Hypothalamus Research Articles

The Influences of Chrysin on Stress-Induced Changes of Melanin-Concentrating Hormone and Orexin Gene Expression in Rats

Introduction: Chrysin is a bioactive component of herbal medicines such as Passiflora incarnate, Passiflora caerulea, and Oroxylum indicum. Although evidence has demonstrated the neuroprotective, anti-inflammatory, and pain-relieving effects of chrysin, the intra-hypothalamic molecular mechanisms underlying the anxiolytic effects of chrysin are still unclear. This study aimed to explore the effects of chrysin on hypothalamic orexin and melanin-concentrating hormone (MCH) gene expression in a rat model of stress. Methods: Twenty male Wistar rats (200±10 g) were segregated into four groups (n=5). For the induction of stress, the animals were placed in the restraint cage for 2 hours. The intact and stressed groups received saline. Thirty minutes before the induction of stress, chrysin was injected into the other two groups of the stress model at a dosage of 20 or 40 µg via the third cerebral ventricle. Hypothalamic samples were removed and frozen, and the relative gene expression of orexin and MCH was measured using the real-time polymerase chain reaction technique. Results: The induction of stress significantly increased mRNA levels of orexin and MCH compared to the control rats. The mRNA levels of MCH and orexin significantly declined in rats receiving chrysin compared to the stress group. Conclusion: The inhibition of the hypothalamic MCH and orexin neuronal circuits may be involved in the preventive effects of chrysin against stressful situations. Chrysin may be a potential target to manage anxiogenic behaviors due to the down-regulation of MCH and orexin gene expression upstream the hypothalamic corticotropin-releasing hormone.

Effect of Xiaoyaosan on brain volume and microstructure diffusion changes to exert antidepressant-like effects in mice with chronic social defeat stress.

Depression is a prevalent mental disorder characterized by persistent negative mood and loss of pleasure. Although there are various treatment modalities available for depression, the rates of response and remission remain low. Xiaoyaosan (XYS), a traditional Chinese herbal formula with a long history of use in treating depression, has shown promising effects. However, the underlying mechanism of its therapeutic action remains elusive. The aim of this study is to investigate the neuroimaging changes in the brain associated with the antidepressant-like effects of XYS. Here, we combined voxel-based morphometry of T2-weighted images and voxel-based analysis on diffusion tensor images to evaluate alterations in brain morphometry and microstructure between chronic social defeat stress (CSDS) model mice and control mice. Additionally, we examined the effect of XYS treatment on structural disruptions in the brains of XYS-treated mice. Furthermore, we explored the therapeutic effect of 18β-glycyrrhetinic acid (18β-GA), which was identified as the primary compound present in the brain following administration of XYS. Significant differences in brain structure were utilized as classification features for distinguishing mice with depression model form the controls using a machine learning method. Significant changes in brain volume and diffusion metrics were observed in the CSDS model mice, primarily concentrated in the nucleus accumbens (ACB), primary somatosensory area (SSP), thalamus (TH), hypothalamus (HY), basomedical amygdala nucleus (BMA), caudoputamen (CP), and retrosplenial area (RSP). However, both XYS and 18β-GA treatment prevented disruptions in brain volume and diffusion metrics in certain regions, including bilateral HY, right SSP, right ACB, bilateral CP, and left TH. The classification models based on each type of neuroimaging feature achieved high accuracy levels (gray matter volume: 76.39%, AUC=0.83; white matter volume: 76.39%, AUC=0.92; fractional anisotropy: 82.64%, AUC=0.9; radial diffusivity: 76.39%, AUC=0.82). Among these machine learning analyses, the right ACB, right HY, and right CP were identified as the most important brain regions for classification purposes. These findings suggested that XYS can prevent abnormal changes in brain volume and microstructure within TH, SSP, ACB, and CP to exert prophylactic antidepressant-like effects in CSDS model mice. The neuroimaging features within these regions demonstrate excellent performance for classifying CSDS model mice from controls while providing valuable insights into the antidepressant effects of XYS.

Alpha-synuclein expression in GnRH neurons of young and old bovine hypothalami.

