RESUMEN
Female puberty is subject to Polycomb Group (PcG)-dependent transcriptional repression. Kiss1, a puberty-activating gene, is a key target of this silencing mechanism. Using a gain-of-function approach and a systems biology strategy we now show that EED, an essential PcG component, acts in the arcuate nucleus of the hypothalamus to alter the functional organization of a gene network involved in the stimulatory control of puberty. A central node of this network is Kdm6b, which encodes an enzyme that erases the PcG-dependent histone modification H3K27me3. Kiss1 is a first neighbor in the network; genes encoding glutamatergic receptors and potassium channels are second neighbors. By repressing Kdm6b expression, EED increases H3K27me3 abundance at these gene promoters, reducing gene expression throughout a gene network controlling puberty activation. These results indicate that Kdm6b repression is a basic mechanism used by PcG to modulate the biological output of puberty-activating gene networks.
Asunto(s)
Histona Demetilasas con Dominio de Jumonji/genética , Kisspeptinas/genética , Complejo Represivo Polycomb 2/genética , Pubertad/genética , Animales , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Humanos , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Neuronas/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Proteínas del Grupo Polycomb/genética , Regiones Promotoras Genéticas/genética , Pubertad/fisiología , Ratas , Biología de SistemasRESUMEN
Research into the physiological actions of anti-Müllerian hormone (AMH) has rapidly expanded from its classical role in male sexual differentiation to the regulation of ovarian function, routine clinical use in reproductive health and potential use as a biomarker in the diagnosis of polycystic ovary syndrome (PCOS). During the past 10 years, the notion that AMH could act exclusively at gonadal levels has undergone another paradigm shift as several exciting studies reported unforeseen AMH actions throughout the Hypothalamic-Pituitary-Gonadal (HPG) axis. In this review, we will focus on these findings reporting novel AMH actions across the HPG axis and we will discuss their potential impact and significance to better understand human reproductive disorders characterized by either developmental alterations of neuroendocrine circuits regulating fertility and/or alterations of their function in adult life. Finally, we will summarize recent preclinical studies suggesting that elevated levels of AMH may potentially be a contributing factor to the central pathophysiology of PCOS and other reproductive diseases.
Asunto(s)
Hormona Antimülleriana/metabolismo , Gónadas/metabolismo , Hipotálamo/metabolismo , Hipófisis/metabolismo , Femenino , Humanos , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Reproducción , Transducción de SeñalRESUMEN
The paraventricular nucleus (PVN) of the hypothalamus harbors diverse neurosecretory cells with critical physiological roles for the homeostasis. Decades of research in rodents have provided a large amount of information on the anatomy, development, and function of this important hypothalamic nucleus. However, since the hypothalamus lies deep within the brain in mammals and is difficult to access, many questions regarding development and plasticity of this nucleus still remain. In particular, how different environmental conditions, including stress exposure, shape the development of this important nucleus has been difficult to address in animals that develop in utero. To address these open questions, the transparent larval zebrafish with its rapid external development and excellent genetic toolbox offers exciting opportunities. In this review, we summarize recent information on the anatomy and development of the neurosecretory preoptic area (NPO), which represents a similar structure to the mammalian PVN in zebrafish. We will then review recent studies on the development of different cell types in the neurosecretory hypothalamus both in mouse and in fish. Lastly, we discuss stress-induced plasticity of the PVN mainly discussing the data obtained in rodents, but pointing out tools and approaches available in zebrafish for future studies. This review serves as a primer for the currently available information relevant for studying the development and plasticity of this important brain region using zebrafish.
