Oxytocin-MCH circuit regulates monosynaptic inputs to MCH neurons and modulates social recognition memory.

Oxytocin regulates social behaviors and has been linked to the etiology of autism and schizophrenia. Oxytocin and another hypothalamic neuropeptide, melanin concentrating hormone (MCH), share several physiological actions such as emotion, social behavior and recognition, maternal care, sexual behavior and stress, which suggests that these two systems may interact, however, how they would do it is not known. Here, we study the interactions between the oxytocin and MCH systems in behaviors related to autism and schizophrenia. Specifically, we examined the synaptic inputs of the oxytocin-to the MCH neurons. We selectively deleted oxytocin receptors (OXTR) from MCH neurons (OXTR-cKO mice) using a Cre/loxP recombinase-technology, and used rabies-mediated circuit mapping technique to reveal the changes in the direct monosynaptic inputs to MCH neurons. We examined the behavioral responses of OXTR-cKO mice. Deletion of OXTR from MCH neurons induced a significant decrease in the primary inputs received by MCH neurons from the paraventricular nucleus and the lateral hypothalamus, and from the nucleus accumbens and ventral tegmental area. While OXTR-cKO mice exhibited similar social interactions as control mice, they displayed significantly impaired social recognition memory and increased stereotypic behavior. Our study identifies a selective role for the oxytocin-MCH pathway in social recognition memory and stereotyped behavior that are relevant to psychiatric disorders such as schizophrenia and autism, and warrant further investigation of this circuit to uncover potential benefit of targeting the oxytocin-MCH circuit as a novel therapeutic target for treatment of social recognition deficits in these two disorders.

Tracing key genes associated with the Pinctada margaritifera albino phenotype from juvenile to cultured pearl harvest stages using multiple whole transcriptome sequencing.

BACKGROUND: Albino mutations are commonly observed in the animal kingdom, including in bivalves. In the black-lipped pearl oyster Pinctada margaritifera, albino specimens are characterized by total or partial absence of colouration resulting in typical white shell phenotype expression. The relationship of shell colour with resulting cultured pearl colour is of great economic interest in P. margaritifera, on which a pearl industry is based. Hence, the albino phenotype provides a useful way to examine the molecular mechanisms underlying pigmentation. RESULTS: Whole transcriptome RNA-sequencing analysis comparing albino and black wild-type phenotypes at three stages over the culture cycle of P. margaritifera revealed a total of 1606, 798 and 187 differentially expressed genes in whole juvenile, adult mantle and pearl sac tissue, respectively. These genes were found to be involved in five main molecular pathways, tightly linked to known pigmentation pathways: melanogenesis, calcium signalling pathway, Notch signalling pathway, pigment transport and biomineralization. Additionally, significant phenotype-associated SNPs were selected (N = 159), including two located in the Pif biomineralization gene, which codes for nacre formation. Interestingly, significantly different transcript splicing was detected between juvenile (N = 1366) and adult mantle tissue (N = 313) in, e.g., the tyrosinase Tyr-1 gene, which showed more complex regulation in mantle, and the Notch1 encoding gene, which was upregulated in albino juveniles. CONCLUSION: This multiple RNA-seq approach provided new knowledge about genes associated with the P. margaritifera albino phenotype, highlighting: 1) new molecular pathways, such as the Notch signalling pathway in pigmentation, 2) associated SNP markers with biomineraliszation gene of interest like Pif for marker-assisted selection and prevention of inbreeding, and 3) alternative gene splicing for melanin biosynthesis implicating tyrosinase.

Albinism: epidemiology, genetics, cutaneous characterization, psychosocial factors.

