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Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.
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Wildfires have increased in frequency in many ecosystems, with implications for human health and the environment, including water quality. Increased fire frequency and urbanization also raise the prospect of fires burning into urban areas, mobilizing pollutants few have considered to date. As a result, water quality managers lack information to anticipate, respond to and potentially mitigate wildfire impacts. Here, we reviewed the scientific literature to assess wildfire effects on response endpoints of a conceptual model linking fire to water quality, quantifying response directionality, magnitude and duration. Physically, water yield, sediments, and temperature all increased post-fire. Chemically, nutrients, ions, organic chemicals, and metals increased in burned watersheds, sometimes by orders of magnitude over pre-fire or reference conditions. In select cases, post-fire concentrations exceeded aquatic life criteria or drinking water standards, at times even in the finished drinking water. Biological assemblages commonly declined after post-fire runoff events. The duration of effects was less than 5 yr for most endpoints (e.g., metals) on average following fire, although effects did extend 15 yr or more in some individual cases. We found only a few studies on pollutants mobilized from wildfire impacted urban areas with benzene contamination in drinking water and high metal concentrations in ash prominent exceptions. Overall, this review provides a resource for understanding wildfire impacts on water quality endpoints, with the goal of informing the response of managers and other decision makers to this growing problem.
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Understanding hydrologic connectivity between wetlands and perennial streams is critical to understanding the reliance of stream flow on inputs from wetlands. We used the isotopic evaporation signal in water and remote sensing to examine wetland-stream hydrologic connectivity within the Pipestem Creek watershed, North Dakota, a watershed dominated by prairie-pothole wetlands. Pipestem Creek exhibited an evaporated-water signal that had approximately half the isotopic-enrichment signal found in most evaporatively enriched prairie-pothole wetlands. Groundwater adjacent to Pipestem Creek had isotopic values that indicated recharge from winter precipitation and had no significant evaporative enrichment, indicating that enriched surface water did not contribute significantly to groundwater discharging into Pipestem Creek. The estimated surface-water area necessary to generate the evaporation signal within Pipestem Creek was highly dynamic, varied primarily with the amount of discharge, and was typically greater than the immediate Pipestem Creek surface-water area, indicating that surficial flow from wetlands contributed to stream flow throughout the summer. We propose a dynamic range of spilling thresholds for prairie-pothole wetlands across the watershed allowing for wetland inputs even during low flow periods. Combining Landsat estimates with the isotopic approach allowed determination of potential (Landsat) and actual (isotope) contributing areas in wetland-dominated systems. This combined approach can give insights into the changes in location and magnitude of surface water and groundwater pathways over time. This approach can be used in other areas where evaporation from wetlands results in a sufficient evaporative isotopic signal.
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A positive-control, natural exposure noninferiority field study was conducted to test the efficacy of a novel glycolic acid-based postmilking barrier teat disinfectant compared with a commercial iodine-based postmilking barrier teat disinfectant (positive control). Cows from 2 pens from a California Central Valley dairy farm were dipped after milking either with the positive-control product (PC) or the experimental product (EX) over 12 wk. New intramammary infections (NIMI) were determined by biweekly sampling of all quarters of study cows and classified as a NIMI based on somatic cell count and milk bacteriological culture results. The mean quarter-level incidence risks during a 2 wk study period were 3.50% (EX) and 4.28% (PC). The majority of NIMI were caused by coagulase-negative staphylococci, followed by non-agalactiae streptococci. The study results indicated that EX was noninferior to PC, with a 17% relative efficacy (improvement) in reducing NIMI compared with the PC group. Also, quarter somatic cell count was not affected by the postmilking teat disinfectant used. Finally, the EX product was safe in terms of teat conditioning: teat condition scores were not different between study groups. The study concluded that the glycolic acid-based experimental post-dip barrier was noninferior to the control, and could be considered a safe and effective postmilking teat disinfectant.
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Desinfectantes , Yodo , Animales , Bovinos , Femenino , Glándulas Mamarias Animales , Mastitis Bovina/prevención & control , Leche/citología , Infecciones Estafilocócicas/veterinariaRESUMEN
Maternal consumption of a high-fat diet (HFD) during pregnancy is found to stimulate the genesis of hypothalamic orexigenic peptide neurons in the offspring, while HFD intake in adult animals produces a systemic low-grade inflammation which increases neuroimmune factors that may affect neurogenesis and neuronal migration. Building on this evidence and our recent study showing that the inflammatory chemokine, CCL2, stimulates the migration of hypothalamic neurons and expression of orexigenic neuropeptides, we tested here the possibility that prenatal exposure to a HFD in rats affects this chemokine system, both CCL2 and its receptors, CCR2 and CCR4, and alters its actions on hypothalamic neurons, specifically those expressing the neuropeptides, enkephalin (ENK) and galanin (GAL). Using primary dissociated hypothalamic neurons extracted from embryos on embryonic day 19, we found that prenatal HFD exposure compared to chow control actually reduces the expression of CCL2 in these hypothalamic neurons, while increasing CCR2 and CCR4 expression, and also reduces the sensitivity of hypothalamic neurons to CCL2. The HFD abolished the dose-dependent, stimulatory effect of CCL2 on the number of migrated neurons and even shifted its normal stimulatory effect on migrational velocity and distance traveled by control neurons to an inhibition of migration. Further, it abolished the dose-dependent, stimulatory effect of CCL2 on neuronal expression of ENK and GAL. These results demonstrate that prenatal HFD exposure greatly disturbs the functioning of the CCL2 chemokine system in embryonic hypothalamic neurons, reducing its endogenous levels and ability to promote the migration of neurons and their expression of orexigenic peptides.
