Melanin-Concentrating Hormone Is Associated With Delayed Neurocognitive Recovery in Older Adult Patients With Preoperative Sleep Disorders Undergoing Spinal Anesthesia.

BACKGROUND: Aging and preoperative sleep disorders are the main risk factors affecting postoperative cognitive outcomes. However, the pathogenesis of delayed neurocognitive recovery after surgery remains ambiguous, and there is still a lack of potential biomarkers for delayed neurocognitive recovery in older adult patients with preoperative sleep disorders. Our study aimed to explore the relationship between melanin-concentrating hormone (MCH) and delayed neurocognitive recovery early after surgery in older adult patients with preoperative sleep disorders. METHODS: In this monocentric prospective observational study, 156 older adult patients (aged 65 years or older) with preoperative sleep disorders undergoing elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) were included at an academic medical center in Inner Mongolia, China, from October 2021 to November 2022, and all patients underwent spinal anesthesia. The Pittsburgh Sleep Quality Index (PSQI) was applied to assess the preoperative sleep quality of all patients, and preoperative sleep disorders were defined as a score of PSQI >5. We measured the levels of cerebrospinal fluid (CSF) MCH and plasma MCH of all patients. The primary outcome was delayed neurocognitive recovery early after surgery. All patients received cognitive function assessment through the Montreal Cognitive Assessment (MoCA) 1 day before and 7 days after surgery (postoperative day 7 [POD7]). Delayed neurocognitive recovery was defined as a score of POD7 MoCA <26. The potential confounders included variables with P < .2 in the univariate logistic analysis, as well as the important risk factors of delayed neurocognitive recovery reported in the literature. Multivariable logistic regression model based on the Enter method assessed the association of MCH and delayed neurocognitive recovery in older adult patients with preoperative sleep disorders. RESULTS: Fifty-nine (37.8%) older adult patients with preoperative sleep disorders experienced delayed neurocognitive recovery at POD7. Increase in CSF MCH levels (odds ratio [OR] for an increase of 1 pg/mL = 1.16, 95% confidence interval [CI], 1.09-1.23, P < .001) and decrease in plasma MCH levels (OR for an increase of 1 pg/mL = 0.92, 95% CI, 0.86-0.98, P = .003) were associated with delayed neurocognitive recovery, after adjusting for age, sex, education, baseline MoCA scores, American Society of Anesthesiologists (ASA) grade, and coronary heart disease (CHD). CONCLUSIONS: In older adult patients with preoperative sleep disorders, MCH is associated with the occurrence of delayed neurocognitive recovery after surgery. Preoperative testing of CSF MCH or plasma MCH may increase the likelihood of identifying the high-risk population for delayed neurocognitive recovery in older adult patients with preoperative sleep disorders.

Control of Feeding Behavior by Cerebral Ventricular Volume Transmission of Melanin-Concentrating Hormone.

Classical mechanisms through which brain-derived molecules influence behavior include neuronal synaptic communication and neuroendocrine signaling. Here we provide evidence for an alternative neural communication mechanism that is relevant for food intake control involving cerebroventricular volume transmission of the neuropeptide melanin-concentrating hormone (MCH). Results reveal that the cerebral ventricles receive input from approximately one-third of MCH-producing neurons. Moreover, MCH cerebrospinal fluid (CSF) levels increase prior to nocturnal feeding and following chemogenetic activation of MCH-producing neurons. Utilizing a dual viral vector approach, additional results reveal that selective activation of putative CSF-projecting MCH neurons increases food intake. In contrast, food intake was reduced following immunosequestration of MCH endogenously present in CSF, indicating that neuropeptide transmission through the cerebral ventricles is a physiologically relevant signaling pathway for energy balance control. Collectively these results suggest that neural-CSF volume transmission signaling may be a common neurobiological mechanism for the control of fundamental behaviors.

Normal Morning Melanin-Concentrating Hormone Levels and No Association with Rapid Eye Movement or Non-Rapid Eye Movement Sleep Parameters in Narcolepsy Type 1 and Type 2.