Oculocutaneous albinism is an autosomal recessive disease caused by the complete absence or decrease of melanin biosynthesis in melanocytes. Due to the reduction or absence of melanin, albinos are highly susceptible to the harmful effects of ultraviolet radiation and are at increased risk of actinic damage and skin cancer. In Brazil, as in other parts of the world, albinism remains a little known disorder, both in relation to epidemiological data and to phenotypic and genotypic variation. In several regions of the country, individuals with albinism have no access to resources or specialized medical care, and are often neglected and deprived of social inclusion. Brazil is a tropical country, with a high incidence of solar radiation during the year nationwide. Consequently, actinic damage and skin cancer occur early and have a high incidence in this population, often leading to premature death. Skin monitoring of these patients and immediate therapeutic interventions have a positive impact in reducing the morbidity and mortality associated with this condition. Health education is important to inform albinos and their families, the general population, educators, medical professionals, and public agencies about the particularities of this genetic condition. The aim of this article is to present a review of the epidemiological, clinical, genetic, and psychosocial characteristics of albinism, with a focus in skin changes caused by this rare pigmentation disorder.

Albinism: epidemiology, genetics, cutaneous characterization, psychosocial factors

Abstract Oculocutaneous albinism is an autosomal recessive disease caused by the complete absence or decrease of melanin biosynthesis in melanocytes. Due to the reduction or absence of melanin, albinos are highly susceptible to the harmful effects of ultraviolet radiation and are at increased risk of actinic damage and skin cancer. In Brazil, as in other parts of the world, albinism remains a little known disorder, both in relation to epidemiological data and to phenotypic and genotypic variation. In several regions of the country, individuals with albinism have no access to resources or specialized medical care, and are often neglected and deprived of social inclusion. Brazil is a tropical country, with a high incidence of solar radiation during the year nationwide. Consequently, actinic damage and skin cancer occur early and have a high incidence in this population, often leading to premature death. Skin monitoring of these patients and immediate therapeutic interventions have a positive impact in reducing the morbidity and mortality associated with this condition. Health education is important to inform albinos and their families, the general population, educators, medical professionals, and public agencies about the particularities of this genetic condition. The aim of this article is to present a review of the epidemiological, clinical, genetic, and psychosocial characteristics of albinism, with a focus in skin changes caused by this rare pigmentation disorder.

Increased virulence of albino mutant of Fonsecaea monophora in Galleria mellonella.

Fonsecaea monophora has been the predominant pathogen of chromoblastomycosis in Southern China, but its pathogenic mechanism remains unclear. New models are needed to study this infection. In the current study, we examined the role of melanin on the pathogenicity of F. monophora in Galleria mellonella model using melanin and albino strain. Interestingly, the albino mutant strain displayed higher pathogenicity compared to the melanin stain and restoration of melanin of albino mutant could reverse the pathogenicity. Histopathology showed that inflammatory nodules were bigger than that infected with albino cells, which suggested that melanized cells could trigger a robust cellular immune response of G. mellonella than albino cells. The activated immune response in G. mellonella induced by melanized cells might explain the decreased virulence of melanized cells in larvae model. While further study was needed to gain full insights into the molecular immunological mechanism in G. mellonella activated by melanin.

Novel analgesic effects of melanin-concentrating hormone on persistent neuropathic and inflammatory pain in mice.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons in the lateral hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, indicating the involvements of many physiological functions, but the role in pain has yet to be determined. In this study, we found that pMCH-/- mice showed lower baseline pain thresholds to mechanical and thermal stimuli than did pMCH+/+ mice, and the time to reach the maximum hyperalgesic response was also significantly earlier in both inflammatory and neuropathic pain. To examine its pharmacological properties, MCH was administered intranasally into mice, and results indicated that MCH treatment significantly increased mechanical and thermal pain thresholds in both pain models. Antagonist challenges with naltrexone (opioid receptor antagonist) and AM251 (cannabinoid 1 receptor antagonist) reversed the analgesic effects of MCH in both pain models, suggesting the involvement of opioid and cannabinoid systems. MCH treatment also increased the expression and activation of CB1R in the medial prefrontal cortex and dorsolateral- and ventrolateral periaqueductal grey. The MCH1R antagonist abolished the effects induced by MCH. This is the first study to suggest novel analgesic actions of MCH, which holds great promise for the application of MCH in the therapy of pain-related diseases.

Contrast Between Orange- and Black-Colored Sclerotial Isolates of Botrytis cinerea: Melanogenesis and Ecological Fitness.

