Chemogenetic Excitation of Ventromedial Hypothalamic Steroidogenic Factor 1 (SF1) Neurons Increases Muscle Thermogenesis in Mice.

Allostatic adaptations to a perceived threat are crucial for survival and may tap into mechanisms serving the homeostatic control of energy balance. We previously established that exposure to predator odor (PO) in rats significantly increases skeletal muscle thermogenesis and energy expenditure (EE). Evidence highlights steroidogenic factor 1 (SF1) cells within the central and dorsomedial ventromedial hypothalamus (c/dmVMH) as a modulator of both energy homeostasis and defensive behavior. However, the brain mechanism driving elevated EE and muscle thermogenesis during PO exposure has yet to be elucidated. To assess the ability of SF1 neurons of the c/dmVMH to induce muscle thermogenesis, we used the combined technology of chemogenetics, transgenic mice, temperature transponders, and indirect calorimetry. Here, we evaluate EE and muscle thermogenesis in SF1-Cre mice exposed to PO (ferret odor) compared to transgenic and viral controls. We detected significant increases in muscle temperature, EE, and oxygen consumption following the chemogenetic stimulation of SF1 cells. However, there were no detectable changes in muscle temperature in response to PO in either the presence or absence of chemogenetic stimulation. While the specific role of the VMH SF1 cells in PO-induced thermogenesis remains uncertain, these data establish a supporting role for SF1 neurons in the induction of muscle thermogenesis and EE similar to what is seen after predator threats.

Steroidogenic Factor-1 Regulation of Dorsomedial Ventromedial Hypothalamic Nucleus Ghrh Neuron Transmitter Marker and Estrogen Receptor Gene Expression in Male Rat.

Ventromedial hypothalamic nucleus (VMN) growth hormone-releasing hormone (Ghrh) neurotransmission shapes counterregulatory hormone secretion. Dorsomedial VMN Ghrh neurons express the metabolic-sensitive transcription factor steroidogenic factor-1/NR5A1 (SF-1). In vivo SF-1 gene knockdown tools were used here to address the premise that in male rats, SF-1 may regulate basal and/or hypoglycemic patterns of Ghrh, co-transmitter biosynthetic enzyme, and estrogen receptor (ER) gene expression in these neurons. Single-cell multiplex qPCR analyses showed that SF-1 regulates basal profiles of mRNAs that encode Ghrh and protein markers for neurochemicals that suppress (γ-aminobutyric acid) or enhance (nitric oxide; glutamate) counterregulation. SF-1 siRNA pretreatment respectively exacerbated or blunted hypoglycemia-associated inhibition of glutamate decarboxylase67 (GAD67/GAD1) and -65 (GAD65/GAD2) transcripts. Hypoglycemia augmented or reduced nitric oxide synthase and glutaminase mRNAs, responses that were attenuated by SF-1 gene silencing. Ghrh and Ghrh receptor transcripts were correspondingly refractory to or increased by hypoglycemia, yet SF-1 knockdown decreased both gene profiles. Hypoglycemic inhibition of ER-alpha and G protein-coupled-ER gene expression was amplified by SF-1 siRNA pretreatment, whereas as ER-beta mRNA was amplified. SF-1 knockdown decreased (corticosterone) or elevated [glucagon, growth hormone (GH)] basal counterregulatory hormone profiles, but amplified hypoglycemic hypercorticosteronemia and -glucagonemia or prevented elevated GH release. Outcomes document SF-1 control of VMN Ghrh neuron counterregulatory neurotransmitter and ER gene transcription. SF-1 likely regulates Ghrh nerve cell receptivity to estradiol and release of distinctive neurochemicals during glucose homeostasis and systemic imbalance. VMN Ghrh neurons emerge as a likely substrate for SF-1 control of glucose counterregulation in the male rat.

Sex-specific role of high-fat diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus.