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Quimiocina CCL2/metabolismo , Grasas de la Dieta/efectos adversos , Hipotálamo/embriología , Hipotálamo/metabolismo , Neuronas/metabolismo , Complicaciones del Embarazo/metabolismo , Animales , Movimiento Celular/fisiología , Células Cultivadas , Encefalinas/metabolismo , Femenino , Galanina/metabolismo , Embarazo , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores CCR2/metabolismo , Receptores CCR4/metabolismoRESUMEN
Gestational exposure to a fat-rich diet, while elevating maternal circulating fatty acids, increases in the offspring's hypothalamus and amygdala the proliferation and density of neurons that express neuropeptides known to stimulate consummatory behavior. To understand the relationship between these phenomena, this study examined in the brain of postnatal offspring (day 15) the effect of prenatal fat exposure on the transcription factor, peroxisome proliferator-activated receptor (PPAR) ß/δ, which is sensitive to fatty acids, and the relationship of PPAR ß/δ to the orexigenic neuropeptides, orexin, melanin-concentrating hormone, and enkephalin. Prenatal exposure to a fat-rich diet compared to low-fat chow increased the density of cells immunoreactive for PPAR ß/δ in the hypothalamic paraventricular nucleus (PVN), perifornical lateral hypothalamus (PFLH), and central nucleus of the amygdala (CeA), but not the hypothalamic arcuate nucleus or basolateral amygdaloid nucleus. It also increased co-labeling of PPAR ß/δ with the cell proliferation marker, BrdU, or neuronal marker, NeuN, and the triple labeling of PPAR ß/δ with BrdU plus NeuN, indicating an increase in proliferation and density of new PPAR ß/δ neurons. Prenatal fat exposure stimulated the double-labeling of PPAR ß/δ with orexin or melanin-concentrating hormone in the PFLH and enkephalin in the PVN and CeA and also triple-labeling of PPAR ß/δ with BrdU and these neuropeptides, indicating that dietary fat increases the genesis of PPAR ß/δ neurons that produce these peptides. These findings demonstrate a close anatomical relationship between PPAR ß/δ and the increased proliferation and density of peptide-expressing neurons in the hypothalamus and amygdala of fat-exposed offspring.
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Grasas de la Dieta/farmacología , Neuronas/fisiología , PPAR delta/metabolismo , PPAR-beta/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Amígdala del Cerebelo , Animales , Conducta Consumatoria , Dieta Alta en Grasa , Susceptibilidad a Enfermedades/metabolismo , Encefalinas/metabolismo , Femenino , Hormonas Hipotalámicas/metabolismo , Hipotálamo/citología , Melaninas/metabolismo , Neurogénesis , Hormonas Hipofisarias/metabolismo , Embarazo , Ratas Sprague-DawleyRESUMEN
The objective of this study was to complete a positive-control, natural exposure, noninferiority design field study to test the efficacy of a novel glycolic acid-based postmilking teat disinfectant as compared with a previously proven iodine-based postmilking teat disinfectant (positive control). The primary outcome of interest was the effect of treatment on incidence of new intramammary infections. Secondary outcomes included the effect of treatment on prevalence of infection, somatic cell count, and teat condition. After blocking by parity, approximately 300 early- to mid-lactation cows on a large Wisconsin dairy farm were randomly assigned to 1 of 2 groups. For a 12-wk period between May and August 2014, the 2 groups were dipped after each milking with either the experimental (EX) or positive control (PC) product. Individual quarters were sampled to establish bacteriological infection status at the beginning of the study, and every 2 wk thereafter, by use of a 2-stage process evaluating somatic cell count (SCC), and then culturing milk samples only when SCC exceeded a parity-specific threshold. Teat condition scoring was completed at the beginning of the study and on wk 4, 8, and 12. Mixed logistic regression was used to evaluate the effect of treatment on dichotomous outcome measures including the odds of acquiring a new infection during a given 2-wk sampling interval (incidence), the odds for presence of infection at sampling (prevalence), and odds for a normal teat skin condition score. Mixed linear regression was used to evaluate the effect of treatment on somatic cell count. For the noninferiority analysis, the upper bound of the 95% confidence interval for the difference in new infection rate between the 2 treatments (EX - PC), had to be to the left of the critical value d (0.035) to conclude that EX was noninferior relative to PC with respect to risk for new infections. Results showed that the incidence of new infections was not different for quarters dipped with EX (3.2%) as compared with PC (4.2%). Similarly, the prevalence of infection tended to be lower for quarters dipped with EX (3.92%) as compared with PC (5.03%). No overall difference was found between treatments when evaluating somatic cell count measures and teat condition scores. Because the upper bound of the 95% confidence interval of the new IMI rate difference was smaller than the predefined noninferiority limit, it was concluded that the experimental product was not inferior compared with the positive control. As such, the glycolic acid-based teat disinfectant evaluated in this study can be considered an effective postmilking teat disinfectant, as well as safe, in so far as the product was not irritating to teat skin and did not negatively affect skin condition measures, as compared with the positive control group.