Botrytis cinerea usually produces grayish mycelia and conidia as well as black-colored sclerotia (BS) due to accumulation of melanin. An isolate (XN-1) of B. cinerea producing orange-colored sclerotia (OS) on agar media was obtained from an orange-colored apothecium of an uncultured soil fungus. Whether or not the OS B. cinerea occurs on plants and how they differ from the BS isolates in melanogensis and ecological fitness remained unknown. This study, for the first time, confirmed the presence of the OS B. cinerea in strawberry and tomato plants that were surveyed in Hubei Province of China. Only five OS isolates were obtained from a total of 2,031 isolates surveyed from the two crops. The OS isolate XN-1 was compared and contrasted with the BS isolate B05.10 in sclerotial melanogenesis and ecological fitness. Sclerotial melanogenesis was evident in B05.10 but was deficient in XN-1. The OS were more susceptible to the two mycoparasites Trichoderma koningiopsis and Clonostachys rosea than the BS. The percentage of viable sclerotia after the mycoparasitism study was significantly (P < 0.01) lower in OS (21%) than in BS (48%). This study also reaffirmed the importance of melanization for survival of B. cinerea sclerotia.

Computational analysis of histidine mutations on the structural stability of human tyrosinases leading to albinism insurgence.

Misfolding and structural alteration in proteins lead to serious malfunctions and cause various diseases in humans. Mutations at the active binding site in tyrosinase impair structural stability and cause lethal albinism by abolishing copper binding. To evaluate the histidine mutational effect, all mutated structures were built using homology modelling. The protein sequence was retrieved from the UniProt database, and 3D models of original and mutated human tyrosinase sequences were predicted by changing the residual positions within the target sequence separately. Structural and mutational analyses were performed to interpret the significance of mutated residues (N180, R202, Q202, R211, Y363, R367, Y367 and D390) at the active binding site of tyrosinases. CSpritz analysis depicted that 23.25% residues actively participate in the instability of tyrosinase. The accuracy of predicted models was confirmed through online servers ProSA-web, ERRAT score and VERIFY 3D values. The theoretical pI and GRAVY generated results also showed the accuracy of the predicted models. The CCA negative correlation results depicted that the replacement of mutated residues at His within the active binding site disturbs the structural stability of tyrosinases. The predicted CCA scores of Tyr367 (-0.079) and Q/R202 (0.032) revealed that both mutations have more potential to disturb the structural stability. MD simulation analyses of all predicted models justified that Gln202, Arg202, Tyr367 and D390 replacement made the protein structures more susceptible to destabilization. Mutational results showed that the replacement of His with Q/R202 and Y/R363 has a lethal effect and may cause melanin associated diseases such as OCA1. Taken together, our computational analysis depicts that the mutated residues such as Q/R202 and Y/R363 actively participate in instability and misfolding of tyrosinases, which may govern OCA1 through disturbing the melanin biosynthetic pathway.

Meta-analysis of melanin-concentrating hormone signaling-deficient mice on behavioral and metabolic phenotypes.

The demand for meta-analyses in basic biomedical research has been increasing because the phenotyping of genetically modified mice does not always produce consistent results. Melanin-concentrating hormone (MCH) has been reported to be involved in a variety of behaviors that include feeding, body-weight regulation, anxiety, sleep, and reward behavior. However, the reported behavioral and metabolic characteristics of MCH signaling-deficient mice, such as MCH-deficient mice and MCH receptor 1 (MCHR1)-deficient mice, are not consistent with each other. In the present study, we performed a meta-analysis of the published data related to MCH-deficient and MCHR1-deficient mice to obtain robust conclusions about the role of MCH signaling. Overall, the meta-analysis revealed that the deletion of MCH signaling enhanced wakefulness, locomotor activity, aggression, and male sexual behavior and that MCH signaling deficiency suppressed non-REM sleep, anxiety, responses to novelty, startle responses, and conditioned place preferences. In contrast to the acute orexigenic effect of MCH, MCH signaling deficiency significantly increased food intake. Overall, the meta-analysis also revealed that the deletion of MCH signaling suppressed the body weight, fat mass, and plasma leptin, while MCH signaling deficiency increased the body temperature, oxygen consumption, heart rate, and mean arterial pressure. The lean phenotype of the MCH signaling-deficient mice was also confirmed in separate meta-analyses that were specific to sex and background strain (i.e., C57BL/6 and 129Sv). MCH signaling deficiency caused a weak anxiolytic effect as assessed with the elevated plus maze and the open field test but also caused a weak anxiogenic effect as assessed with the emergence test. MCH signaling-deficient mice also exhibited increased plasma corticosterone under non-stressed conditions, which suggests enhanced activity of the hypothalamic-pituitary-adrenal axis. To the best of our knowledge, the present work is the first study to systematically compare the effects of MCH signaling on behavioral and metabolic phenotypes.