BACKGROUND: Scientific evidence highlights the influence of biological sex on the relationship between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress concurrently contribute to metabolic dysregulation in both males and females. Our study aimed to investigate the combined effects of high-fat diet (HFD) induced obesity and repeated stress on fear-related behaviors, metabolic, immune, and hypothalamic outcomes in male and female mice. METHODS: To investigate this, we used a highly reliable rodent behavioral model that faithfully recapitulates key aspects of post-traumatic stress disorder (PTSD)-like fear. We subjected mice to footshock stressor followed by a weekly singular footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. At weeks 10 and 14 we conducted glucose tolerance and insulin sensitivity measurements. Additionally, we placed the mice in metabolic chambers to perform indirect calorimetric measurements. Finally, we collected brain and peripheral tissues for cellular analysis. RESULTS: We observed that HFD-induced obesity disrupted fear memory extinction, increased glucose intolerance, and affected energy expenditure specifically in male mice. Conversely, female mice on HFD exhibited reduced respiratory exchange ratio (RER), and a significant defect in glucose tolerance only when subjected to repeated stress. Furthermore, the combination of repeated stress and HFD led to sex-specific alterations in proinflammatory markers and hematopoietic stem cells across various peripheral metabolic tissues. Single-nuclei RNA sequencing (snRNAseq) analysis of the ventromedial hypothalamus (VMH) revealed microglial activation in female mice on HFD, while male mice on HFD exhibited astrocytic activation under repeated stress. CONCLUSIONS: Overall, our findings provide insights into complex interplay between repeated stress, high-fat diet regimen, and their cumulative effects on health, including their potential contribution to the development of PTSD-like stress and metabolic dysfunctions, emphasizing the need for further research to fully understand these interconnected pathways and their implications for health.

In our study, we attempted to investigate how the combination of diet, stress, and sex can affect various aspects of health in mice. Specifically, we aimed to elucidate the neurobiology of underlying stress and metabolic dysfunction with a focus on sex-specific differences. We recognize that stress and metabolic disorders often co-occur and exhibit distinct patterns between sexes. In the present study, we observed that male mice fed a high-fat diet exhibited an inability to extinguish fear memory, mirroring a hallmark symptom observed in PTSD patients. We also observed sex-specific differences in metabolic and immune function in response to the diet and stress challenge. We uncovered that both repeated stress and a HFD can induce alterations in the quantity and types of immune cells present in various peripheral tissues, suggesting potential pathways through which metabolic diseases may develop. Our investigation further revealed that the ventromedial hypothalamus, responsible for regulating metabolism and stress behavior, exhibited distinct transcriptomic activity patterns in males and females. These findings shed light on the complex connections between high fat diet, stress levels, and overall health, emphasizing the importance of continued research in this area.

Glucose transporter-2 regulation of VMN GABA neuron metabolic sensor and transmitter gene expression.

Glucose transporter-2 (GLUT2) monitors cellular glucose uptake. Astrocyte GLUT2 controls glucose counterregulatory hormone secretion. In vivo gene silencing and laser-catapult-microdissection tools were used here to investigate whether ventromedial hypothalamic nucleus (VMN) GLUT2 may regulate dorsomedial (VMNdm) and/or ventrolateral (VMNvl) γ-aminobutyric acid (GABA) neurotransmission to control this endocrine outflow in female rats. VMN GLUT2 gene knockdown suppressed or stimulated hypoglycemia-associated glutamate decarboxylase (GAD)1 and GAD2 mRNA expression in VMNdm versus VMNvl GABAergic neurons, respectively. GLUT2 siRNA pretreatment also modified co-expressed transmitter marker gene profiles in each cell population. VMNdm GABA neurons exhibited GLUT2 knockdown-sensitive up-regulated 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) transcripts during hypoglycemia. Hypoglycemic augmentation of VMNvl GABA neuron AMPKα2 was refractory to GLUT2 siRNA. GLUT2 siRNA blunted (VMNdm) or exacerbated (VMNvl) hypoglycemic stimulation of GABAergic neuron steroidogenic factor-1 (SF-1) mRNA. Results infer that VMNdm and VMNvl GABA neurons may exhibit divergent, GLUT2-dependent GABA neurotransmission patterns in the hypoglycemic female rat. Data also document differential GLUT2 regulation of VMNdm versus VMNvl GABA nerve cell SF-1 gene expression. Evidence for intensification of hypoglycemic hypercorticosteronemia and -glucagonemia by GLUT2 siRNA infers that VMN GLUT2 function imposes an inhibitory tone on these hormone profiles in this sex.

Sex-Dimorphic Effects of Hypoglycemia on Metabolic Sensor mRNA Expression in Ventromedial Hypothalamic Nucleus-Dorsomedial Division (VMNdm) Growth Hormone-Releasing Hormone Neurons.