Context Understanding of central nervous system mechanisms related to age-related infertility remains limited. Fibril α-synuclein, distinct from its monomer form, is implicated in age-related diseases and propagates among neurons akin to prions. Aims We compared α-synuclein expression in gonadotropin-releasing hormone-expressing neurons (GnRH neurons) in the pre-optic area, arcuate nucleus, and median eminence of healthy heifers and aged cows to determine its role in age-related infertility. Methods We analysed mRNA and protein expression, along with fluorescent immunohistochemistry for GnRH and α-synuclein, followed by Congo red staining to detect amyloid deposits, and confocal microscopy. Key results Both mRNA and protein expressions of α-synuclein were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and western blots in bovine cortex, hippocampus, and anterior and posterior hypothalamus tissues. Significant differences in α-synuclein mRNA expression were observed in the cortex and hippocampus between young and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomer, dimer, and oligomers, in the cortex, hippocampus, hypothalamus tissues, and there were significant differences in some bands between young and old cows. Bright-field and polarised light microscopy did not detect obvious amyloid deposition in aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signal of Congo red and α-synuclein in GnRH neurons in aged hypothalami. Additionally, α-synuclein expression was detected in immortalised GnRH neurons, GT1-7 cells. Conclusion Alpha-synuclein was expressed in GnRH neurons, and some differences were observed between young and old hypothalami. Implications Alpha-synuclein may play an important role in aging-related infertility.

Differential effects of sleep deprivation on behavior and microglia in a brain-region-specific manner in young and aged male mice

Microglia, resident immune cells in the central nervous system, constantly monitor the state of the surrounding brain activity. The animal model induced by sleep deprivation (SD) is widely used to study the pathophysiological mechanisms of insomnia and bipolar disorder. However, it remains unclear whether SD affects behaviors in young and aged male mice and microglia in various brain regions. In this study, we confirmed brain region-specific changes in microglial density and morphology in the accumbens nucleus (Acb), amygdala (AMY), cerebellum (Cb), corpus callosum (cc), caudate putamen, hippocampus (HIP), hypothalamus (HYP), medial prefrontal cortex (mPFC), and thalamus (TH) of young mice. In addition, the density of microglia in old mice was higher than that in young mice. Compared with young mice, old mice showed a markedly increased microglial size, decreased total length of microglial processes, and decreased maximum length. Importantly, we found that 48-h SD decreased microglial density and morphology in old mice, whereas SD increased microglial density and morphology in most observed brain regions in young mice. SD-induced hyperactivity was observed only in young mice but not in old mice. Moreover, microglial density (HIP, AMY, mPFC, CPu) was significantly positively correlated with behaviors in SD- and vehicle-treated young mice. Contrarily, negative correlations were shown between the microglial density (cc, Cb, TH, HYP, Acb, AMY) and behaviors in vehicle-treated young and old mice. These results suggest that SD dysregulates the homeostatic state of microglia in a region- and age-dependent manner. Microglia may be involved in regulating age-related behavioral responses to SD.

Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice

The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.

Peripheral Branch Injury Induces Oxytocin Receptor Expression at the Central Axon Terminals of Primary Sensory Neurons.

Considerable evidence suggests that oxytocin, as a regulatory nonapeptide, participates in modulatory mechanisms of nociception. Nonetheless, the role of this hypothalamic hormone and its receptor in the sensory pathway has yet to be fully explored. The present study performed immunohistochemistry, enzyme-linked immunosorbent assay, and RT-qPCR analysis to assess changes in the expression of the neuronal oxytocin receptor in female rats following tight ligation of the sciatic nerve after 1, 3, and 7 days of survival. Oxytocin receptor immunoreactivity was present in both dorsal root ganglia and lumbar spinal cord segments, but not accumulated at the site of the ligation of the peripheral nerve branch. We found a time-dependent change in the expression of oxytocin receptor mRNA in L5 dorsal root ganglion neurons, as well as an increase in the level of the receptor protein in the lumbar segment of the spinal cord. A peak in the expression was observed on day 3, which downturned slightly by day 7 after the nerve ligation. These results show that OTR expression is up-regulated in response to peripheral nerve lesions. We assume that the importance of OTR is to modify spinal presynaptic inputs of the sensory neurons upon injury-induced activation, thus to be targets of the descending oxytocinergic neurons from supraspinal levels. The findings of this study support the concept that oxytocin plays a role in somatosensory transmission.