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Desinfectantes/farmacología , Lactancia/efectos de los fármacos , Animales , Bovinos , Recuento de Células , Femenino , Glándulas Mamarias Animales/efectos de los fármacos , Mastitis Bovina/prevención & control , Leche/efectos de los fármacos , EsterilizaciónRESUMEN
Embryonic exposure to ethanol is known to affect neurochemical systems in rodents and increase alcohol drinking and related behaviors in humans and rodents. With zebrafish emerging as a powerful tool for uncovering neural mechanisms of numerous diseases and exhibiting similarities to rodents, the present report building on our rat studies examined in zebrafish the effects of embryonic ethanol exposure on hypothalamic neurogenesis, expression of orexigenic neuropeptides, and voluntary ethanol consumption and locomotor behaviors in larval and adult zebrafish, and also effects of central neuropeptide injections on these behaviors affected by ethanol. At 24h post-fertilization, zebrafish embryos were exposed for 2h to ethanol, at low concentrations of 0.25% and 0.5%, in the tank water. Embryonic ethanol compared to control dose-dependently increased hypothalamic neurogenesis and the proliferation and expression of the orexigenic peptides, galanin (GAL) and orexin (OX), in the anterior hypothalamus. These changes in hypothalamic peptide neurons were accompanied by an increase in voluntary consumption of 10% ethanol-gelatin and in novelty-induced locomotor and exploratory behavior in adult zebrafish and locomotor activity in larvae. After intracerebroventricular injection, these peptides compared to vehicle had specific effects on these behaviors altered by ethanol, with GAL stimulating consumption of 10% ethanol-gelatin more than plain gelatin food and OX stimulating novelty-induced locomotor behavior while increasing intake of food and ethanol equally. These results, similar to those obtained in rats, suggest that the ethanol-induced increase in genesis and expression of these hypothalamic peptide neurons contribute to the behavioral changes induced by embryonic exposure to ethanol.
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Depresores del Sistema Nervioso Central/farmacología , Embrión no Mamífero/efectos de los fármacos , Etanol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo , Neuropéptidos/metabolismo , Factores de Edad , Consumo de Bebidas Alcohólicas/patología , Análisis de Varianza , Animales , Bromodesoxiuridina/metabolismo , Proteína 3 Similar a ELAV/metabolismo , Proteína 4 Similar a ELAV/metabolismo , Femenino , Galanina/genética , Galanina/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Larva , Neurogénesis/efectos de los fármacos , Neuropéptidos/genética , Neuropéptidos/farmacología , Orexinas/genética , Orexinas/metabolismo , Embarazo , Pez CebraRESUMEN
Clinical and animal studies indicate that maternal consumption of ethanol during pregnancy increases alcohol drinking in the offspring. Possible underlying mechanisms may involve orexigenic peptides, which are stimulated by prenatal ethanol exposure and themselves promote drinking. Building on evidence that ethanol stimulates neuroimmune factors such as the chemokine CCL2 that in adult rats is shown to colocalize with the orexigenic peptide, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), the present study sought to investigate the possibility that CCL2 or its receptor CCR2 in LH is stimulated by prenatal ethanol exposure, perhaps specifically within MCH neurons. Our paradigm of intraoral administration of ethanol to pregnant rats, at low-to-moderate doses (1 or 3g/kg/day) during peak hypothalamic neurogenesis, caused in adolescent male offspring twofold increase in drinking of and preference for ethanol and reinstatement of ethanol drinking in a two-bottle choice paradigm under an intermittent access schedule. This effect of prenatal ethanol exposure was associated with an increased expression of MCH and density of MCH(+) neurons in LH of preadolescent offspring. Whereas CCL2(+) cells at this age were low in density and unaffected by ethanol, CCR2(+) cells were dense in LH and increased by prenatal ethanol, with a large percentage (83-87%) identified as neurons and found to colocalize MCH. Prenatal ethanol also stimulated the genesis of CCR2(+) and MCH(+) neurons in the embryo, which co-labeled the proliferation marker, BrdU. Ethanol also increased the genesis and density of neurons that co-expressed CCR2 and MCH in LH, with triple-labeled CCR2(+)/MCH(+)/BrdU(+) neurons that were absent in control rats accounting for 35% of newly generated neurons in ethanol-exposed rats. With both the chemokine and MCH systems believed to promote ethanol consumption, this greater density of CCR2(+)/MCH(+) neurons in the LH of preadolescent rats suggests that these systems function together in promoting alcohol drinking during adolescence.