Growth hormone-releasing hormone (Ghrh) neurons in the dorsomedial ventromedial hypothalamic nucleus (VMNdm) express the metabolic transcription factor steroidogenic factor-1 and hypoglycemia-sensitive neurochemicals of diverse chemical structures, transmission modes, and temporal signaling profiles. Ghrh imposes neuromodulatory control of coexpressed transmitters. Multiple metabolic sensory mechanisms are employed in the brain, including screening of the critical nutrient glucose or the energy currency ATP. Here, combinatory laser-catapult-microdissection/single-cell multiplex qPCR tools were used to investigate whether these neurons possess molecular machinery for monitoring cellular metabolic status and if these biomarkers exhibit sex-specific sensitivity to insulin-induced hypoglycemia. Data show that hypoglycemia up- (male) or downregulated (female) Ghrh neuron glucokinase (Gck) mRNA; Ghrh gene silencing decreased baseline and hypoglycemic patterns of Gck gene expression in each sex. Ghrh neuron glucokinase regulatory protein (Gckr) transcript levels were respectively diminished or augmented in hypoglycemic male vs female rats; this mRNA profile was decreased by Ghrh siRNA in both sexes. Gene transcripts encoding catalytic alpha subunits of the energy monitor 5-AMP-activated protein kinase (AMPK), i.e., Prkaa1 and 2, were increased by hypoglycemia in males, yet only the former mRNA was hypoglycemia-sensitive in females. Ghrh siRNA downregulated baseline and hypoglycemia-associated Prkaa subunit mRNAs in males but elicited divergent changes in Prkaa2 transcripts in eu- vs hypoglycemic females. Results provide unique evidence that VMNdm Ghrh neurons express the characterized metabolic sensor biomarkers glucokinase and AMPK and that the corresponding gene profiles exhibit distinctive sex-dimorphic transcriptional responses to hypoglycemia. Data further document Ghrh neuromodulation of baseline and hypoglycemic transcription patterns of these metabolic gene profiles.

Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs.

OBJECTIVE: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established. METHODS: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips. RESULTS: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue. CONCLUSIONS: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.

Stress during pubertal development affects female sociosexual behavior in mice.

Puberty is a crucial phase for the development of female sexual behavior. Growing evidence suggests that stress during this period may interfere with the development of sexual behavior. However, the neural circuits involved in this alteration remain elusive. Here, we demonstrated in mice that pubertal stress permanently disrupted sexual performance without affecting sexual preference. This was associated with a reduced expression and activation of neuronal nitric oxide synthase (nNOS) in the ventrolateral part of the ventromedial hypothalamus (VMHvl). Fiber photometry revealed that VMHvl nNOS neurons are strongly responsive to male olfactory cues with this activation being substantially reduced in pubertally stressed females. Finally, treatment with a NO donor partially restored sexual performance in pubertally stressed females. This study provides insights into the involvement of VMHvl nNOS in the processing of olfactory cues important for the expression of female sexual behavior. In addition, exposure to stress during puberty disrupts the integration of male olfactory cues leading to reduced sexual behavior.

A dedicated hypothalamic oxytocin circuit controls aversive social learning.

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.

Alpha1- and Beta-norepinephrinergic receptors of dorsomedial and ventromedial hypothalamic nuclei modulate panic attack-like defensive behaviour elicited by diencephalic GABAergic neurotransmission disinhibition.

Gamma-aminobutyric acid (GABA) disinhibition in medial hypothalamus (MH) nuclei of rats elicits some defensive reactions that are considered panic attack-like behaviours. Recent evidence showed that the norepinephrine-mediated system modulates fear-related defensive behaviours organised by MH neurons at least in part via noradrenergic receptors recruitment on midbrain tegmentum. However, it is unknown whether noradrenergic receptors of the MH also modulate the panic attack-like reactions. The aim of this work was to investigate the distribution of noradrenergic receptors in MH, and the effects of either α1-, α2- or ß-noradrenergic receptors blockade in the MH on defensive behaviours elaborated by hypothalamic nuclei. Defensive behaviours were evaluated after the microinjection of the selective GABAA receptor antagonist bicuculline into the MH that was preceded by microinjection of either WB4101, RX821002, propranolol (α1-, α2- and ß-noradrenergic receptor selective antagonists, respectively), or physiological saline into the MH of male Wistar rats. The α1-, α2- and ß-noradrenergic receptors were found in neuronal perikarya of all MH nuclei, and the α2-noradrenergic receptor were also found on glial cells mainly situated in the ventrolateral division of the ventromedial hypothalamic nucleus. The α1- and ß-noradrenergic receptors blockade in the MH decreased defensive attention and escape reactions elicited by the intra-MH microinjections of bicuculline. These findings suggest that, despite the profuse distributions of α1-, α2- and ß-noradrenergic receptors in the MH, both α1- and ß-noradrenergic receptor- rather than α2-noradrenergic receptor-signalling in MH are critical for the neuromodulation of panic-like behaviour.