Asunto(s)
Hipotálamo/anatomía & histología , Hipotálamo/crecimiento & desarrollo , Plasticidad Neuronal/fisiología , Sistemas Neurosecretores/anatomía & histología , Sistemas Neurosecretores/crecimiento & desarrollo , Pez Cebra/anatomía & histología , Pez Cebra/crecimiento & desarrollo , Animales , Área Preóptica/anatomía & histología , Área Preóptica/crecimiento & desarrollo , Estrés FisiológicoRESUMEN
Increasing evidence suggests that multiple factors can produce effects on the immature brain that are distinct and more long-lasting than those produced in adults. The hypothalamic paraventricular nucleus (PVN) is a region integral to the hypothalamic-pituitary-adrenal axis and is affected by anxiety, depression, and drugs used to treat these disorders, yet receptor signaling mechanisms operative in hypothalamus prior to maturation remain to be elucidated. In peripubertal male rats, systemic injection of the selective serotonin 1A (5-HT1A) receptor agonist (+)8-OH-DPAT (0.2 mg/kg) markedly elevated plasma levels of oxytocin and adrenocorticotropic hormone (ACTH) at 5 and 15 min post-injection. The 5-HT1A receptor selectivity was demonstrated by the ability of the 5-HT1A receptor selective antagonist WAY100635 to completely block both oxytocin and ACTH responses at 5 min, with some recovery of the ACTH response at 15 min. At 15 min post-injection, (+)8-OH-DPAT also increased levels of phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated protein kinase B (pAkt) in the PVN. As previously observed in adults, (+)8-OH-DPAT reduced levels of pERK in hippocampus. WAY100635 also completely blocked (+)8-OH-DPAT-mediated elevations in hypothalamic pERK and pAkt and the reductions in hippocampal pERK, demonstrating 5-HT1A receptor selectivity of both kinase responses. This study provides the first demonstration of functional 5-HT1A receptor-mediated ERK and Akt signaling pathways in the immature hypothalamus, activated by a dose of (+)8-OH-DPAT that concomitantly stimulates neuroendocrine responses. This information is fundamental to identifying potential signaling pathways targeted by biased agonists in the development of safe and effective treatment strategies in children and adolescents.
Asunto(s)
Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Proteínas Quinasas/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Hipotálamo/efectos de los fármacos , Masculino , Sistemas Neurosecretores/efectos de los fármacos , Piperazinas/farmacología , Piridinas/farmacología , Ratas Sprague-Dawley , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Maduración SexualRESUMEN
Vitamin D (VitD) deficiency affects more than 1 billion people worldwide with a higher prevalence in reproductive-aged women and children. The physiological effects of maternal VitD deficiency on the reproductive health of the offspring has not been studied. To determine whether maternal VitD deficiency affects reproductive physiology in female offspring, we monitored the reproductive physiology of C57BL/6J female offspring exposed to diet-induced maternal VitD deficiency at three specific developmental stages: 1) in utero, 2) preweaning, or 3) in utero and preweaning. We hypothesized that exposure to maternal VitD deficiency disrupts reproductive function in exposed female offspring. To test this hypothesis, we assessed vaginal opening and cytology and ovary and pituitary function as well as gonadotropin and gonadal steroid levels in female offspring. The in utero, preweaning, and in utero and preweaning VitD deficiency did not affect puberty. However, all female mice exposed to maternal VitD deficiency developed prolonged and irregular estrous cycles characterized by oligoovulation and extended periods of diestrus. Despite similar gonadal steroid levels and GnRH neuron density, females exposed to maternal VitD deficiency released less LH on the evening of proestrus. When compared with control female offspring, there was no significant difference in the ability of females exposed to maternal VitD deficiency to respond robustly to exogenous GnRH peptide or controlled ovarian hyperstimulation. These findings suggest that maternal VitD deficiency programs reproductive dysfunction in adult female offspring through adverse effects on hypothalamic function.