STUDY OBJECTIVES: Other than hypocretin-1 (HCRT-1) deficiency in narcolepsy type 1 (NT1), the neurochemical imbalance of NT1 and narcolepsy type 2 (NT2) with normal HCRT-1 levels is largely unknown. The neuropeptide melanin-concentrating hormone (MCH) is mainly secreted during sleep and is involved in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep regulation. Hypocretin neurons reciprocally interact with MCH neurons. We hypothesized that altered MCH secretion contributes to the symptoms and sleep abnormalities of narcolepsy and that this is reflected in morning cerebrospinal fluid (CSF) MCH levels, in contrast to previously reported normal evening/afternoon levels. METHODS: Lumbar CSF and plasma were collected from 07:00 to 10:00 from 57 patients with narcolepsy (subtypes: 47 NT1; 10 NT2) diagnosed according to International Classification of Sleep Disorders, Third Edition (ICSD-3) and 20 healthy controls. HCRT-1 and MCH levels were quantified by radioimmunoassay and correlated with clinical symptoms, polysomnography (PSG), and Multiple Sleep Latency Test (MSLT) parameters. RESULTS: CSF and plasma MCH levels were not significantly different between narcolepsy patients regardless of ICSD-3 subtype, HCRT-1 levels, or compared to controls. CSF MCH and HCRT-1 levels were not significantly correlated. Multivariate regression models of CSF MCH levels, age, sex, and body mass index predicting clinical, PSG, and MSLT parameters did not reveal any significant associations to CSF MCH levels. CONCLUSIONS: Our study shows that MCH levels in CSF collected in the morning are normal in narcolepsy and not associated with the clinical symptoms, REM sleep abnormalities, nor number of muscle movements during REM or NREM sleep of the patients. We conclude that morning lumbar CSF MCH measurement is not an informative diagnostic marker for narcolepsy.

MCH levels in the CSF, brain preproMCH and MCHR1 gene expression during paradoxical sleep deprivation, sleep rebound and chronic sleep restriction.

Neurons that utilize melanin-concentrating hormone (MCH) as neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area. These neurons project throughout the central nervous system and play a role in sleep regulation. With the hypothesis that the MCHergic system function would be modified by the time of the day as well as by disruptions of the sleep-wake cycle, we quantified in rats the concentration of MCH in the cerebrospinal fluid (CSF), the expression of the MCH precursor (Pmch) gene in the hypothalamus, and the expression of the MCH receptor 1 (Mchr1) gene in the frontal cortex and hippocampus. These analyses were performed during paradoxical sleep deprivation (by a modified multiple platform technique), paradoxical sleep rebound and chronic sleep restriction, both at the end of the active (dark) phase (lights were turned on at Zeitgeber time zero, ZT0) and during the inactive (light) phase (ZT8). We observed that in control condition (waking and sleep ad libitum), Mchr1 gene expression was larger at ZT8 (when sleep predominates) than at ZT0, both in frontal cortex and hippocampus. In addition, compared to control, disturbances of the sleep-wake cycle produced the following effects: paradoxical sleep deprivation for 96 and 120 h reduced the expression of Mchr1 gene in frontal cortex at ZT0. Sleep rebound that followed 96 h of paradoxical sleep deprivation increased the MCH concentration in the CSF also at ZT0. Twenty-one days of sleep restriction produced a significant increment in MCH CSF levels at ZT8. Finally, sleep disruptions unveiled day/night differences in MCH CSF levels and in Pmch gene expression that were not observed in control (undisturbed) conditions. In conclusion, the time of the day and sleep disruptions produced subtle modifications in the physiology of the MCHergic system.

The role of melanin concentrating hormone (MCH) in the central chemoreflex: a knockdown study by siRNA in the lateral hypothalamus in rats.