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Consumo de Bebidas Alcohólicas/fisiopatología , Depresores del Sistema Nervioso Central/toxicidad , Etanol/toxicidad , Hormonas Hipotalámicas/metabolismo , Hipotálamo/efectos de los fármacos , Melaninas/metabolismo , Neuronas/metabolismo , Hormonas Hipofisarias/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Receptores CCR2/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Quimiocina CCL2/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Hormonas Hipotalámicas/genética , Hipotálamo/metabolismo , Recién Nacido , Masculino , Melaninas/genética , Neuronas/efectos de los fármacos , Fosfopiruvato Hidratasa/metabolismo , Hormonas Hipofisarias/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Recent studies in zebrafish have shown that exposure to ethanol in tank water affects various behaviors, including locomotion, anxiety and aggression, and produces changes in brain neurotransmitters, such as serotonin and dopamine. Building on these investigations, the present study had two goals: first, to develop a method for inducing voluntary ethanol intake in individual zebrafish, which can be used as a model in future studies to examine how this behavior is affected by various manipulations, and second, to characterize the effects of this ethanol intake on different behaviors and the expression of hypothalamic orexigenic peptides, galanin (GAL) and orexin (OX), which are known in rodents to stimulate consumption of ethanol and alter behaviors associated with alcohol abuse. Thus, we first developed a new model of voluntary intake of ethanol in fish by presenting this ethanol mixed with gelatin, which they readily consume. Using this model, we found that individual zebrafish can be trained in a short period to consume stable levels of 10% or 20% ethanol (v/v) mixed with gelatin and that their intake of this ethanol-gelatin mixture leads to pharmacologically relevant blood ethanol concentrations which are strongly, positively correlated with the amount ingested. Intake of this ethanol-gelatin mixture increased locomotion, reduced anxiety, and stimulated aggressive behavior, while increasing expression of GAL and OX in specific hypothalamic areas. These findings, confirming results in rats, provide a method in zebrafish for investigating with forward genetics and pharmacological techniques the role of different brain mechanisms in controlling ethanol intake.
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Consumo de Bebidas Alcohólicas , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Galanina/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Orexinas/metabolismo , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/patología , Consumo de Bebidas Alcohólicas/fisiopatología , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Etanol/sangre , Conducta Exploratoria/efectos de los fármacos , Femenino , Galanina/genética , Gelatina/administración & dosificación , Hipotálamo/metabolismo , Locomoción/efectos de los fármacos , Masculino , Neuropéptidos/genética , Neuropéptidos/metabolismo , Orexinas/genética , Tiempo de Reacción/genética , Pez CebraRESUMEN
Fat, ethanol, and nicotine share a number of properties, including their ability to reinforce behavior and produce overconsumption. To test whether these substances act similarly on the same neuronal populations in specific brain areas mediating these behaviors, we administered the substances short-term, using the same methods and within the same experiment, and measured their effects, in areas of the hypothalamus (HYPO), amygdala (AMYG), and nucleus accumbens (NAc), on mRNA levels of the opioid peptide, enkephalin (ENK), using in situ hybridization and on c-Fos immunoreactivity (ir) to indicate neuronal activity, using immunofluorescence histochemistry. In addition, we examined for comparison another reinforcing substance, sucrose, and also took measurements of stress-related behaviors and circulating corticosterone (CORT) and triglycerides (TG), to determine if they contribute to these substances' behavioral and physiological effects. Adult Sprague-Dawley rats were gavaged three times daily over 5 days with 3.5 mL of water, Intralipid (20% v/v), ethanol (12% v/v), nicotine (0.01% w/v) or sucrose (22% w/v) (approximately 7 kcal/dose), and tail vein blood was collected for measurements of circulating CORT and TG. On day five, animals were sacrificed, brains removed, and the HYPO, AMYG, and NAc processed for single- or double-labeling of ENK mRNA and c-Fos-ir. Fat, ethanol, and nicotine, but not sucrose, increased the single- and double-labeling of ENK and c-Fos-ir in precisely the same brain areas, the middle parvocellular but not lateral area of the paraventricular nucleus, central but not basolateral nucleus of the AMYG, and core but not shell of the NAc. While having little effect on stress-related behaviors or CORT levels, fat, ethanol, and nicotine all increased circulating levels of TG. These findings suggest that the overconsumption of these three substances and their potential for abuse are mediated by the same populations of ENK-expressing neurons in specific nuclei of the hypothalamus and limbic system.