FERTILITY FACTORS. D-HORMONE IN PREVENTION OF REPRODUCOPATHIES CAUSED BY BENIGN PROSTATIC HYPERPLASIA (Literature review)

In accordance with the statistical data, the spreading of benign prostatic hyperplasia (BPH) is increasing, because modern stressful lifestyle causes sex hormones disbalances and other dyshormonal conditions which lead to pathologies’ development at younger ages. The pathogenesis of BPH is connected with disturbances of regulation in the hypothalamo-hypophyseal system and with the changes of the regulatory signals intensity which go to the reproductive organs. The central pathogenic links of this pathology’ development are: the declining of efficacy of hypothalamus functioning regulation which carries out on the basis of feedback; the changes of the pituitary gland cells sensitivity to the releasing hormones of hypothalamus and disbalance of sex hormones. In addition to gonadotropins prolactin has a significant impact on the BPH development. Its hypersecretion causes the development of hyperplastic age-related changes in prostate gland. The introduction of dopamine receptors antagonists such as sulpiride causes the increasing of prolactin concentration and declining of gonadotropins releasing. “Sulpiride model” is broadly used in the experimental endocrinology for studying prostate-active drugs and is characterized by sex hormones disbalance' and inflammation processes’ development. The development of the pathology is linked with the disturbance of testosterone synthesis in the testicles, insufficiency of prostate gland functioning and increasing of prolactin and estradiol concentrations which provoke proliferative changes. The androgens disbalance is the main cause of BHP development, therefore, the “Testosterone model” based on testosterone’ and estradiol’ slow releasing implants is broadly used for modeling of urination disturbance in rats which imitates the same condition in elderly men with benign prostatic hyperplasia. The prostatitis, which developed under the condition of BHP, causes the disturbances of spermatogenesis during experimental modeling and in the clinical practice when spermatopathies, sexual disturbances and hypofertility are diagnosed in patients. The traditional BHP therapeutic methods are not always effective and the new therapeutic approaches of hypofertility caused by prostate gland pathologies are developed by investigators. Thus, there are data about correlation between increased vitamin D consumption and decreasing of BHP spreading, between gland volume and cells proliferation in patients with this pathology. Vitamin D level influences the quantity and quality of ejaculate. The deficiency of vitamin D is associated with lower proportion of sex hormones in young men and choriogonin sensitivity of Leydig's cells to be diminished. It has been experimentally shown that cholecalciferol regulates steroid hormones genesis, mitigates the age-related declining of testicles activity, protects the testicles in old animals and the unchanged spermatogenesis in normal males which received vitamin D3 can be considered to be the result of estrogens and androgens balance. The androgens receptors as well as vitamin D receptors have been found in prostate gland in health males and in those with hyperplasia. In addition to its classical function in calcium homeostasis and bones health, vitamin D inhibits tumor growth in different tissues including prostate gland. Vitamin D metabolites have been determined to be anti-inflammatory, proapoptotic and antiproliferative. D-hormone application potentiates the specific properties of prostate gland protectors, recovers reproductive capacity under the condition of experimental chronic prostatitis of inflammatory genesis as well as traumatic. All facts listed above allow to confirm the positive role of D-hormone in the regulation of prostate gland and reproductive function in patients with BHP and recovering of fertility under the condition of this pathology. The literature search for this review has been carried out on databases PubMed, Science Direct, Europa PMC, BMC, MedLine etc.

The differential sensitivity of the hypothalamic-hypophysial-ovarian axis to 5-hydroxytryptophan alters the secretion of estradiol.