Melanin concentrating hormone (MCH), a neuropeptide produced mainly in neurons localized to the lateral hypothalamic area (LHA), has been implicated in the regulation of food intake, energy balance, sleep state, and the cardiovascular system. Hypothalamic MCH neurons also have multisynaptic connections with diaphragmatic motoneurons and project to many central chemoreceptor sites. However, there are few studies of MCH involvement in central respiratory control. To test the hypothesis that MCH plays a role in the central chemoreflex, we induced a down regulation of MCH in the central nervous system by knocking down the MCH precursor (pMCH) mRNA in the LHA using a pool of small interfering RNA (siRNA), and measured the resultant changes in breathing, metabolic rate, body weight, and blood glucose levels in conscious rats. The injections of pMCH-siRNA into the LHA successfully produced a ∼ 62% reduction of pMCH mRNA expression in the LHA and a ∼ 43% decrease of MCH levels in the cerebrospinal fluid relative to scrambled-siRNA treatment (P = 0.006 and P = 0.02 respectively). Compared to the pretreatment baseline and the scrambled-siRNA treated control rats, knockdown of MCH resulted in: 1) an enhanced hypercapnic chemoreflex (∼ 42 & 47% respectively; P < 0.05) only in wakefulness; 2) a decrease in body weight and basal glucose levels; and 3) an unchanged metabolic rate. Our results indicate that MCH participates not only in the regulation of glucose and sleep-wake homeostasis but also the vigilance-state dependent regulation of the central hypercapnic chemoreflex and respiratory control.

Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease.

Ancillary to decline in cognitive abilities, patients with Alzheimer's disease (AD) frequently suffer from behavioural and psychological symptoms of dementia (BPSD). Hypothalamic polypeptides such as melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) are promoters of sleep-wake regulation and energy homeostasis and are found to impact on cognitive performance. To investigate the role of MCH and HCRT-1 in AD, cerebrospinal fluid (CSF) levels were measured in 33 patients with AD and 33 healthy subjects (HS) using a fluorescence immunoassay (FIA). A significant main effect of diagnosis (F(1,62) = 8.490, p<0.01) on MCH levels was found between AD (93.76±13.47 pg/mL) and HS (84.65±11.40 pg/mL). MCH correlated with T-tau (r = 0.47; p<0.01) and P-tau (r = 0.404; p<0.05) in the AD but not in the HS. CSF-MCH correlated negatively with MMSE scores in the AD (r = -0.362, p<0.05) and was increased in more severely affected patients (MMSE≤20) compared to HS (p<0.001) and BPSD-positive patients compared to HS (p<0.05). In CSF-HCRT-1, a significant main effect of sex (F(1,31) = 4.400, p<0.05) with elevated levels in females (90.93±17.37 pg/mL vs. 82.73±15.39 pg/mL) was found whereas diagnosis and the sex*diagnosis interaction were not significant. Elevated levels of MCH in patients suffering from AD and correlation with Tau and severity of cognitive impairment point towards an impact of MCH in AD. Gender differences of CSF-HCRT-1 controversially portend a previously reported gender dependence of HCRT-1-regulation. Histochemical and actigraphic explorations are warranted to further elucidate alterations of hypothalamic transmitter regulation in AD.

Melanin concentrating hormone (MCH) in the cerebrospinal fluid of ewes during spontaneous oestrous cycles and ram effect induced follicular phases.