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Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encefalinas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Animales , Depresores del Sistema Nervioso Central/farmacología , Corticosterona/sangre , Sacarosa en la Dieta/administración & dosificación , Emulsiones/administración & dosificación , Etanol/farmacología , Emulsiones Grasas Intravenosas/administración & dosificación , Técnica del Anticuerpo Fluorescente , Hibridación in Situ , Masculino , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fosfolípidos/administración & dosificación , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Aceite de Soja/administración & dosificación , Triglicéridos/sangreRESUMEN
Exposure to ethanol during the prenatal period contributes to increased alcohol consumption and preference in rodents and increased risk for alcoholism in humans. With studies in adult animals showing the orexigenic peptides, enkephalin (ENK), galanin (GAL) and orexin (OX), to stimulate ethanol consumption, the question addressed here is whether prenatal ethanol alters the development in utero of specific neurons that express these peptides. With reports describing suppressive effects of high doses of ethanol, we examined the offspring of dams gavaged from embryonic day 9 to parturition with a control solution or lower ethanol doses, 1 and 3g/kg/day, known to promote ethanol consumption in the offspring. To understand underlying mechanisms, measurements were taken in postnatal offspring of the expression of ENK in the hypothalamic paraventricular nucleus (PVN) and nucleus accumbens (NAc), GAL in the PVN, and OX in the perifornical lateral hypothalamus (PFLH) using real-time qPCR and in situ hybridization, and also of the cell proliferation marker, 5-bromo-2-deoxyuridine (BrdU), and its double-labeling with either neuronal nuclei (NeuN), a marker of mature neurons, or the peptides. On postnatal day 15 (P15), after two weeks without ethanol, the offspring showed increased expression of ENK in the PVN and NAc core but not shell, GAL in the PVN, and OX in the PFLH. In these same areas, prenatal ethanol compared to control increased the density at birth (P0) of neurons expressing these peptides and at P0 and P15 of neurons double-labeling BrdU and NeuN, indicating increased neurogenesis. These BrdU-positive neurons were found to express ENK, GAL and OX, indicating that prenatal ethanol promotes neurogenesis in these specific peptide systems. There were no changes in gliogenesis or apoptosis. This increase in neurogenesis and density of peptide-expressing neurons suggests the involvement of these hypothalamic and accumbal peptide systems in mediating the increased alcohol consumption observed in prenatal ethanol-exposed offspring.
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Alcoholismo/etiología , Depresores del Sistema Nervioso Central/efectos adversos , Etanol/efectos adversos , Hipotálamo/metabolismo , Sistema Límbico/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/psicología , Alcoholismo/psicología , Animales , Antimetabolitos , Encéfalo/patología , Bromodesoxiuridina , Depresores del Sistema Nervioso Central/sangre , Digoxigenina , Encefalinas/biosíntesis , Etanol/sangre , Femenino , Técnica del Anticuerpo Fluorescente , Galanina/biosíntesis , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Hibridación in Situ , Etiquetado Corte-Fin in Situ , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Sistema Límbico/efectos de los fármacos , Neuropéptidos/biosíntesis , Neuropéptidos/fisiología , Orexinas , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The nucleus accumbens shell (NAcS) has been implicated in controlling stress responses through corticotropin-releasing factor (CRF). In addition to studies indicating that CRF in the NAcS increases appetitive motivation, there is indirect evidence suggesting that NAcS CRF may also cause aversive responses and that these behaviors may be mediated through local dopamine (DA) and acetylcholine (ACh) systems. To provide a direct test of this hypothesis, we used male Sprague-Dawley rats with implanted cannulas aimed at the NAcS. Experiment 1 showed local CRF injection (10 or 50 ng/side) to increase immobility in the forced swim test and a CRF antagonist D-Phe-CRF ((12-41)) to attenuate this depressive-like behavior. In Experiment 2, injection of CRF (250 ng/side) also decreased the rats' preference for sucrose, while in Experiment 3, CRF (50 or 250 ng/side) induced anxiety-like behaviors in an elevated plus maze and open field. These same doses of CRF in Experiment 4 failed to alter the rats' locomotor activity, indicating that these behavioral changes were not caused by deficits in activity. In Experiment 5, results from in vivo microdialysis revealed that CRF in the NAcS markedly increased local extracellular ACh, while also producing a small increase in DA. These results show that NAcS CRF can generate a variety of aversive behaviors, including swim depression, anhedonia, and anxiety, in addition to approach behavior. They suggest that these behaviors may occur, in part, through enhanced activation of ACh and DA in the NAcS, respectively, supporting a role for this brain area in mediating the dual effects of stress.