Serotonin [5-hydroxytryptamine (5-HT)] modulates ovarian function. The precursor of 5-HT, 5-hydroxytryptophan (5-HTP), has been used to treat depression. However, the effects of 5-HTP on ovarian and reproductive physiology remain unknown. In this research, we analysed the impact of 5-HTP on the monoaminergic system and its interactions with the reproductive axis and ovarian estradiol secretion when administered by distinct routes. Female rats 30 days of age were injected with 5-HTP i.p. (100mg/kg), into the ovarian bursa (1.5µg/40µL) or into the median raphe nucleus (20µg/2.5µL) and were killed 60 or 120min after injection. As controls, we used rats of the same age injected with vehicle (0.9% NaCl). Monoamine, gonadotrophin and steroid ovarian hormone concentrations were measured. The injection of 5-HTP either i.p. or directly into the ovarian bursa increased the concentrations of 5-HT and the metabolite 5-hydroxyindole-3-acetic acid in the ovary. For both routes of administration, the serum concentration of estradiol increased. After i.p. injection of 5-HTP, the concentrations of luteinizing hormone were decreased and follicle-stimulating hormone increased after 120min. Micro-injection of 5-HTP into the median raphe nucleus increased the concentrations of 5-HT in the anterior hypothalamus and dopamine in the medial hypothalamus after 120min. Our results suggest that the administration of 5-HTP either i.p. or directly into the ovarian bursa enhances ovarian estradiol secretion.

Are noradrenergic and orexinergic systems contributing to sleep‐wake patterns in early and late‐onset Alzheimer’s Disease?

AbstractBackgroundNeuropsychiatric symptoms, including sleep‐wake disturbances, are more common in Early‐onset Alzheimer’s disease (EOAD) than in Late‐onset AD (LOAD)(Falgàs, EurJNeurol2022). The pattern of tau‐related degeneration of wake and sleep‐promoting neurons determine sleep‐wake profiles in neurodegenerative disorders (Oh, JAMANeurol2022). We hypothesize that distinct patterns of noradrenergic (locus coeruleus‐LC) and orexigenic (hypothalamus‐HT) degeneration contribute for the differential sleep‐wake patterns between EOAD and LOAD.MethodA group of 21 participants (7 EOAD, 18 LOAD) with a diagnosis of AD confirmed by cerebrospinal fluid biomarkers (CSF) were recruited from Hospital Clínic de Barcelona. Participants underwent sleep questionnaires (Pittsburg Sleep Quality Inventory‐PSQI and Epworth Sleepiness Scale‐ESS), 2‐week actigraphy (MotionWatch8, CamnTech) and 3T‐neuromelanin‐sensitive MRI to measure locus coeruleus (LC) and hypothalamus (HT) volumes. Sleep, napping, and circadian parameters were obtained (MotionWare).ResultThe preliminary results showed no differences in sex (71vs.61% women) or disease stage (CDR 0.5: 85% vs.72%). The amnestic phenotype was prevalent (100 vs.78%). EOAD had longer daytime napping (93.2±74 vs. 58.2±28min, p<0.05), later fell asleep times (0:42am vs. 11:30pm, p<0.05) and higher central phase measure (4.4±0.5 vs. 3.5±1 h, p<0.05, midpoint between fell asleep and wake‐up) than LOAD. Daytime napping correlated with ESS (r = 0.53, p<0.01). Other parameters such as actual sleep time, sleep efficiency, sleep latency, or fragmentation index showed no differences. PSQI did not correlate to any measures. LC‐volumes were lower in EOAD than in LOAD (24.4±7mm3 vs. 33.3±6 p<0.01). In contrast, HT‐ trended towards higher volumes in EOAD (416.8±38 vs. 392.9±36, p = 0.09), being inversely correlated to the age at onset (r = ‐0.47, p<0.05). The central phase measure was inversely correlated to LC‐volumes (r = ‐0.47, p<0.05) but not to HT. Further analyses with increased sample size, CSF noradrenaline and orexin will be performed.ConclusionGreater daytime sleepiness and circadian dysfunction could be main differing traits regarding sleep‐wake patterns between EOAD and LOAD. An opposite pattern of degeneration within wake‐promoting systems consisting of higher degeneration of the LC‐noradrenergic system and relative preservation of the HT‐orexigenic in EOAD in contrast to LOAD might underlie differing sleep‐wake phenotypes. Age‐related hypothalamic volume loss can be adding to AD driven loss resulting in higher volumes in EOAD.

Hindbrain adrenergic/noradrenergic control of integrated endocrine and autonomic stress responses.