Asunto(s)
Sistemas Neurosecretores/fisiopatología , Complicaciones del Embarazo/fisiopatología , Reproducción/fisiología , Deficiencia de Vitamina D/fisiopatología , Animales , Animales Recién Nacidos , Femenino , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiopatología , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Masculino , Ratones Endogámicos C57BL , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Ovario/embriología , Ovario/crecimiento & desarrollo , Ovario/fisiopatología , Hipófisis/embriología , Hipófisis/crecimiento & desarrollo , Hipófisis/fisiopatología , Embarazo , Maduración Sexual/fisiología , Factores de Tiempo , DesteteRESUMEN
There is increasing evidence to suggest that the perinatal environment may alter the developmental programming of hypothalamic neuroendocrine systems in a manner that predisposes offspring to the development of metabolic syndrome. Although it is unclear how these effects might be mediated, it has been shown that changes in neuroendocrine programing during critical periods of development, either via maternal metabolic programming or other factors, can alter a fetus's metabolic fate. This review summarizes the hypothalamic circuits that mediate energy homeostasis and discusses the various factors that may influence the development and functioning of these neural systems, as well as the possible cognitive impairments that may arise as a result of these metabolic influences.
Asunto(s)
Desarrollo Fetal , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiología , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/fisiología , Animales , Metabolismo Energético/fisiología , Femenino , Humanos , EmbarazoRESUMEN
In this review for the first time systematized available in modern literature data, which characterize the structural and functional organization of the reproductive centers of corticomedial division of the Amygdala. Given information about physiological mechanisms of their involvement in the organization of sexual behavior, regulation of secretion and excretion of gonadotropines, influence on the processes of sexual maturation of organisms. Involvement of Amygdala in functional systems of the brain, which determine reproductive functions, predefined its participation in the processes of sexual differentiation of the brain. Important role in the implementation of reproductive functions plays the olfactory stimuli, which through the Amygdala switches to the centers of the pre-optic-hypothalamic region, which controls the secretion of gonadotropins and sexual behavior.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Encéfalo/metabolismo , Gonadotropinas/metabolismo , Sistemas Neurosecretores/fisiología , Amígdala del Cerebelo/fisiología , Animales , Encéfalo/crecimiento & desarrollo , Complejo Nuclear Corticomedial , Humanos , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Ratas , Reproducción/fisiología , Diferenciación Sexual/fisiología , Conducta Sexual/fisiología , Maduración Sexual/fisiologíaRESUMEN
BACKGROUND: In this study discussed the primary and regulatory roles of fatty acids, and investigated the affects of fatty acids on metabolic programming. METHODS: Review of the literature was carried out on three electronic databases to assess the roles of fatty acids in metabolic programming. All abstracts and full-text articles were examined, and the most relevant articles were selected for screening and inclusion in this review. RESULTS: The mother's nutritional environment during fetal period has important effects on long term health. Fatty acids play a primary role in growth and development. Alterations in fatty acid intake in the fetal period may increase the risk of obesity and metabolic disorders in later life. Maternal fatty acid intakes during pregnancy and lactation are passed to the fetus and the newborn via the placenta and breast milk, respectively. Imbalances in fatty acid intake during the fetal period change the fatty acid composition of membrane phospholipids, which can cause structural and functional problems in cells. Additionally, the metabolic and neuroendocrine environments of the fetus and the newborn play key roles in the regulation of energy balance. CONCLUSIONS: Imbalances in fatty acid intake during pregnancy and lactation may result in permanent changes in appetite control, neuroendocrine function and energy metabolism in the fetus, leading to metabolic programming. Further studies are needed to determine the role of fatty acid intake in metabolic programming.