Maternal obesity and late effects on offspring metabolism / Obesidade materna e efeitos tardios sobre o metabolismo da prole

Objective : The aim of this study was to evaluate the late effects of maternal obesity induced by lesion of the ventromedial hypothalamus on offspring metabolism.Materials and methods : Thirty days after the bilateral lesion of the ventromedial hypothalamus, female rats were mated and divided into 2 groups of pregnant animals: Control (C) – false lesion (sham) and Obese (OB) – lesion. Three months after that, with the groups of mothers, offspring were divided into control and obese animals that received a normocaloric diet (C-N and OB-N), and control and obese animals that received a hypercaloric diet (C-H and OB-H). At 120 days of age, the animals were euthanized and their carcasses, feces and food were submitted to calorimetric analysis to determine energy balance and body composition.Results : During the growth period, offspring from obese mothers showed higher values of body weight and food intake than controls. Obese animals showed higher body weight gain and gross food efficiency than control animals in adulthood. The hypercaloric diet led to increased metabolizable energy intake, percentage of absorbed energy and energy expenditure in both groups. Body composition was only affected by the association of hypercaloric diet and maternal obesity that led to increased body fat.Conclusions : Maternal obesity has led to the development of later overweight in offspring, suggesting fetal programming. According to the trend presented, it is believed that the prolonged intake of hypercaloric diets in adult animals may, as an additional effect, induce worsening of the overweight induced by maternal obesity. Arq Bras Endocrinol Metab. 2014;58(3):301-7.

Objetivo Avaliar os efeitos tardios da obesidade materna induzida por lesão do núcleo ventromedial do hipotálamo sobre o metabolismo da prole. Trinta dias após a lesão bilateral do hipotálamo ventromedial, ratos fêmeas foram colocadas para acasalar e divididas em dois grupos de animais gestantes: Controle (C) – falsa lesão e Obeso (OB) – lesionados. Três meses após o nascimento, de acordo com os grupos das mães, os filhotes foram divididos em animais controle e obesos que recebiam dieta normocalórica (C-N and OB-N) e animais controle e obesos que recebiam dieta hipercalórica (C-H and OB-H). Aos 120 dias de idade, os animais foram eutanasiados e as carcaças, fezes e ração foram submetidas à análise calorimétrica para determinação do balanço energético e composição corporal.Resultados Durante o período de crescimento, os filhos de mães obesas mostraram maiores valores de peso corporal e ingestão alimentar que animais controle. Os animais obesos apresentaram maiores valores de ganho de peso corporal e eficiência metabólica que os animais controle quando adultos. A dieta hipercalórica levou ao aumento da energia metabolizável, percentagem de energia absorvida e gasto energético para ambos os grupos. A composição corporal foi somente afetada pela associação da dieta hipercalórica com a obesidade materna que levou ao aumento da gordura corporal.Conclusões : A obesidade materna levou ao sobrepeso tardio na prole, sugerindo uma programação fetal. Pela tendência apresentada, acreditamos que a ingestão prolongada de dietas hipercalóricas em animais adultos possa induzir uma piora no quadro de sobrepeso induzido pela obesidade materna. Arq Bras Endocrinol Metab. 2014;58(3):301-7.

Confabulaciones (I): Concepto, clasificación y neuropatología / Confabulations (I): Concept, classification and neuropathology

Introducción. Una definición operativa de confabulaciones sería aquella que los describe como falsos recuerdos resultado de un problema de recuperación, de los que el paciente no es consciente, y cuya creencia en la veracidad del recuerdo es genuina. Han sido descritos varios tipos de confabulaciones, utilizando una gran diversidad de criterios. Las confabulaciones pueden llegar a verse en trastornos neurológicos muy distintos, existiendo controversia en torno a sus mecanismos patofisiológicos. Objetivo. Realizar una revisión actualizada en castellano sobre la definición, tipos, regiones cerebrales implicadas y correlatos neuropsicológicos de las confabulaciones. Desarrollo. Tras revisar el concepto y los distintos tipos de confabulaciones, se describen las regiones cerebrales dañadas en dos patologías donde pueden aparecer confabulaciones, el síndrome de Korsakoff y pacientes con rupturas de aneurismas de la arteria comunicante anterior. Se revisan posteriormente los correlatos neuropsicológicos asociados a las mismas. Conclusiones. Las confabulaciones son un fenómeno complejo y de difícil definición. Probablemente la clasificación más aceptada es la que, atendiendo al modo en que aparecen, distingue las confabulaciones espontáneas de las provocadas, aunque no está clara la validez de esta distinción. En cuanto a las regiones cerebrales cruciales implicadas en las confabulaciones, parece que lesiones en el córtex prefrontal, específicamente en áreas ventromediales y orbitofrontales, son necesarias para que el fenómeno aparezca. La evidencia neuropsicológica sugiere la presencia, en la mayoría de los casos, de disfunción ejecutiva y al menos cierto grado de disfunción de memoria como mecanismos subyacentes a las mismas; sin embargo, las características específicas de estas disfunciones neuropsicológicas no son bien conocidas (AU)