Hindbrain adrenergic/noradrenergic nuclei facilitate endocrine and autonomic responses to physical and psychological challenges. Neurons that synthesize adrenaline and noradrenaline target hypothalamic structures to modulate endocrine responses while descending spinal projections regulate sympathetic function. Furthermore, these neurons respond to diverse stress-related metabolic, autonomic, and psychosocial challenges. Accordingly, adrenergic and noradrenergic nuclei are integrative hubs that promote physiological adaptation to maintain homeostasis. However, the precise mechanisms through which adrenaline- and noradrenaline-synthesizing neurons sense interoceptive and exteroceptive cues to coordinate physiological responses have yet to be fully elucidated. Additionally, the regulatory role of these cells in the context of chronic stress has received limited attention. This mini-review consolidates reports from pre-clinical rodent studies on the organization and function of brainstem adrenaline and noradrenaline cells to provide a framework for how these nuclei coordinate endocrine and autonomic physiology. This includes identification of hindbrain adrenaline- and noradrenaline-producing cell groups and their role in stress responding through neurosecretory and autonomic engagement. Although temporally and mechanistically distinct, the endocrine and autonomic stress axes are complementary and interconnected. Therefore, the interplay between brainstem adrenergic/noradrenergic nuclei and peripheral physiological systems is necessary for integrated stress responses and organismal survival.

Gender Differences in Pain Threshold, Unpleasantness, and Descending Pain Modulatory Activation Across the Adult Life Span: A Cross Sectional Study

The neurobiological underpinnings of gender differences in pain perception, and how these differences may be modified by age, are incompletely understood, placing patients at risk of suboptimal pain management. Using functional magnetic resonance imaging, we examined brain responses in the descending pain modulatory system (DPMS, specifically, dorsolateral prefrontal cortex, anterior cingulate cortex, insula, hypothalamus, amygdala, and periaqueductal gray, during an evoked pain task. We investigated the interaction of age and gender in our sample of healthy adults (27 females, 32 males, 30–86 years) on DPMS response. In a perceptually matched thermal pain paradigm, we investigated pain unpleasantness and neural responses for 3 heat pain percepts: just noticeable pain, weak pain, and moderate pain (MP). Females reported just noticeable pain at a lower temperature, but reported less unpleasantness at weak pain and MP percepts, compared to males. There was a significant age-by-gender interaction during moderate pain in the right anterior cingulate cortex and bilateral insula, such that, males had a stronger positive relationship between DPMS response and age compared to females in these regions. Our results indicate that differences in DPMS responses may explain some gender differences in pain perception and that this effect may change across the adult lifespan. PerspectiveGender differences in pain have been well-documented but the brain mechanisms for these differences are still unclear. This article describes potential differences in brain functioning during different levels of pain that could explain differences in pain responses between men and women across the adult lifespan.

Growth hormone promotes the reconstruction of injured axons in the hypothalamo-neurohypophyseal system.

JOURNAL/nrgr/04.03/01300535-202410000-00026/figure1/v/2024-02-06T055622Z/r/image-tiff Previous studies have shown that growth hormone can regulate hypothalamic energy metabolism, stress, and hormone release. Therefore, growth hormone has great potential for treating hypothalamic injury. In this study, we established a specific hypothalamic axon injury model by inducing hypothalamic pituitary stalk electric lesions in male mice. We then treated mice by intraperitoneal administration of growth hormone. Our results showed that growth hormone increased the expression of insulin-like growth factor 1 and its receptors, and promoted the survival of hypothalamic neurons, axonal regeneration, and vascular reconstruction from the median eminence through the posterior pituitary. Altogether, this alleviated hypothalamic injury-caused central diabetes insipidus and anxiety. These results suggest that growth hormone can promote axonal reconstruction after hypothalamic injury by regulating the growth hormone-insulin-like growth factor 1 axis.

Correlational Study of Aminopeptidase Activities between Left or Right Frontal Cortex versus the Hypothalamus, Pituitary, Adrenal Axis of Spontaneously Hypertensive Rats Treated with Hypotensive or Hypertensive Agents.