Asunto(s)
Desarrollo Infantil , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/administración & dosificación , Desarrollo Fetal , Fenómenos Fisiológicos Nutricionales del Lactante , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Grasas de la Dieta/metabolismo , Ingestión de Energía , Metabolismo Energético , Ácidos Grasos/metabolismo , Femenino , Humanos , Lactante , Recién Nacido , Metabolismo de los Lípidos , Masculino , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , EmbarazoRESUMEN
Testis growth during early life is important for future male fertility and shows acceleration during the first months of life in humans. This acceleration coincides with the peak in gonadotropic hormones in the blood, while the role of hypothalamic factors remains vague. Using neonatal rats to assess this issue, we found that day 9 of life is likely critical for testis development in rats. Before this day, testicular growth was proportional to body weight gain, but after that the testes showed accelerated growth. Hypothalamic kisspeptin and its receptor mRNA levels begin to elevate 2 days later, at day 11. A significant increase in the mRNA levels for gonadotropin-releasing hormone (GnRH) receptors in the hypothalamus between days 5 and 7 was followed by a 3-fold decrease in GnRH mRNA levels in this brain region during the next 2 days. Starting from day 9, hypothalamic GnRH mRNA levels increased significantly and positively correlated with accelerated testicular growth. Triptorelin, an agonist of GnRH, at a dose that had no effect on testicular growth during "proportional" period, increased testis weights during the period of accelerated growth. The insensitivity of testicular growth to GnRH during "proportional" period was supported by inability of a 2.5-fold siRNA knockdown of GnRH expression in the hypothalamus of the 7-day-old animals to produce any effect on their testis weights. GnRH receptor blockade with cetrorelix was also without effect on testis weights during "proportional" period but the same doses of this GnRH antagonist significantly inhibited "accelerated" testicular growth. GnRH receptor mRNA levels in the pituitary as well as plasma LH concentrations were higher during "accelerated" period of testicular growth than during "proportional" period. In general, our data defined two distinct periods in rat testicular development that are primarily characterized by different responses to GnRH signaling.
Asunto(s)
Envejecimiento/fisiología , Hormonas Gonadales/metabolismo , Hipotálamo/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Testículo/crecimiento & desarrollo , Envejecimiento/efectos de los fármacos , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Kisspeptinas/metabolismo , Luteolíticos/farmacología , Masculino , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptores LHRH/biosíntesis , Transducción de Señal , Pamoato de Triptorelina/farmacologíaRESUMEN
The paraventricular nucleus of the hypothalamus (PVH) consists of distinct functional compartments regulating neuroendocrine, behavioral, and autonomic activities that are involved in the homeostatic control of energy balance. These compartments receive synaptic inputs from neurons of the arcuate nucleus of the hypothalamus (ARH) that contains orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neuropeptides. The axon outgrowth from the ARH to PVH occurs during a critical postnatal period and is influenced by the adipocyte-derived hormone leptin, which promotes its development. However, little is known about leptin's role in specifying patterns of cellular connectivity in the different compartments of the PVH. To address this question, we used retrograde and immunohistochemical labeling to evaluate neuronal inputs onto sympathetic preautonomic and neuroendocrine neurons in PVH of leptin-deficient mice (Lep(ob)/Lep(ob)) exposed to a postnatal leptin treatment. In adult Lep(ob)/Lep(ob) mice, densities of AgRP- and α-melanocortin stimulating hormone (αMSH)-immunoreactive fibers were significantly reduced in neuroendocrine compartments of the PVH, but only AgRP were reduced in all regions containing preautonomic neurons. Moreover, postnatal leptin treatment significantly increased the density of AgRP-containing fibers and peptidergic inputs onto identified preautonomic, but not onto neuroendocrine cells. Neonatal leptin treatment neither rescued αMSH inputs onto neuroendocrine neurons, nor altered cellular ratios of inhibitory and excitatory inputs. These effects were associated with attenuated body weight gain, food intake and improved physiological response to sympathetic stimuli. Together, these results provide evidence that leptin directs cell type-specific patterns of ARH peptidergic inputs onto preautonomic neurons in the PVH, which contribute to normal energy balance regulation.