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Conducta Animal/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Núcleo Accumbens/metabolismo , Estrés Psicológico/metabolismo , Acetilcolina/análisis , Acetilcolina/metabolismo , Anhedonia/fisiología , Animales , Ansiedad/metabolismo , Depresión/metabolismo , Dopamina/análisis , Dopamina/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , NataciónRESUMEN
Recent studies show that the non-opioid peptides, galanin (GAL) and orexin (OX), are similar to the opioid enkephalin (ENK) in being stimulated by dietary fat and also in enhancing the consumption of a high-fat diet (HFD). This suggests that, when an HFD is provided, these non-opioids may stimulate the opioid system to promote excess consumption of this diet. Using single- and double-labeling immunohistochemistry, the present study sought to identify possible neuroanatomical substrates for this close relationship. Focusing on the hypothalamic paraventricular nucleus (PVN), and particularly its anterior (aPVN), middle (mPVN) and posterior (pPVN) parts, the experiments examined whether GAL itself or the receptors for GAL and OX are stimulated by an HFD in the same areas and possibly the same neurons as ENK. Compared to animals fed a standard chow diet, rats consuming an HFD exhibited an increased density of medial parvocellular neurons immunoreactive (IR) for GAL in the mPVN and aPVN and for ENK in the mPVN and pPVN, distinguishing the mPVN as an area where both peptides were affected. While showing little evidence for GAL and ENK colocalization with a chow diet, double-labeling studies in HFD-fed rats revealed significant colocalization specifically in medial parvocellular neurons of the mPVN. Immediately posterior to this site, further analyses revealed a similar relationship between the OX 2 receptor (OX(2)R) and ENK in HFD-treated animals. While increasing the density of neurons immunoreactive for OX(2)R as well as for the GAL 1 receptor but not OX 1 receptor, HFD consumption increased the colocalization only of OX(2)R and ENK, specifically in the medial parvocellular neurons of the pPVN. These changes in HFD-fed rats, showing GAL and OX(2)R to colocalize with ENK exclusively in neurons of the medial parvocellular mPVN and pPVN, respectively, suggest possible neural substrates through which the non-opioid peptides may functionally interact with ENK when exposed to an HFD.
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Grasas de la Dieta/administración & dosificación , Encefalinas/metabolismo , Flavonoides/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Animales , Masculino , Neuronas/metabolismo , Receptores de Orexina , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Sucrose-rich diets compared to starch-rich diets are known to stimulate overeating under chronic conditions. The present study in normal-weight rats established an acute "preload-to-test meal" paradigm for demonstrating sucrose-induced hyperphagia and investigating possible mechanisms that mediate this behavioral phenomenon. In this acute paradigm, the rats were first given a small (15 kcal) sucrose preload (30% sucrose) for 30 min compared to an equicaloric, starch preload (25% starch with 5% sucrose) and then allowed to freely consume a subsequent test meal of lab chow. The sucrose preload, when compared to a starch preload equal in energy density and palatability, consistently increased food intake in the subsequent test meal occurring between 60 and 120 min after the end of the preload. Measurements of hormones, metabolites and hypothalamic peptides immediately preceding this hyperphagia revealed marked differences between the sucrose vs starch groups that could contribute to the increase in food intake. Whereas the sucrose group compared to the starch group immediately after the preload (at 10 min) had elevated levels of glucose in serum and cerebrospinal fluid (CSF) along with reduced expressions of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC), the subsequent effects (at 30-60 min) just preceding the test meal hyperphagia were the reverse. Along with lower levels of glucose, they included markedly elevated serum and CSF levels of corticosterone and mRNA levels of NPY and AgRP in the ARC. In addition to establishing an animal model for sucrose-induced hyperphagia, these results demonstrate peripheral and central mechanisms that may mediate this behavioral phenomenon.