The melanin-concentrating hormone (MCH) is a neuropeptide synthesized by neurons of the lateral hypothalamus and incerto-hypothalamic area that project throughout the central nervous system. The aims of the present report were: (1) to determine if MCH levels in cerebrospinal fluid (CSF) of ewes vary between the mid-luteal and the oestrous phase of spontaneous oestrous cycles; and (2) to study if MCH levels in CSF of ewes vary acutely during the follicular phase induced with the ram effect in anoestrous ewes. In the first experiment, CSF was collected from 8 adult ewes during spontaneous oestrous and during the mid-luteal phase (8-10 days after natural oestrus). In the second experiment, performed during the mid non-breeding season, a follicular phase was induced with the ram effect. After isolating a group of 16 ewes from rams, CSF was obtained from 5 of such ewes (control group). Three rams were joined with the ewes, and samples were obtained 12h (n=6) and 24h (n=5) later. In Experiment 1, there were no differences in MCH concentrations in CSF measured during the mid-luteal phase and spontaneous oestrus (0.14 ± 0.04 vs. 0.16 ± 0.05 ng/mL respectively). In Experiment 2, MCH concentrations tended to increase 12h after rams introduction (0.15 ± 0.08 vs. 0.35 ± 0.21 ng/mL, P=0.08), and increased significantly 24h after rams introduction (0.37 ± 0.15 ng/mL, P=0.02). We concluded that MCH concentration measured in the CSF from ewes increased markedly during the response to the ram effect but not during the natural oestrous cycle of ewes.

Melanin concentrating hormone in central hypersomnia.

BACKGROUND: Narcolepsy with cataplexy (NC) is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, due to a deficient hypocretin/orexin neurotransmission. Melanin concentrating hormone (MCH) neurons involved in the homeostatic regulation of REM sleep are intact. We hypothesized that an increased release of MCH in NC would be partly responsible for the abnormal REM sleep manifestations. METHODS: Twenty-two untreated patients affected with central hypersomnia were included: 14 NC, six idiopathic hypersomnia with long sleep time, and two post-traumatic hypersomnia. Fourteen neurological patients without any sleep disorders were included as controls. Using radioimmunoassays, we measured hypocretin-1 and MCH levels in cerebrospinal fluid (CSF). RESULTS: The MCH level was slightly but significantly lower in patients with hypersomnia (98 ± 32 pg/ml) compared to controls (118 ± 20 pg/ml). After exclusion of patients affected with post-traumatic hypersomnia the difference became non-significant. We also failed to find any association between MCH level and hypocretin level, the severity of daytime sleepiness, the number of SOREMPs, the frequency of cataplexy, and the presence of hypnagogic hallucinations or sleep paralysis. CONCLUSION: This study reports the first measurement of MCH in CSF using radioimmunoassay technology. It appears to be a non-informative tool to differentiate etiologies of central hypersomnia with or without REM sleep dysregulation.

Prolactin release during the estradiol-induced LH surge in ewes: modulation by progesterone but no evidence for prolactin-releasing peptide involvement.

An estradiol-induced prolactin surge accompanies the LH surge in several species, including sheep. However, the neural mechanisms underlying this surge remain poorly understood. A first study on estradiol- and progesterone-treated ovariectomized ewes examined whether the prolactin surge, like the LH surge, is sensitive to progesterone. Our data clearly showed that the estradiol-induced prolactin surge in the ewe is blocked by continuous exposure to progesterone and, importantly, that this blockade is overcome by pretreatment with the progesterone receptor antagonist, RU486. In a second study, we established that the generation of the prolactin surge is not dependent on the co-secretion of a prolactin-releasing peptide in the hypophyseal portal blood or cerebrospinal fluid. The neuronal pathways targeted by estradiol and progesterone to modulate prolactin secretion at the time of the LH surge remain to be identified. Importantly, it has not been established whether there is any overlap in the neuronal systems generating the gonadotropin-releasing hormone and prolactin surges.

Neurochemical analysis of cerebrospinal fluid.

The use of cerebrospinal fluid (CSF) analysis for studying in vivo alterations in central neuronal activity requires a relatively sophisticated knowledge of CSF physiology and pathology. Ventriculospinal concentration gradients, circadian rhythms, physical activity, stress, medications, precursor intake, concomitant illness, obstructed CSF circulation, age, and sex alter the baseline neurochemical composition of CSF. Differential probenecid blockade of the egress of acidic monoamine metabolites and cyclic nucleotides from the CSF may complicate interpretations of their accumulations. Degradation of CSF constituents during collection, storage, and analysis may introduce errors in quantification. These sources of CSF variability can be minimized with proper methodolology.