Asunto(s)
Animales Recién Nacidos/fisiología , Hipotálamo/crecimiento & desarrollo , Leptina/deficiencia , Leptina/farmacología , Sistema Nervioso Parasimpático/crecimiento & desarrollo , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/genética , Regulación de la Temperatura Corporal/fisiología , Peso Corporal/fisiología , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Ácido Glutámico/fisiología , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Leptina/genética , Masculino , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Sistemas Neurosecretores/citología , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/crecimiento & desarrollo , Sistema Nervioso Parasimpático/citología , Sistema Nervioso Parasimpático/efectos de los fármacos , Péptidos/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ before the establishment of the blood-brain barrier (BBB), in rats up to the first postnatal week. Dopamine (DA) was selected as a marker of the brain endocrine activity. The hypothesis was supported by the observations in rats of: (i) the physiological concentration of DA in peripheral blood of fetuses and neonates, before the BBB establishment, and its drop by prepubertal period, after the BBB development; (ii) a drop of the DA concentration in the brain for 54% and in blood for 74% on the 3rd postnatal day after the intraventricular administration of 50 µg of α-methyl-p-tyrosine, an inhibitor of DA synthesis, with no changes in the DA metabolism in peripheral DA-producing organs. Thus, the developing brain is a principal source of circulating DA which is capable of providing an endocrine regulation of peripheral organs and the brain.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Dopamina/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Ácido 3,4-Dihidroxifenilacético/sangre , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/crecimiento & desarrollo , Encéfalo/embriología , Encéfalo/metabolismo , Dopamina/sangre , Femenino , Hipotálamo/metabolismo , Masculino , Mesencéfalo/metabolismo , Sistemas Neurosecretores/embriología , Embarazo , Ratas , Ratas Wistar , Rombencéfalo/metabolismo , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , alfa-Metiltirosina/farmacologíaRESUMEN
Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; or estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor α (ERα) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ERα, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA(B) receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGFα. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function.
Asunto(s)
Disruptores Endocrinos/toxicidad , Hipotálamo/efectos de los fármacos , Hipotálamo/crecimiento & desarrollo , Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Factores de Edad , Animales , Animales Recién Nacidos , Femenino , Hipotálamo/embriología , Masculino , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Embarazo , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyAsunto(s)
Envejecimiento/fisiología , Homeostasis/fisiología , Hipotálamo/fisiología , Sistemas Neurosecretores/fisiología , Envejecimiento/metabolismo , Animales , Dopamina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Neurosecreción/fisiología , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Ratas , Serotonina/metabolismoRESUMEN
The maintaining of homeostasis in the organism in response to a variable environment is provided by the highly hierarchic neuroendocrine-immune system. The crucial component of this system is the hypothalamus providing the endocrine regulation of key peripheral organs, and the adenohypophysis. In this case, neuron-derived signaling molecules (SM) are delivered to the blood vessels in hypothalamic "neurohaemal organs" lacking the blood-brain barrier (BBB), the posterior lobe of the pituitary and the median eminence. The release of SM to the blood vessels in most other brain regions is prohibited by BBB. According to the conventional concept, the development of the neuroendocrine system in ontogenesis begins with the "maturation" of peripheral endocrine glands which first are self-governed and then operate under the adenohypophysial control. Meantime, the brain maturation is under the control of SM secreted by endocrine glands of the developing organism and coming from the placenta and maternal organism. The hypothalamus is involved in the neuroendocrine regulation only after its full maturation that is followed by the conversion of the opened-looped neuroendocrine system to the closed-looped system as in adulthood. Neurons of the developing brain begin to secrete SM shortly after their origin and long before the establishment of specific interneuronal relations providing initially autocrine and paracrine morphogenetic influence on differentiating target neurons. Taking into account that the brain lacks BBB over this ontogenetic period, we hypothesized that it operates as the multipotent endocrine gland secreting SM to the general circulation and thereby providing the endocrine regulation of peripheral organs and the brain. The term "multipotent" means that the spectrum of the brain-derived circulating SM and their occupancy at the periphery in the developing organism should greatly exceed those in adulthood. In order to test this hypothesis, gonadotropin-releasing hormone (GnRH), dopamine (DA), and serotonin (5-hydroxytryptamine, 5-HT) were chosen as the markers of the presumptive endocrine function of the brain in ontogenesis. According to our data, the concentrations of GnRH, DA, and 5-HT in the rat general circulation during the perinatal period, i.e. before the establishment of BBB, was as high as those in the portal circulation in adulthood. The concentrations of circulating GnRH and DA dropped to almost undetectable level after the development of BBB suggesting their brain origin. This suggestion has been proven by showing an essential decrease of GnRH, DA, and 5-HT concentrations in general circulation of perinatal rats after microsurgical elimination of synthesizing neurons or the inhibition of specific syntheses in the brain before the establishment of BBB. GnRH, DA, and 5-HT apparently as dozens of other brain-derived SM appear to be capable of providing the endocrine influence on their peripheral targets like the adenohypophysis, gonads, kidney, heart, blood vessels, and the brain (endocrine autoregulation). Although the ontogenetic period of the brain operation as the multipotent endocrine gland is relatively short, the brain-derived SM are thought to be capable of providing long-lasting morphogenetic effects on peripheral targets and the brain. Thus, the developing brain operates as the multipotent endocrine gland from the onset of neurogenesis to the establishment of BBB providing the endocrine regulation of the developing organism.