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Núcleo Arqueado del Hipotálamo/metabolismo , Corticosterona/metabolismo , Hiperfagia/inducido químicamente , Péptidos/metabolismo , Sacarosa/efectos adversos , Animales , Secuencia de Bases , Cartilla de ADN , Hibridación in Situ , Masculino , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-DawleyRESUMEN
The peptide melanin-concentrating hormone (MCH), produced mainly by cells in the lateral hypothalamus (LH), perifornical area (PF) and zona incerta (ZI), is suggested to have a role in the consumption of rewarding substances, such as ethanol, sucrose and palatable food. However, there is limited information on the specific brain sites where MCH acts to stimulate intake of these rewarding substances and on the feedback effects that their consumption has on the expression of endogenous MCH. The current study investigated MCH in relation to ethanol consumption, in Sprague-Dawley rats. In Experiment 1, chronic consumption of ethanol (from 0.70 to 2.7 g/kg/day) dose-dependently reduced MCH gene expression in the LH. In Experiments 2-4, the opposite effect was observed with acute oral ethanol, which stimulated MCH expression specifically in the LH but not the ZI. In Experiment 5, the effect of MCH injection in brain-cannulated rats on ethanol consumption was examined. Compared to saline, MCH injected in the paraventricular nucleus (PVN) and nucleus accumbens (NAc) selectively stimulated ethanol consumption without affecting food or water intake. In contrast, it reduced ethanol intake when administered into the LH, while having no effect in the ZI. These results demonstrate that voluntary, chronic consumption of ethanol leads to local negative feedback control of MCH expression in the LH. However, with a brief exposure, ethanol stimulates MCH-expressing neurons in this region, which through projections to the feeding-related PVN and reward-related NAc can promote further drinking behavior.
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Consumo de Bebidas Alcohólicas/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Área Hipotalámica Lateral/metabolismo , Hormonas Hipotalámicas/metabolismo , Melaninas/metabolismo , Hormonas Hipofisarias/metabolismo , Análisis de Varianza , Animales , Mapeo Encefálico , Relación Dosis-Respuesta a Droga , Retroalimentación Fisiológica , Fórnix/efectos de los fármacos , Fórnix/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Área Hipotalámica Lateral/efectos de los fármacos , Hormonas Hipotalámicas/administración & dosificación , Hormonas Hipotalámicas/genética , Masculino , Melaninas/administración & dosificación , Melaninas/genética , Microinyecciones , Vías Nerviosas/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Hormonas Hipofisarias/administración & dosificación , Hormonas Hipofisarias/genética , Ratas , Ratas Sprague-Dawley , Subtálamo/efectos de los fármacos , Subtálamo/metabolismoRESUMEN
Recent studies have shown that the opioid enkephalin (ENK), acting in part through the hypothalamic paraventricular nucleus (PVN), can stimulate consumption of a high-fat diet. The objective of the present study was to examine sub-populations of Sprague-Dawley rats naturally prone to overconsuming a high-fat diet and determine whether endogenous ENK, in different brain regions, is altered in these animals and possibly contributes to their behavioral phenotype. An animal model, involving a measure of initial high-fat diet intake during a few days of access that predicts long-term intake, was designed to classify rats at normal weight that are either high-fat consumers (HFC), which ingest 35% more calories of the high-fat than low-fat chow diet, or controls, which consume similar calories of these two diets. Immediately after their initial access to the diet, the HFC compared to control rats exhibited significantly greater expression of ENK mRNA, in the PVN, nucleus accumbens and central nucleus of the amygdala, but not the arcuate nucleus or basolateral amygdala. This site-specific increase in ENK persisted even when the HFC rats were maintained on a chow diet, suggesting that it reflects an inherent characteristic that can be expressed independently of the diet. It was also accompanied by a greater responsiveness of the HFC rats to the stimulatory effect of a PVN-injected, ENK analogue, D-ala2-met-enkephalinamide, compared to saline on consumption of the high-fat diet. Thus, normal-weight rats predicted to overconsume a fat-rich diet exhibit disturbances in endogenous ENK expression and functioning that may contribute to their long-term, behavioral phenotype.
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Amígdala del Cerebelo/metabolismo , Mapeo Encefálico , Encefalinas/metabolismo , Hiperfagia/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Animales , Grasas de la Dieta , Ingestión de Energía/fisiología , Encefalinas/genética , Preferencias Alimentarias/fisiología , Masculino , Vías Nerviosas/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
Recent studies in normal-weight rats have linked circulating triglycerides (TG), when elevated by a high-fat (HF) compared to equicaloric low-fat (LF) meal, to an increase in subsequent food intake and hypothalamic expression of orexigenic peptides. The present study tested whether natural variations between rats in their TG levels after a small HF meal can also be related to their individual patterns of eating and peptide expression. In tail vein blood collected on three separate days 60 min after a HF meal, levels of TG were found to be strongly, positively correlated within rats from day to day but were highly variable between rats (75-365 mg/dl), allowing distinct subgroups (33% lowest or highest) to be formed. Compared to "Low-TG responders" with post-meal levels averaging 109 mg/dl, "High-TG responders" with 240 mg/dl showed in two separate experiments a significant increase in caloric intake in a subsequent laboratory chow meal. Before this larger meal, these rats with elevated TG consistently exhibited higher expression levels and synthesis of the orexigenic peptides, enkephalin, orexin and melanin-concentrating hormone, as revealed using real-time quantitative PCR, radiolabeled in situ hybridization, and immunofluorescence histochemistry. Over the long-term, the High-TG responders also showed an increased propensity to overeat, gain weight and accumulate excess body fat on a chronic HF diet. This simple measure of TG levels after a HF meal may offer a useful tool for identifying subpopulations with increased risk for overeating and dietary obesity and detecting early signs of brain disturbances that may contribute to this high-risk phenotype.