The genome sequence of the corn snake (Pantherophis guttatus), a valuable resource for EvoDevo studies in squamates.

Squamates (snakes and lizards) exhibit a striking variety of phenotypes, with little known on their generative mechanisms. Studies aiming to understand the genetic basis of this wide diversity in morphology, physiology and ecology will greatly benefit from whole genome sequencing initiatives, as they provide the foundation for comparative analyses and improve our understanding of the evolution, development and diversification of traits. Here, we present the first draft genome of the corn snake Pantherophis guttatus, an oviparous snake that we promote as a particularly appropriate model species for evolutionary developmental studies in squamates. We sequenced 100-base paired-end reads from multiple individuals of a single family (parents and offspring) that produced a genome assembly of 1.53 gigabases (Gb), roughly covering 75% of the expected total genome size, and 297,768 scaffolds >1 Kb. We were able to fully retrieve 86, and partially another 106, of the 248 CEGMA core genes, indicating that a high genome completeness was achieved, even though the assembly is fragmented. Using MAKER2, we annotated 10,917 genes with high confidence (Annotation Edit Distance (AED)<1) and an additional 5,263 predicted genes matched with the species' transcriptome. Numerous colour and colour pattern morphs exist in P. guttatus, making it an ideal model to study the genetic determinism, development, and evolution of adaptive colour traits in reptiles. Using our draft genome and a Single-Nucleotide Polymorphism (SNP) calling approach, we confirmed the interval with the causative mutation for the amelanistic phenotype, a result supported by a parallel exome-based study.

Melanin-concentrating hormone regulates beat frequency of ependymal cilia and ventricular volume.

Ependymal cell cilia help move cerebrospinal fluid through the cerebral ventricles, but the regulation of their beat frequency remains unclear. Using in vitro, high-speed video microscopy and in vivo magnetic resonance imaging in mice, we found that the metabolic peptide melanin-concentrating hormone (MCH) positively controlled cilia beat frequency, specifically in the ventral third ventricle, whereas a lack of MCH receptor provoked a ventricular size increase.

Pmch-deficiency in rats is associated with normal adipocyte differentiation and lower sympathetic adipose drive.

The orexigenic neuropeptide melanin-concentrating hormone (MCH), a product of Pmch, is an important mediator of energy homeostasis. Pmch-deficient rodents are lean and smaller, characterized by lower food intake, body-, and fat mass. Pmch is expressed in hypothalamic neurons that ultimately are components in the sympathetic nervous system (SNS) drive to white and interscapular brown adipose tissue (WAT, iBAT, respectively). MCH binds to MCH receptor 1 (MCH1R), which is present on adipocytes. Currently it is unknown if Pmch-ablation changes adipocyte differentiation or sympathetic adipose drive. Using Pmch-deficient and wild-type rats on a standard low-fat diet, we analyzed dorsal subcutaneous and perirenal WAT mass and adipocyte morphology (size and number) throughout development, and indices of sympathetic activation in WAT and iBAT during adulthood. Moreover, using an in vitro approach we investigated the ability of MCH to modulate 3T3-L1 adipocyte differentiation. Pmch-deficiency decreased dorsal subcutaneous and perirenal WAT mass by reducing adipocyte size, but not number. In line with this, in vitro 3T3-L1 adipocyte differentiation was unaffected by MCH. Finally, adult Pmch-deficient rats had lower norepinephrine turnover (an index of sympathetic adipose drive) in WAT and iBAT than wild-type rats. Collectively, our data indicate that MCH/MCH1R-pathway does not modify adipocyte differentiation, whereas Pmch-deficiency in laboratory rats lowers adiposity throughout development and sympathetic adipose drive during adulthood.

