upon these cells. VTA neurons projecting to the mPFC or the mNAcs were traced retrogradely by Cav2-Cre virus and identified by expression of yellow fluorescent protein (YFP). Immunocytochemical analysis showed that a higher proportion of all orexin-innervated DA neurons projected to the mNAcs (34.5%) than to the mPFC (5.2%). Of all sampled VTA neurons projecting either to the mPFC or mNAcs, the dopaminergic (68.3 vs. 79.6%) and orexin-innervated DA neurons (68.9 vs. 64.4%) represented the major phenotype. Whole-cell current clamp recordings were obtained from fluorescently labeled neurons in slices during baseline periods and bath application of orexin A. Orexin similarly increased the firing rate of VTA dopamine neurons projecting to mNAcs (1.99 ± 0.61 Hz to 2.53 ± 0.72 Hz) and mPFC (0.40 ± 0.22 Hz to 1.45 ± 0.56 Hz). Thus, the hypothalamic orexin system targets mNAcs and to a lesser extent mPFC-projecting dopaminergic neurons of the VTA and exerts facilitatory effects on both clusters of dopamine neurons.

Changes in the Orexin System in Rats Exhibiting Learned Helplessness Behaviors.

Orexin-A (OX-A) and orexin-B (OX-B) are neuropeptides produced in the hypothalamus. Preclinical and clinical studies suggest that depression and anxiety are associated with the orexin system. In the current study, we used the learned helplessness (LH) animal model of depression to identify rats displaying LH behaviors (LH rats) and those that did not (No-LH rats). We compared the number of orexin-containing neurons in the hypothalamus of LH, No-LH, and control rats. Orexin peptides, orexin receptor 1 (OXR1) and 2 (OXR2) in brain areas involved in major depression and serum OX-A and corticosterone (CORT) concentrations were quantified and compared between rat groups. We found that LH and No-LH rats displayed higher serum OX-A concentrations compared with control rats. Comparison between LH and No-LH rats revealed that No-LH rats had significantly higher OX-A levels in the brain, more OX-A neurons, and more OX-A neuron activation. LH rats had more OX-B neurons and more OX-B neuron activation. Orexin peptides and receptors in the brain areas involved in major depression exhibited different patterns in LH and NoLH rats. Our findings revealed that activation of OX-A neurons could promote resilient behaviors under stressful situations and OX-A and OX-B neuropeptides exhibit dissimilar functions in LH behaviors.

Loss of sensitivity to insulin-like growth factor I in orexin neurons is associated to perturbed sleep patterns during aging.

Sleep disturbances are common during aging. Old mice show altered sleep structure, with changes in both slow and fast electro-corticographic (ECG) activity, and less transitions between sleep and wake stages, as compared to young animals. Insulin-like growth factor I (IGF-I), that is involved in hormonal changes during aging, was previously shown to increase ECG patterns in young mice and monkeys. More recently, we observed that IGF-I shapes sleep architecture through modulation of the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both stimulation of ECG patterns and activation of orexin neurons by systemic IGF-I were abrogated in old mice. Further, activation of orthodromically stimulated LH neurons by either systemic or local IGF-I in young mice was absent in old mice. As orexin neurons of old mice show markedly increased IGF-I receptor (IGF-IR) levels, suggesting loss of sensitivity to IGF-I, we treated them with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of ECG patterns. Thus, disturbed sleep structure in aging mice may be related to IGF-I resistance in orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

Metabolomics Signature of Patients With Narcolepsy.

Narcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m2). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status. We used a targeted liquid chromatography-mass spectrometry metabolomics approach to measure 141 circulating, low-molecular-weight metabolites in drug-free fasted plasma samples from 117 patients with NT1 (including 41 obese individuals) compared with 116 BMI-matched controls (including 57 obese individuals). Common metabolites driving the difference between patients with NT1 and controls, regardless of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long-chain lysophosphatidylcholine acyls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidylcholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolism. The metabolites driving these differences were glutamate, sarcosine, and ornithine (glycine and serine metabolism); glutamate and PC aa C34:4 (arachidonic acid metabolism); and glutamate, serotonin, and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e., slow-wave sleep duration, sleep latency, and periodic leg movement) and metabolite concentrations seen in the controls were lost. These results represent the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine, and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1. This study provides Class II evidence that a distinct metabolic profile can differentiate patients with NT1 from patients without the disorder.

Hypersomnia and excessive daytime sleepiness in ischemic stroke

A number of studies have demonstrated a high incidence of sleep disturbances in patients with stroke. The paper reviews the variants of wakefulness disorders observed in ischemic stroke, taking into account the current terminology, as well as methods for their diagnosis. Currently, the origin of post-stroke hypersomnolence and its pathophysiology remain debatable. Various mechanisms including orexin ligand deficiency, degeneration of orexin neurons, as well as disruption of the links between the histaminergic and orexinergic systems are considered as links in the pathogenesis of hypersomnolence caused by ischemic stroke. The paper discusses the pathophysiology of hypersomnia and excessive daytime sleepiness in patients with ischemic stroke, demonstrates various points of view on the relationship of these pathological phenomena with ischemic stroke. A hypothesis on the compensatory nature of hypersomnia and excessive daytime sleepiness in acute ischemic stroke and their possible neuroprotective effect on the brain in patients with stroke is presented.