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Ingestión de Energía/fisiología , Hipotálamo/metabolismo , Neuropéptidos/metabolismo , Obesidad/metabolismo , Triglicéridos/sangre , Tejido Adiposo/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Peso Corporal/fisiología , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/sangre , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Técnica del Anticuerpo Fluorescente , Hormonas Hipotalámicas/genética , Hormonas Hipotalámicas/metabolismo , Procesamiento de Imagen Asistido por Computador , Hibridación in Situ , Insulina/sangre , Leptina/sangre , Masculino , Melaninas/genética , Melaninas/metabolismo , Microscopía Fluorescente , Neuropéptidos/genética , Hormonas Hipofisarias/genética , Hormonas Hipofisarias/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Puberty is a time of rapid change, including a marked increase in fat consumption and body fat accrual, particularly in females. The mechanisms underlying these changes are unknown. Building on the results obtained in adult rats, the present study in pubertal rats focused on the orexigenic peptides, galanin (GAL) and enkephalin (ENK), in the paraventricular nucleus (PVN) and medial preoptic nucleus (MPN), which are known to be responsive to female steroids and have a role in both energy balance and reproductive function. The present study examined female rats maintained on pure macronutrient diets from before weaning (day 15) to day 70. After an initial burst in protein intake (days 21-35), rats showed an increase, specifically in preference for fat, from 15% to 30%. In rats examined at different ages before (day 30) and after (days 45 and 60) puberty, this rise in fat intake was associated with a marked increase, from days 30-45, in levels of oestradiol and progesterone and in GAL and ENK mRNA or peptide levels, specifically in the PVN and MPN, but not other hypothalamic areas examined. This positive relationship with increased fat intake, steroids and peptides across ages was also observed when comparing pubertal rats that naturally preferred fat (> 25% of total diet) with those consuming little fat (< 15%) or rats that reached puberty at an early age (days 30-34) with those that were late (days 37-40). These rats with early puberty onset exhibited a strong fat preference 3-4 days before vaginal opening, which was positively related to steroid levels, GAL, fat intake and body fat accrual after puberty. These findings suggest that, in addition to providing a signal for puberty onset, early fat ingestion acting through mechanisms involving the steroids and orexigenic peptides may be related to long-term patterns of eating and body weight regulation.
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Grasas de la Dieta , Encefalinas/metabolismo , Galanina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Área Preóptica/metabolismo , Esteroides/metabolismo , Animales , Peso Corporal , Encéfalo/metabolismo , Dieta , Ingestión de Alimentos , Encefalinas/genética , Estrógenos/metabolismo , Femenino , Galanina/genética , Masculino , Ovario/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Embarazo , Área Preóptica/citología , Progesterona/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Previous studies in male rats have demonstrated that the orexigenic peptide galanin (GAL), in neurones of the anterior parvocellular region of the paraventricular nucleus (aPVN) projecting to the median eminence (ME), is stimulated by consumption of a high-fat diet and may have a role in the hyperphagia induced by fat. In addition to confirming this relationship in female rats and distinguishing the aPVN-ME from other hypothalamic areas, the present study identified two additional extra-hypothalamic sites where GAL is stimulated by dietary fat in females but not males. These sites were the medial preoptic nucleus (MPN), located immediately rostral to the aPVN, and the anterior pituitary (AP). The involvement of ovarian steroids, oestradiol (E(2)) and progesterone (PROG), in this phenomenon was suggested by an observed increase in circulating levels of these hormones and GAL in MPN and AP with fat consumption and an attenuation of this effect on GAL in ovariectomised (OVX) rats. Furthermore, in the same four areas affected by dietary fat, levels of GAL mRNA and peptide immunoreactivity were stimulated by E(2) and further by PROG replacement in E(2)-primed OVX rats and were higher in females compared to males. Because both GAL and PROG stimulate feeding, their increase on a fat-rich diet may have functional consequences in females, possibly contributing to the increased caloric intake induced by dietary fat. This is supported by the findings that PROG administration in E(2)-primed OVX rats reverses the inhibitory effect of E(2) on total caloric intake while increasing voluntary fat ingestion, and that female rats with higher GAL exhibit increased preference for fat compared to males. Thus, ovarian steroids may function together with GAL in a neurocircuit, involving the MPN, aPVN, ME and AP, which coordinate feeding behaviour with reproductive function to promote consumption of a fat-rich diet at times of increased energy demand.