RESUMO
Astroglial cells are the most abundant cell type in the mammalian brain. They are implicated in almost every aspect of brain physiology, including maintaining homeostasis, building and maintaining the blood brain barrier, and the development and maturation of neuronal networks. Critically, astroglia also express receptors for gonadal sex hormones, respond rapidly to gonadal hormones, and are able to synthesize hormones. Thus, they are positioned to guide and mediate sexual differentiation of the brain, particularly neuronal networks in typical and pathological conditions. In this review, we describe astroglial involvement in the organization and development of the brain, and consider known sex differences in astroglial responses to understand how astroglial cell-mediated organization may play a role in forebrain sexual dimorphisms in human populations. Finally, we consider how sexually dimorphic astroglial responses and functions in development may lead to sex differences in vulnerability for neuropsychiatric disorders.
Assuntos
Astrócitos , Transtornos Mentais , Animais , Encéfalo , Feminino , Humanos , Masculino , Sistemas Neurossecretores , Prosencéfalo , Caracteres SexuaisRESUMO
In early lactation (EL), stressor salience modulates neuroendocrine stress responses, but it is unclear whether this persists throughout lactation and which neural structures are implicated. We hypothesized that this process is specific to EL and that the infralimbic (IL) medial prefrontal cortex (mPFC) might provide a critical link between assessment of threat and activation of the hypothalamo-pituitary-adrenal (HPA) axis in EL. We measured neuroendocrine responses and neuronal Fos induction to a salient (predator odor) or non-salient (tail pinch) psychogenic stressor in EL and late lactation (LL) females. We found that EL females exhibited a large response to predator stress only in the presence of pups, while responses to tail pinch were reduced independently of pup presence. In LL, HPA axis responses were independent of pup presence for both stressors and only responses to tail pinch were modestly reduced compared to virgins. Intracerebral injection of the local anesthetic bupivacaine (BUP) (0.75%; 0.5 µl/side) in the IL mPFC did not differentially affect neuroendocrine responses to predator odor in virgin and EL females, suggesting that lactation-induced changes in this structure might not regulate stressor salience for the HPA axis. However, the IL mPFC displayed morphological changes in lactation, with significant increases in dendritic spine numbers and density in EL compared to LL and virgin females. EL females also showed improved performance in the attention set-shifting task (AST), which could reflect early plasticity in the IL mPFC at a time when rapid adaptation of the maternal brain is necessary for pup survival.
Assuntos
Córtex Cerebral/fisiopatologia , Lactação , Sistema Límbico/fisiopatologia , Plasticidade Neuronal , Sistemas Neurossecretores/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Atenção , Feminino , Hormônios/sangue , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Odorantes , Estimulação Física , Sistema Hipófise-Suprarrenal/fisiopatologia , Comportamento Predatório , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Ratos Sprague-Dawley , Enquadramento Psicológico , Estresse Psicológico/psicologiaRESUMO
Ghrelin, a hormone produced primarily by the stomach, has been associated with motivational processes that include reward-seeking behaviors. In male laboratory mice, elevation of ghrelin levels enhances some aspects of sexual motivation and behavior, whereas in other experiments with male mice, rats, and other species, ghrelin treatment or food deprivation decreases sexual motivation and/or behavior. The present tested the hypothesis that stimulation of ghrelin receptors in different brain regions have opposite effects on male sexual motivation and behavior. To do this we examined appetitive and consummatory sex behaviors of male rats with a truncated ghrelin receptor (FHH-GHSRm1/Mcwi), and that of their WT (FHH) littermates. We also examined the effects of ghrelin or the ghrelin antagonist D-Lys-GHRP6 delivered into the VTA or the MPOA on appetitive and consummatory sex behaviors in male Long Evans rats. Results demonstrate that rats with a truncated ghrelin receptor, or rats that are food deprived, show deficits in anticipatory sex. Furthermore, although ghrelin does not further stimulate sex anticipation in rats when infused into the VTA, intra-VTA infusions of D-Lys-GHRP6 into the VTA further decreases in sex anticipation in food deprived rats. In contrast, ghrelin delivery into the mPOA decreased sex anticipation compared to saline or D-Lys-GHRP6 infused rats. Overall, these data suggest that ghrelin receptor signalling is important for full expression of appetitive sex behaviors. Within the VTA, ghrelin may act to enhance sex motivation, while acting on the mPOA to decrease sex motivation and promote foraging.