Reduced intestinal tumorigenesis in APCmin mice lacking melanin-concentrating hormone.

BACKGROUND: Melanin-concentrating hormone (MCH) is an evolutionary conserved hypothalamic neuropeptide that in mammals primarily regulates appetite and energy balance. We have recently identified a novel role for MCH in intestinal inflammation by demonstrating attenuated experimental colitis in MCH deficient mice or wild type mice treated with an anti-MCH antibody. Therefore, targeting MCH has been proposed for the treatment of inflammatory bowel disease. Given the link between chronic intestinal inflammation and colorectal cancer, in the present study we sought to investigate whether blocking MCH might have effects on intestinal tumorigenesis that are independent of inflammation. METHODOLOGY: Tumor development was evaluated in MCH-deficient mice crossed to the APCmin mice which develop spontaneously intestinal adenomas. A different cohort of MCH-/- and MCH+/+ mice in the APCmin background was treated with dextran sodium sulphate (DSS) to induce inflammation-dependent colorectal tumors. In Caco2 human colorectal adenocarcinoma cells, the role of MCH on cell survival, proliferation and apoptosis was investigated. RESULTS: APCmin mice lacking MCH developed fewer, smaller and less dysplastic tumors in the intestine and colon which at the molecular level are characterized by attenuated activation of the wnt/beta-catenin signaling pathway and increased apoptotic indices. Form a mechanistic point of view, MCH increased the survival of colonic adenocarcinoma Caco2 cells via inhibiting apoptosis, consistent with the mouse studies. CONCLUSION: In addition to modulating inflammation, MCH was found to promote intestinal tumorigenesis at least in part by inhibiting epithelial cell apoptosis. Thereby, blocking MCH as a therapeutic approach is expected to decrease the risk for colorectal cancer.

Ablation of the hypothalamic neuropeptide melanin concentrating hormone is associated with behavioral abnormalities that reflect impaired olfactory integration.

Melanin-concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide. At least one receptor, MCH receptor 1 (MCHR1), is present in all mammals and is expressed widely throughout the brain, including cortex, striatum and structures implicated in the integration of olfactory cues such as the piriform cortex and olfactory bulb. Consistent with a potential role for MCH in mediating olfactory function, MCH knockout mice demonstrate abnormal olfactory behaviors. These behaviors include impaired food seeking by both genders in the context of normal levels of exploratory behavior, suggesting impaired olfaction. Males also exhibit increased aggression while females show defects in several olfactory mediated behaviors including mating, estrous cycle synchronization and maternal behavior. These findings suggest that hypothalamic inputs through MCH play an important role in regulating sensory integration from olfactory pathways.

You deserve what you eat: lessons learned from the study of the melanin-concentrating hormone (MCH)-deficient mice.

OBJECTIVES: Diet plays a crucial role in the development of obesity and insulin resistance via multiple mechanisms. Saturated fatty acids can directly trigger tissue specific proinflammatory pathways via Toll-like receptor-4 (TLR4)-dependent mechanisms. Moreover, diet can change the gut microbiome and increase gut permeability. However, very few studies have addressed the obesity-independent role of diet. Dissecting the effects of diet from those of obesity per se will enhance our understanding of the underlying pathogenesis, and, at the translational level, advance our treatment approaches for obesity and its co-morbidities. METHODS: Melanin-concentrating hormone (MCH) is an important regulator of appetite and energy balance. MCH-deficient mice are resistant to diet-induced obesity, primarily due to increased locomotor activity. We took advantage of the unique phenotype of these mice to examine the metabolic and inflammatory consequences of a 15-week consumption of a diet high in saturated fat. RESULTS: MCH-deficient mice chronically exposed to a high-fat diet gain less weight compared to their wild-type littermates, despite similar food intake, and are protected from hepatosteatosis. They also lack obesity-associated upregulation of serum leptin and insulin levels and have improved total body insulin sensitivity. Nevertheless, we found indistinguishable liver-specific innate immune responses in both genotypes associated with high-fat feeding, which involved activation of TLR4 and its downstream effectors, MyD88, p38 MAP kinase and STAT-3. CONCLUSIONS: Our findings indicate that high-fat feeding is deleterious to the liver, independently of the obesity status. They also suggest that MCH is not necessary for the TLR4-dependent immune response triggered by the high-fat diet.