Asunto(s)
Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Animales , Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/crecimiento & desarrollo , Barrera Hematoencefálica/fisiología , Encéfalo/fisiología , Dopamina/sangre , Hormona Liberadora de Gonadotropina/sangre , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiología , Neurogénesis , Sistemas Neurosecretores/fisiología , Ratas , Serotonina/sangreRESUMEN
A large body of epidemiological data suggests that adverse early environments, including obesity during pregnancy or early postnatal life, are linked to an elevated prevalence of metabolic disease in adult offspring. The mechanisms underlying these effects are still poorly understood, but recent data from rodents provide insight into a potential role for the brain in this 'metabolic programming.' This review summarizes the developmental changes that have been observed in the hypothalamus in response to changes in the early nutritional and hormonal environment. It also discusses how resetting a diverse array of neuroendocrine systems may have long-term effects on the regulation of metabolism and energy balance.
Asunto(s)
Desarrollo Infantil , Hipotálamo/fisiología , Fenómenos Fisiológicos Nutricionales del Lactante , Leptina/fisiología , Fenómenos Fisiologicos Nutricionales Maternos , Enfermedades Metabólicas/etiología , Animales , Metabolismo Energético , Femenino , Humanos , Hipotálamo/crecimiento & desarrollo , Lactante , Sistemas Neurosecretores/crecimiento & desarrollo , Obesidad/etiología , Obesidad/fisiopatología , Embarazo , Complicaciones del Embarazo , Efectos Tardíos de la Exposición PrenatalRESUMEN
Leptin plays a pivotal role in the regulation of energy homeostasis and neuroendocrine functions, and increasing evidence indicates that leptin acts on the brain to mediate many of these effects. Recent data have also suggested that leptin influences brain development during early postnatal life. Here we examined the distribution of cells that express mRNA encoding the long form of the leptin receptor (LepRb) in postnatal and adult mouse brains by using in situ hybridization. In both adults and neonates, LepRb mRNA was largely restricted to regions known to control energy balance. Labeled cells were found in the arcuate, ventromedial, and dorsomedial nuclei of the hypothalamus as well as in the lateral hypothalamic area. Heavily labeled cells were also found in the median preoptic and ventral premammillary nuclei, two hypothalamic nuclei that are known to control reproduction. Moreover, during postnatal and adult life, clearly labeled cells were found in extrahypothalamic autonomic control sites such as the nucleus of the tractus solitarius. Importantly, this receptor can induce intracellular signaling because peripheral injection of leptin caused STAT3 phosphorylation in most sites in which LepRb mRNA was expressed. LepRb mRNA was also transiently elevated in certain regions of the postnatal mouse brain, such as the cortex, hippocampus, and laterodorsal nucleus of the thalamus. Taken together, these observations are consistent with the proposed roles of leptin in feeding and neuroendocrine regulation. They also identify regions where LepRb mRNA is expressed during early postnatal life and suggest new roles for leptin in the nervous system during development.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Leptina/metabolismo , Neuronas/metabolismo , ARN Mensajero/metabolismo , Receptores de Leptina/genética , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Apetito/fisiología , Peso Corporal/fisiología , Encéfalo/citología , Mapeo Encefálico , Metabolismo Energético/fisiología , Femenino , Hipotálamo/citología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Hibridación in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Sistemas Neurosecretores/citología , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Prosencéfalo/citología , Prosencéfalo/crecimiento & desarrollo , Prosencéfalo/metabolismo , ARN Mensajero/análisis , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