It has been suggested that the neuro-visceral integration works asymmetrically and that this asymmetry is dynamic and modifiable by physio-pathological influences. Aminopeptidases of the renin-angiotensin system (angiotensinases) have been shown to be modifiable under such conditions. This article analyzes the interactions of these angiotensinases between the left or right frontal cortex (FC) and the same enzymes in the hypothalamus (HT), pituitary (PT), adrenal (AD) axis (HPA) in control spontaneously hypertensive rats (SHR), in SHR treated with a hypotensive agent in the form of captopril (an angiotensin-converting enzyme inhibitor), and in SHR treated with a hypertensive agent in the form of the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). In the control SHR, there were significant negative correlations between the right FC with HPA and positive correlations between the left FC and HPA. In the captopril group, the predominance of negative correlations between the right FC and HPA and positive correlations between the HPA and left FC was maintained. In the L-NAME group, a radical change in all types of interactions was observed; particularly, there was an inversion in the predominance of negative correlations between the HPA and left FC. These results indicated a better balance of neuro-visceral interactions after captopril treatment and an increase in these interactions in the hypertensive animals, especially in those treated with L-NAME.

Neurohormonal response patterns to hunger, satiation, and postprandial fullness in normal weight, anorexia nervosa, and obesity.

Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN. During an adlibitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs). A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m2 ), and 29 with OB (BMI ≥30 kg/m2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK. Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical tricals

Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 (KP54) can induce oocyte maturation during in vitro fertilization treatment, including in women at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported. ObjectiveTo determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (Phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (Phase-2a trial). DesignTwo randomized, placebo-controlled, parallel group, dose-finding trials. SettingClinical trials unit, Netherlands. ParticipantsHealthy women aged 18-35 years, either without (Phase-1; n=24), or with ovarian stimulation (Phase-2a; n=75). InterventionsPhase-1: Single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 μg) or placebo, (n=6 per dose).Phase-2a: Single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 μg; n=16-17 per dose), triptorelin 0.2 mg (n=5; active comparator), or placebo (n=5). Main Objectives and Outcome MeasuresPhase-1: Safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones).Phase-2a: Safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); time to ovulation assessed by transvaginal ultrasound. ResultsIn both trials, MVT-602 was safe and well-tolerated across the entire dose-range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours.In the Phase-2a trial, LH concentrations increased dose-dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3μg MVT-602 and remained above 15 IU/L for 33 hours. Time to ovulation following drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 μg), 88% (1μg), 82% (0.3μg), and 75% (0.1μg), of women after MVT-602, 100% after triptorelin, and 60% after placebo. ConclusionsMVT-602 induces LH concentrations of similar amplitude and duration as the physiological mid-cycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR. Trial RegistrationsEUDRA-CT: 2017-003812-38, 2018-001379-20

Association between Air Pollution and Lipid Profiles.

Dyslipidemia is a critical factor in the development of atherosclerosis and consequent cardiovascular disease. Numerous pieces of evidence demonstrate the association between air pollution and abnormal blood lipids. Although the results of epidemiological studies on the link between air pollution and blood lipids are unsettled due to different research methods and conditions, most of them corroborate the harmful effects of air pollution on blood lipids. Mechanism studies have revealed that air pollution may affect blood lipids via oxidative stress, inflammation, insulin resistance, mitochondrial dysfunction, and hypothalamic hormone and epigenetic changes. Moreover, there is a risk of metabolic diseases associated with air pollution, including fatty liver disease, diabetes mellitus, and obesity, which are often accompanied by dyslipidemia. Therefore, it is biologically plausible that air pollution affects blood lipids. The overall evidence supports that air pollution has a deleterious effect on blood lipid health. However, further research into susceptibility, indoor air pollution, and gaseous pollutants is required, and the issue of assessing the effects of mixtures of air pollutants remains an obstacle for the future.

Multiparametric MR Evaluation of the Photoperiodic Regulation of Hypothalamic Structures in Sheep