Introduction. A working definition of confabulation could be that of describing them as false memories due to a recovery problem, where the patient is unaware that he/she is confabulating, and has the belief that the memory is true. Several types of confabulations have been described, according to a broad variety of criteria. Confabulations can be seen in very different neurological conditions, which have lead to a controversy on their pathophysiological mechanisms. Objective: To obtain an updated revision in Spanish of the definitions, types, brain regions involved and neuropsychological correlates of the confabulations. Development. After reviewing the concept and several types of confabulations, the damaged brain regions associated to two conditions where confabulations occur, such as Korsakoff syndrome and patients with anterior communicating artery aneurysm, are described. The neuropsychological correlates associated to them are then reviewed. Conclusions. Confabulations are a difficult-to-define complex phenomenon. Probably, the most accepted classification, in accordance with how they appear, would be that which distinguishes spontaneous from provoked confabulations, although the validity of this distinction is not clear. Regarding to crucial cerebral regions involved in the confabulations, it seems that prefrontal cortex lesions, specifically in ventromedial and orbitofrontal areas, are necessary. Neuropsychological evidence suggests the presence in most of the cases of executive dysfunction and at least some degree of memory dysfunction as an underlying mechanism of confabulation. Nevertheless, the specific characteristics of these neuropsychological dysfunctions are not well-known (AU)

Experimental model to induce obesity in rats

The etiology of obesity is multifactorial and is becoming a problem of public health, due to its increased prevalence and the consequent repercussion of its comorbidities on the health of the population. The great similarity and homology between the genomes of rodents and humans make these animal models a major tool to study conditions affecting humans, which can be simulated in rats. Obesity can be induced in animals by neuroendocrine, dietary or genetic changes. The most widely used models to induce obesity in rats are a lesion of the ventromedial hypothalamic nucleus (VMH) by administering monosodium glutamate or a direct electrical lesion, ovariectomy, feeding on hypercaloric diets and genetic manipulation for obesity.

A obesidade tem etiologia multifatorial e está se tornando um problema de saúde pública devido ao aumento da sua prevalência e a conseqüente repercusão das suas comorbidades na saúde da população. A grande similaridade e homologia entre os genomas dos roedores e dos humanos tornam esses modelos animais uma importante ferramenta para o estudo de condições que afetam os humanos e que podem ser simuladas em ratos. A obesidade pode ser induzida em animais com alterações neuroendócrinas, dietéticas ou genéticas. Os modelos mais utilizados para indução de obesidade em ratos são lesão do núcleo hipotalâmico venteromedial (VMH) através da administração de glutamato monossódico ou lesão elétrica direta, ooforectomia, alimentação com dietas hipercalóricas e manipulação genética para obesidade.

Postnatal Development of Brain Natriuretic Peptide-immunoreactive Neuron in the Hypothalamus of the Rat / 체질인류학회지

Brain natriuretic peptide (BNP) is a neuropeptide, isolated from porcine brain that is homologous with atriopeptin. Magnocellular neurosecretory cells located in the paraventricular nucleus and supraoptic nucleus synthesize and secrete neurohormones. The purpose of this study was to investigate distribution of BNP immunoreactivity throughout the rat hypothalamus from the day of birth to 30 days and adult using immunoperoxidase and immunofluorescent staining. The first BNP immunoreactive neurons appeared in the paraventricular and supraoptic nucleus at P10. In adult, BNP immunoreactivity was widely distributed throughout regions of the hypothalamus including dorsomedial hypothalamic nucleus, ventromedial hypothalamic nucleus, arcuate nucleus and internal layer of median eminence. The intensity of BNP immunoreactivity was weak in almost all hypothalamic nuclei except the paraventricular and supraoptic nuclei. BNP immunoreactivity was first observed in the lateral hypothalamic area at P15. In retrochiasmatic supraoptic nucleus, BNP immunoreactivity was first observed at P20 and remarkably distributed in adult. In the present study, distinct localization of BNP immunoreactivity was in the hypothalamic cell bodies and fibers. Although the role of BNP in the brain is yet to be determined, these results indicate that BNP in the neurons of hypothalamus play important role in the regulation of a variety of neurosecretory functions as a neuromodulator during postnatal development of the hypothalamus.