The main prerequisite for organism's viability is the maintenance of the internal environment despite changes in the external environment, which is provided by the neuroendocrine control system. The key unit in this system is hypothalamus exerting endocrine effects on certain peripheral organs and anterior pituitary. Physiologically active substances of neuronal origin enter blood vessels in the neurohemal parts of hypothalamus where no blood-brain barrier exists. In other parts of the adult brain, the arrival of physiologically active substances is blocked by the blood-brain barrier. According to the generally accepted concept, the neuroendocrine system formation in ontogeny starts with the maturation of peripheral endocrine glands, which initially function autonomously and then are controlled by the anterior pituitary. The brain is engaged in neuroendocrine control after its maturation completes, which results in a closed control system typical of adult mammals. Since neurons start to secrete physiologically active substances soon after their formation and long before interneuronal connections are formed, these cells are thought to have an effect on brain development as inducers. Considering that there is no blood-brain barrier during this period, we proposed the hypothesis that the developing brain functions as a multipotent endocrine organ. This means that tens of physiologically active substances arrive from the brain to the systemic circulation and have an endocrine effect on the whole body development. Dopamine, serotonin, and gonadotropin-releasing hormone were selected as marker physiologically active substances of cerebral origin to test this hypothesis. In adult animals, they act as neurotransmitters or neuromodulators transmitting information from neuron to neuron as well as neurohormones arriving from the hypothalamus with portal blood to the anterior pituitary. Perinatal rats--before the blood-brain barrier is formed--proved to have equally high concentration of dopamine, serotonin, and gonadotropin-releasing hormone in the systemic circulation as in the adult portal system. After the brain-blood barrier is formed, the blood concentration of dopamine and gonadotropin-releasing hormone drops to zero, which indirectly confirms their cerebral origin. Moreover, the decrease in the blood concentration of dopamine, serotonin, and gonadotropin-releasing hormone before the brain-blood barrier formation after the microsurgical disruption of neurons that synthesize them or inhibition of dopamine and serotonin synthesis in the brain directly confirm their cerebral origin. Before the blood-brain barrier formation, dopamine, serotonin, gonadotropin-releasing hormone, and likely many other physiologically active substances of cerebral origin can have endocrine effects on peripheral target organs--anterior pituitary, gonads, kidney, heart, blood vessels, and the proper brain. Although the period of brain functioning as an endocrine organ is not long, it is crucial for the body development since physiologically active substances exert irreversible effects on the targets as morphogenetic factors during this period. Thus, the developing brain from the neuron formation to the establishment of the blood-brain barrier functions as a multipotent endocrine organ participating in endocrine control of the whole body development.
Asunto(s)
Barrera Hematoencefálica/crecimiento & desarrollo , Encéfalo/crecimiento & desarrollo , Neurogénesis/fisiología , Sistemas Neurosecretores/crecimiento & desarrollo , Animales , Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/fisiología , Encéfalo/embriología , Encéfalo/fisiología , Dopamina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiología , Mamíferos , Neuronas/metabolismo , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/fisiología , Serotonina/metabolismoRESUMEN
Prenatal stress has been reported to alter the development of the central nervous system functions. This alteration is thought to be partly caused by increased fetal exposure to glucocorticoid. To clarify how prenatal stress affects neuroendocrine systems and behaviour in an age-dependent manner, we administered a synthetic glucocorticoid, dexamethasone, as a stressor to pregnant rats at gestational days 16-21 and examined the developmental changes in behaviour, hypothalamic corticotropin-releasing factor mRNA expression, corticosterone response and glucocorticoid receptor expression in male offspring. Prenatal dexamethasone exposure decreased corticotropin-releasing factor mRNA in the hypothalamus and disturbed the plasma corticosterone response to restraint stress in the offspring at postnatal week 4 (PW4). In contrast, it was not until PW10 that increased anxiety-like behaviour emerged in the dexamethasone-exposed offspring. In association with the acquisition of increased anxiety-like behaviour at PW10, glucocorticoid receptor expression was decreased in the amygdala in dexamethasone-exposed offspring at PW7 and PW10. Thus, our longitudinal analysis suggests that prenatal exposure to glucocorticoid hampers neuroendocrinological development in the offspring during early life, and that this disturbance results in the induction of increased anxiety-like behaviour in adulthood.