Most organisms on earth, humans included, have developed strategies to cope with environmental day-night and seasonal cycles to survive. For most of them, their physiological and behavioral functions, including the reproductive function, are synchronized with the annual changes of day length, to ensure winter survival and subsequent reproductive success in the following spring.Sheep are sensitive to photoperiod, which also regulates natural adult neurogenesis in their hypothalamus. We postulate that the ovine model represents a good alternative to study the functional and metabolic changes occurring in response to photoperiodic changes in hypothalamic structures of the brain.Here, the impact of the photoperiod on the neurovascular coupling and the metabolism of the hypothalamic structures was investigated at 3T using BOLD fMRI, perfusion-MRI and proton magnetic resonance spectroscopy (1H-MRS). A longitudinal study involving 8 ewes was conducted during long days (LD) and short days (SD) revealing significant BOLD, rCBV and metabolic changes in hypothalamic structures of the ewe brain between LD and SD. More specifically, the transition between LD and SD revealed negative BOLD responses to hypercapnia at the beginning of SD period followed by significant increases in BOLD, rCBV, Glx and tNAA concentrations towards the end of the SD period. These observations suggest longitudinal mechanisms promoting the proliferation and differentiation of neural stem cells within the hypothalamic niche of breeding ewes.We conclude that multiparametric MRI studies including 1H-MRS could be promising non-invasive translational techniques to investigate the existence of natural adult neurogenesis in-vivo in gyrencephalic brains.

Hypothalamic MCH Neurons: From Feeding to Cognitive Control.

Modern neuroscience is progressively elucidating that the classic view positing distinct brain regions responsible for survival, emotion, and cognitive functions is outdated. The hypothalamus demonstrates the interdependence of these roles, as it is traditionally known for fundamental survival functions like energy and electrolyte balance, but is now recognized to also play a crucial role in emotional and cognitive processes. This review focuses on lateral hypothalamic melanin-concentrating hormone (MCH) neurons, producing the neuropeptide MCH-a relatively understudied neuronal population with integrative functions related to homeostatic regulation and motivated behaviors, with widespread inputs and outputs throughout the entire central nervous system. Here, we review early findings and recent literature outlining their role in the regulation of energy balance, sleep, learning, and memory processes.

Brain proteomic atlas of alcohol use disorder in adult males

Alcohol use disorder (AUD) affects transcriptomic, epigenetic and proteomic expression in several organs, including the brain. There has not been a comprehensive analysis of altered protein abundance focusing on the multiple brain regions that undergo neuroadaptations occurring in AUD. We performed a quantitative proteomic analysis using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of human postmortem tissue from brain regions that play key roles in the development and maintenance of AUD, the amygdala (AMG), hippocampus (HIPP), hypothalamus (HYP), nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral tegmental area (VTA). Brain tissues were from adult males with AUD (n = 11) and matched controls (n = 16). Across the two groups, there were >6000 proteins quantified with differential protein abundance in AUD compared to controls in each of the six brain regions. The region with the greatest number of differentially expressed proteins was the AMG, followed by the HYP. Pathways associated with differentially expressed proteins between groups (fold change > 1.5 and LIMMA p < 0.01) were analyzed by Ingenuity Pathway Analysis (IPA). In the AMG, adrenergic, opioid, oxytocin, GABA receptor and cytokine pathways were among the most enriched. In the HYP, dopaminergic signaling pathways were the most enriched. Proteins with differential abundance in AUD highlight potential therapeutic targets such as oxytocin, CSNK1D (PF-670462), GABAB receptor and opioid receptors and may lead to the identification of other potential targets. These results improve our understanding of the molecular alterations of AUD across brain regions that are associated with the development and maintenance of AUD. Proteomic data from this study is publicly available at www.lmdomics.org/AUDBrainProteomeAtlas/.

Impact and Role of Hypothalamic Corticotropin Releasing Hormone Neurons in Withdrawal from Chronic Alcohol Consumption in Female and Male Mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (World Health Organization, 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine and Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two-bottle choice alcohol consumption blunts the endocrine-mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. GABAergic synaptic transmission was unaffected by alcohol history. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disk test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress-responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol-mediated changes to PVNCRH neurons that alter stress response.SIGNIFICANCE STATEMENT Paraventricular nucleus of the hypothalamus neurons that release corticotropin releasing hormone (PVNCRH) are vital for stress response. These neurons have been understudied in relation to alcohol and withdrawal despite profound relations between stress, alcohol use disorders (AUD), and relapse. In this study, we use a variety of techniques to show that acute withdrawal from a history of alcohol impacts peripheral stress response, PVNCRH neurons, and behavior. Specifically, PVNCRH are in a hyperactive state during withdrawal, which drives an increase in active stress coping behaviors in female mice only. Understanding how alcohol use and withdrawal affects stress responding PVNCRH neurons may contribute to finding new potential targets for the treatment of alcohol use disorder.