Postnatal Development of Brain Natriuretic Peptide-immunoreactive Neuron in the Hypothalamus of the Rat / 체질인류학회지

Brain natriuretic peptide (BNP) is a neuropeptide, isolated from porcine brain that is homologous with atriopeptin. Magnocellular neurosecretory cells located in the paraventricular nucleus and supraoptic nucleus synthesize and secrete neurohormones. The purpose of this study was to investigate distribution of BNP immunoreactivity throughout the rat hypothalamus from the day of birth to 30 days and adult using immunoperoxidase and immunofluorescent staining. The first BNP immunoreactive neurons appeared in the paraventricular and supraoptic nucleus at P10. In adult, BNP immunoreactivity was widely distributed throughout regions of the hypothalamus including dorsomedial hypothalamic nucleus, ventromedial hypothalamic nucleus, arcuate nucleus and internal layer of median eminence. The intensity of BNP immunoreactivity was weak in almost all hypothalamic nuclei except the paraventricular and supraoptic nuclei. BNP immunoreactivity was first observed in the lateral hypothalamic area at P15. In retrochiasmatic supraoptic nucleus, BNP immunoreactivity was first observed at P20 and remarkably distributed in adult. In the present study, distinct localization of BNP immunoreactivity was in the hypothalamic cell bodies and fibers. Although the role of BNP in the brain is yet to be determined, these results indicate that BNP in the neurons of hypothalamus play important role in the regulation of a variety of neurosecretory functions as a neuromodulator during postnatal development of the hypothalamus.

Balance energético: Leptina / Energy balance: Leptin

El estudio de la regulación del balance energético ha ocupado distintas vertientes de investigación y su confluencia ha conducido al descubrimiento de una hormona, la leptina. Los desajustes del balance energético conducen a estados patológicos cuya verdadera etiología no se comprenderá hasta que no se conozca totalmente la regulación de la homeostasis energética. En 1953, se estableció que existía un sistema adipostático en los mamíferos según el cual el equilibrio entre la ingesta y la energía gastada permite mantener estable la masa adiposa. Por otra parte, se había venido estudiando sobre roedores, en los que se producían daños hipotalámicos, el posible control cerebral del apetito, y se estableció que algunos núcleos hipotalámicos, como el ventromedial, el dorsomedial, y el núcleo arcuato, secretan neuropéptidos orexigénicos o anorexigénicos que, fijándose sobre receptores cerebrales, abren o cierran respectivamente el apetito. Se puede afirmar que el descubrimiento de la leptina en 1994, péptido secretado fundamentalmente por el tejido adiposo, ha sido una pieza clave para comprender la interacción entre el almacén de energía, en forma de grasa periférica, y los núcleos hipotalámicos conocidos como reguladores de la conducta de comer. La leptina plasmática disminuye con el ayuno y aumenta después de la sobrealimentación, y existe una correlación positiva entre los niveles de leptina y la masa grasa, así como entre los niveles de leptina e insulina. El conocimiento de la estructura de los receptpres de leptina e insulina. El conocimiento de la estructura de los receptores de leptina y de las señales que emiten, ha permitido identificarlos como pertenecientes uno de los receptores de citoquinas; además, la leptina estimula la proliferación de timocitos. Ello ha llevado a identificar la leptina como una citoquina perteneciente a la familia de la interleuquina -6. Sus acciones más importantes las realiza a través del cerebro, en donde existen sus receptores, y para lo cual tiene que ser transportada a éste desde la periferia. Además del tejido adiposo, es secretada también por la placenta, el tejido esquelético, la pared del estómago y el epitelio mamario. La mayor parte de la ingente investigación realizada sobtr la leptina se ha hecho sobre roedores mutantes con mutación autosomal recesiva, de los cuales los más estudiados han sido los ratones ob/ob y los db/db que no tienen leptina o no tienen sus receptores, respectivamente. Pero su acción fundamental parece ser la de adaptar el organismo, a través del cerebro, a una situación fr syuno, provocando además, con su decrecimiento, la apertura del apetito. Contrariamente, la inyección de leptina periférica o intracerebral produce saciedad. Desde 1999, y sobre todo en los últimos años la ruta cerebral de la leptina, abriendo o inhibiendo el apetito, se ha complicado por el establecimiento del llamado Sistema Melanocortina Central. Se piensa que el mediador de las acciones cerebrales de inhibición de la ingesta que produce la llegada cerebral de leptina, es la hormona Melanocortina Central. Se piensa qu el mediador de las acciones cerebrales de inhibición de la ingesta que produce la llegada cerebral de leptina, es la hormona Melanocortina (AlfaMSH). Muy recientemente está siendo estudiada la posibilidad de utilizar el bloqueo de alfaMSH o sus receptores en la terapéutica de estados de caquexia. La leptina, que comenzó siendo considereda una hormona antiobesidad. La leptina, que comenzó siendo considerada una hormona antiobesidad, ha producido una verdadera revolución científica en el conocimiento de la homeostasis energética (AU)