Identification and function of a polyketide synthase gene responsible for 1,8-dihydroxynaphthalene-melanin pigment biosynthesis in Ascochyta rabiei.

Ascochyta rabiei produces and accumulates one of the well-known fungal polyketides, 1,8-dihydroxynaphthalene-melanin pigment (DHN-melanin), in asexual and sexual fruiting bodies. Degenerate PCR primers were used to isolate an ArPKS1 of A. rabiei encoding a polypeptide with high similarity to polyketide synthase (PKS) involved in biosynthesis of DHN-melanin in other ascomycetous fungi. Site-directed mutagenesis of ArPKS1 in A. rabiei generated melanin-deficient pycnidial mutants but caused no significant reduction of pathogenicity to chickpea. Pycnidiospores in ArPKS1-mutant pycnidia showed higher sensitivity to UV light exposure compared to pycnidiospores in melanized pycnidia of the wild-type progenitor isolate. Integration of an orthologous PKS1 gene from Bipolaris oryzae into the genome of the mutants complemented the dysfunctional ArPKS1 gene. This study demonstrated that A. rabiei uses a DHN-melanin pathway for pigmentation of pycnidia and this molecule may protect pycnidiospores from UV irradiation.

Hipomelanosis macular progresiva / Progressive macular hypomelanosis

La hipomelanosis macular progresiva es una entidad poco conocida y, sin embargo, relativamente frecuente. Cursa con la aparición de máculas hipocrómicas asintomáticas en el tronco de adolescentes y adultos jóvenes, sin inflamación previa. La etiología de esta enfermedad es desconocida, pero se postula la posible intervención de cepas de Propionibacterium acnes. No tiene tratamiento eficaz, pero hay casos que responden a la fototerapia y la antibioterapia tópica (AU)

Progressive macular hypomelanosis is a little-known and yet relatively common condition. It presents with the appearance of asymptomatic hypochromic macules on the trunk of adolescents and young adults, without prior inflammation. This disease if of unknown a etiology, but is thought to involve the possible intervention of strains of Propionibacterium acnes. There is no efficient treatment for this disease, although certain cases respond to phototherapy and topical antibiotherapy (AU)

Absence of strial melanin coincides with age-associated marginal cell loss and endocochlear potential decline.

Cochlear stria vascularis contains melanin-producing intermediate cells that play a critical role in the production of the endocochlear potential (EP) and in maintaining the high levels of K(+) that normally exist in scala media. The melanin produced by intermediate cells can be exported to the intrastrial space, where it may be taken up by strial marginal cells and basal cells. Because melanin can act as an antioxidant and metal chelator, evidence for its role in protecting the stria and organ of Corti against noise, ototoxins, and aging has long been sought. While some evidence supports a protective role of melanin against noise and ototoxins, no evidence yet presented has demonstrated a clear role for melanin in maintaining the EP during aging. We tested this by comparing basal turn EPs and a host of cochlear cellular metrics in aging C57BL/6 (B6) mice and C57BL/6-Tyr(c-2J) mice. The latter mice carry a naturally occurring inactivating mutation of the tyrosinase locus, and produce no strial melanin. Because these two strains are coisogenic, and because pigmented B6 mice show essentially no age-related EP decline, they provide an ideal test of importance of melanin in the aging stria. Pigmented and albino B6 mice showed identical rates of hearing loss and sensory cell loss. However, after two years of age, basal turn EPs significantly diverged, with 42% of albinos showing EPs below 100 mV versus only 18% of pigmented mice. The clearest anatomical correlate of this EP difference was significantly reduced strial thickness in the albinos that was highly correlated with loss of marginal cells. Combined with findings in human temporal bones, plus recent work in BALB/c mice and gerbils, the present findings point to a common etiology in strial presbycusis whereby EP reduction is principally linked to marginal cell loss or dysfunction. For any individual, genetic background, environmental influences, and stochastic events may work together to determine whether marginal cell density or function falls below some critical level, and thus whether EP decline occurs.