Asunto(s)
Ansiedad/etiología , Ansiedad/metabolismo , Dexametasona , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Efectos Tardíos de la Exposición Prenatal , Factores de Edad , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/crecimiento & desarrollo , Amígdala del Cerebelo/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Ansiedad/patología , Conducta Animal/efectos de los fármacos , Corticosterona/genética , Corticosterona/metabolismo , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Femenino , Hipotálamo/efectos de los fármacos , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Restricción Física/métodosRESUMEN
Endocrine disrupting chemicals (EDCs) are natural or synthetic compounds that interfere with the normal function of an organism's endocrine system. Many EDCs are resistant to biodegradation, due to their structural stability, and persist in the environment. The focus of this review is on natural and artificial EDCs that act through estrogenic mechanisms to affect reproductive neuroendocrine systems. This endocrine axis comprises the hypothalamic gonadotropin-releasing hormone (GnRH), pituitary gonadotropins, and gonadal steroid hormones, including estrogens. Although it is not surprising that EDCs that mimic or antagonize estrogen receptors may exert actions upon reproductive targets, the mechanisms for these effects are complex and involve all three levels of the hypothalamic-pituitary-gonadal (HPG) system. Nevertheless, considerable evidence links exposure to estrogenic environmental EDCs with neuroendocrine reproductive deficits in wildlife and in humans. The effects of an EDC are variable across the life cycle of an animal, and are particularly potent when exposure occurs during fetal and early postnatal development. As a consequence, abnormal sexual differentiation, disrupted reproductive function, or inappropriate sexual behavior may be detected later in life. This review will cover the effects of two representative classes of estrogenic EDCs, phytoestrogens and polychlorinated biphenyls (PCBs), on neuroendocrine reproductive function, from molecules to behavior, across the vertebrate life cycle. Finally, we identify the gaps of knowledge in this field and suggest future directions for study.
Asunto(s)
Disruptores Endocrinos/toxicidad , Sistema Endocrino/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Sistemas Neurosecretores/efectos de los fármacos , Animales , Sistema Endocrino/crecimiento & desarrollo , Sistema Endocrino/metabolismo , Femenino , Masculino , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Fitoestrógenos/toxicidad , Bifenilos Policlorados/toxicidad , Maduración Sexual/efectos de los fármacosRESUMEN
The effects of hydrocortisone acetate treatment of rats during the last gestational week on neurochemical and morphological characteristics of the brain in early postnatal and mature offspring were studied. Disappearance of sexual differences both in aromatase and 5alpha-reductase activities and noradrenaline concentration in the preoptic area in 10-day old rats was found. Meanwhile a sexual dimorphism in serotonin metabolism emerged. In adult offspring, the prenatal exposure to glucocorticoids resulted in disappearance of sexual differences in neurocytes' nuclei volume in medial preoptic and suprachiasmatic nuclei. The adrenocortical reaction to noradrenaline infusion to the 3rd brain ventricle was absent in the experimental males and intensified in females. In males, adrenocortical reaction to restraint decreased while post-stress changes in hypothalamic noradrenaline concentration and hippocampal glutamate decarboxylase activity were not observed. In the similar experiments in females both the augmentation of adrenocortical reaction and inhibition of GABA-ergic system were revealed. The results obtained indicate the modifying effect of prenatal exposure to glucocorticoids on sexual dimorphism of neuroendocrine system.