Conducta pseudopsicopática y lesiones cerebrales / Pseudopsychopathic behaviour and brain injuries

Ya en el siglo XIX aparece la primera y más famosa referencia a cambios de conducta social secundarios a lesiones frontales, se trata del famoso caso de Phineas Gage. Durante el siglo XX diversas descripciones de casos de lesión cerebral centran en la región frontal orbital o ventromedial el síndrome de pseudopsicopatía o de sociopatía adquirida. Este síndrome se caracteriza por pérdida de la conducta socialmente adecuada con irritabilidad, agresividad ocasional, desorganización de la conducta, alteración de la toma de decisiones, egocentrismo, desinhibición e incluso conductas delictivas. Este patrón aparece en adultos que han sufrido una lesión en esta región prefrontal. Cuando las lesiones se dan en la primera infancia las características son aún más destacadas, con alteración del razonamiento moral y falta de culpabilidad hacia las propias acciones. Este síndrome conductual puede ir acompañado de rendimiento intelectual y prefrontal cognitivo absolutamente normal, sobre todo en lesiones adultas. En el caso de lesiones infantiles acostubran a aparecer trastornos cognitivos frontales variables (AU)

La actividad de las células excitadoras e inhibidoras de la médula rostroventromedial está modulada por la estimulación vaginocervical / The acti vity of ON and OFF cells at the rostro ventromedial medulla is modulated by vagino-cervical stimulation

En ratas anestesiadas se estudió si la actividad de las células excitadoras e inhibidoras de la médula ro s t ro v e n t romedial estaba modulada por la estimulación mecánica del cuello uterino. Las células excitadoras se identificaron por un brusco aumento de la frecuencia de impulsos antes de p roducirse el movimiento de la cola en respuesta a un estímulo térmico doloroso. Las células inhibidoras se identificaron por un súbito descenso de la frecuencia de impulsos justo antes de producirse el movimiento de la cola. Todas las células excitadoras identificadas (27 de 27) re d u j e ron su f recuencia de impulsos inmediatamente después de la aplicación de un estímulo vaginal. El efecto del estímulo vaginal en la actividad de las células persistió durante todo el periodo de estimulación. Por otra parte, todas las células inhibidoras identificadas (19 de 19) aumentaron su frecuencia de impulsos después del estímulo vaginal. El efecto del estímulo vaginal en la actividad de estas células persistiótambién durante todo el periodo de estimulación. La actividad de las células neutrales no mostró cambio alguno, ni durante la aplicación de un estímulo térmico doloroso ni durante el estímulo vaginal. Estos resultados sugieren que el efecto analgésico producido por el estímulo vaginal puede estar mediado por la actividad del circuito antinociceptivo en la médula rostroventromedial. Además, se ha sugerido que el influjo aferente del tracto genital puede inducir la actividad del circuito antinociceptivo en la médula rostroventromedial, ya sea mediante proyecciones a la sustancia gris periacueductal o proyecciones directas a la médula rostroventromedial (AU)

Location of CNS Labeled Neurons Innervating the Rat Thymus Using the Pseudorabies Virus / 체질인류학회지

This experimental studies was to investigate the location of CNS labeled neurons following injection of pseudorabies virus (PRV), Bartha strain, into the rat thymus. After survival times of 96~120 hours following injection of PRV, the rats were perfused, and their spinal cord and brain were frozen sectioned(30micrometer). These sections were stained by PRV immunohistochemical staining method, and observed with light microscope The results were as follows: 1. The PRV labeled spinal cord segments projecting to the rat thymus were founded in cervical and thoracic segments. Densely labeled areas of each spinal cord segment were founded in lamina V, VII, X, intermediolateral nucleus and dorsal nucleus. 2. In the rhombencephalon, PRV labeled neurons projecting to the thymus were founded in the A1 noradrenalin cells/C1 adrenalin cells/caudoventrolateral reticular nucleus, rostroventro-lateral reticular nucleus, medullary reticular nucleus, area postrema, nucleus solitary tract, nucleus raphe obscurus, nucleus raphe pallidus, nucleus raphe magnus, gigantocellular reticular nucleus, lateral paragigantocellular nucleus and spinal trigeminal nucleus. 3. In the mesencephalon, PRV labeled neurons were founded in parabrachial nucleus, Kolliker-Fuse nucleus, central gray matter, substantia nigra, nucleus dorsal raphe, A8 dopamin cells of retrorubral field, Edinger-Westphal nucleus, locus coeruleus, subcoeruleus nucleus and A5 noradrenalin cells. 4. In the prosencephalon, PRV labeled neurons were founded in reuniens thalamic nucleus, paraventricular thalamic nucleus, precommissural nucleus, paraventricular hypothalamic nucleus, anterior hypothalamic nucleus, lateral hypothalamic nucleus, preoptic hypothalamic nucleus, retrochiasmatic area, arcuate nucleus, dorsomedial hypothalamic nucleus and ventromedial hypothalamic nucleus. These results suggest that PRV labeled neurons of the spinal cord projecting to the rat thymus might be the neurons related to the viscero-somatic sensory and sympathetic preganglionic neurons, and PRV labeled neurons of the brain may be the neurons response to the movement of smooth muscle in blood vessels. These PRV labeled neurons may be central autonomic center related to the integration and modulation of reflex control linked to the sensory system monitoring the internal environment. These observations provide evidence for previously unknown projections from spinal cord and brain to the thymus which may be play an important role in the regulation of thymic function.

Relación entre las lesiones electrolíticas del núcleo hipotalámico ventromedial y la diabetes mellitus insulino dependiente inducida por streptozotocina

Dada la función reguladora del sistema nervioso sobre el endocrino se busca analizar la correlación entre la lesión del núcleo hipotalámico ventromedial (HVM) y la severidad de la diabetes inducida por estreptozotocina (STZ). Se utilizan 29 ratas divididas en cuatro grupos: Grupo I: lesión del HVM e inyección de SS (murieron por complicaciones respiratorias); Grupo III: lesión del HVM e inyección de STZ; Grupo IV: lesión ficticia del HVM e inyección de STZ. Se observan por un período de 6 a 8 semanas. Se exploran semanalmente valores de química sanguínea como glicemia, colesterol y triglicéridos y se mide el peso corporal; cada dos días se determina el consumo de agua y en el momento del sacrificio se pesa la grasa perirrenal y se fijan los cerebros para determinar tamaño y sitio de la lesión. Los resultados muestran que el grupo III es el más afectado en cuanto a severidad de la diabetes y velocidad de deterioro de los animales; mientras que el grupo I sólo muestra aumento de peso corporal pero sin evidencia de diabetes. Todo parece indicar que el aumento de la ingesta inducido por la lesión del "núcleo de la sacidad" y por la misma diabetes produce efectos aditivos sobre el cuadro patológico

Morphological alterations of the rat submandibular gland caused by lesion of the ventromedial nucleus of the hypothalamus

As características morfológicas da glândula submandibular de ratos foram estudadas em diferentes períodos de tempo (5, 10, 20, 40 e 90 dias) após a lesäo do núcleo ventromedial do hipotálamo. O arranjo estrutural da glândula submandibular foi o mesmo em ratos com lesäo do núcleo ventromedial e nos ratos controle ou com lesäo fictícia. No primeiro grupo, entretanto, o septo estava estreito, dificultando a definiçäo dos compartimentos lobulares. Alteraçöes do parênquima foram bastante evidentes nos ratos lesados, com hipotrofia acinar e aumento no número de ductos granulosos. Os componentes submandibulares restantes, entretanto, näo apresentaram alteraçöes quando comparados com aqueles dos animais controles. Em resumo, a lesäo do núcleo ventromedial do hipotálamo produz as seguintes mudanças na glândula submandibular do rato: 1) diminuiçäo da massa glandular; 2) hipotrofia acinar; e 3) aumento no número de ductos granulosos