Assuntos
Grelina/farmacologia , Motivação/efeitos dos fármacos , Área Pré-Óptica/efeitos dos fármacos , Receptores de Grelina/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Privação de Alimentos , Masculino , Motivação/fisiologia , Oligopeptídeos/farmacologia , Área Pré-Óptica/metabolismo , Ratos , Ratos Long-Evans , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/genética , Recompensa , Comportamento Sexual Animal/fisiologia , Área Tegmentar Ventral/metabolismoRESUMO
This article is part of a Special Issue "Parental Care".Producing milk to support the growth of their young is a central element of maternal care in mammals. In spite of the facts that ecological constraints influence nursing frequency, length of time until weaning and the composition of milk, there is considerable similarity in the anatomy and physiology of milk production and delivery across mammalian species. Here we provide an overview of cross species variation in nursing patterns and milk composition as well as the mechanisms underlying mammary gland development, milk production and letdown. Not all women breastfeed their infants, thus in later sections we review studies of factors that facilitate or impede the initiation and duration of breastfeeding. The results of these investigations suggest that the decisions to initiate and maintain breastfeeding are influenced by an array of personal, social and biological factors. Finally, studies comparing the development of breastfed and formula fed infants as well as those investigating associations between breastfeeding, maternal health and mother/infant interaction are reviewed. Leading health agencies including the World Health Organization and CDC advocate breastfeeding for at least the first 6months postpartum. To achieve these rates will require not only institutional support but also a focus on individual mother/infant dyads and their experience.
Assuntos
Aleitamento Materno , Lactação/fisiologia , Comportamento Materno/fisiologia , Relações Mãe-Filho , Período Pós-Parto/fisiologia , Animais , Feminino , Humanos , Lactente , Leite , MãesRESUMO
Among the numerous physiological changes that accompany lactation is the suppression of the reproductive axis. The aim of this study was to investigate a possible role for the kisspeptin system in the restoration of the hypothalamic-pituitary-gonadal axis during late lactation in rats using a food restriction model that allows manipulation of the duration of lactational anovulation. Kiss1 mRNA expression and kisspeptin-immunoreactive cell counts were examined in both food-restricted dams and ad libitum (AL)-fed dams across late lactation when LH concentrations begin to increase. In the arcuate nucleus, Kiss1 mRNA expression and kisspeptin-positive cell counts were suppressed during late lactation. In the anteroventral periventricular (AVPV), day 15 food-restricted dams had significantly lower AVPV Kiss1 mRNA expression and a decreased LH response to exogenous kisspeptin compared with the AL-fed dams. Following 5 days of ad libitum food intake, these values were restored to levels similar to those in dams that had been fed ad libitum throughout lactation. In conclusion, this study shows that delayed restoration of the reproductive axis due to food restriction is associated with a decrease in kisspeptin sensitivity and low AVPV Kiss1 mRNA in late lactation.
Assuntos
Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Kisspeptinas/metabolismo , Kisspeptinas/farmacologia , Lactação/fisiologia , Hormônio Luteinizante/metabolismo , Animais , Anovulação/metabolismo , Anovulação/fisiopatologia , Núcleo Arqueado do Hipotálamo/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/fisiologia , Hipotálamo Anterior/metabolismo , Modelos Animais , RNA Mensageiro/metabolismo , Ratos , Ratos WistarRESUMO
Recent evidence has demonstrated that consumption of high fat diets can trigger brain inflammation and subsequent injury in the absence of any peripheral inflammatory signaling. Here we sought to investigate whether a link exists between the concentration of highly saturated fats in the diet and the development of inflammation in the brain of rats and, whether the source of the saturated fat was an important factor in this process. Adult male rats had access to diets with a moderate level of total fat (32% of calories as fat) varying in level of saturated fat [low (20%) vs high (>60%)] and its source (butter or coconut oil). After 8 weeks of diet exposure peripheral and central tissues were collected for analysis of inflammatory signals. Neither blood nor white adipose tissue exhibited any changes in inflammatory mediators regardless of the saturated fat content or the source. In the brain however, we observed significant hypothalamic upregulation of the expression of markers of glial activation as well as of interleukin (IL)-1,6 and nuclear factor (NF)-IL-6, which were highest in the group fed the butter-based diets. The increase in these inflammatory mediators had no effect on basal body temperature or the temperature response to systemic lipopolysaccharide (LPS). The present results indicate that hypothalamic inflammation associated with consumption of diets high in fat is directly linked to the saturated fat content as well as the source of that fat. These effects are likely linked to other pathophysiological changes in the regulation of metabolism.
Assuntos
Gorduras na Dieta/toxicidade , Hipotálamo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Temperatura Corporal , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Sickness behaviors and fever during infection constitute an adaptive and tightly regulated mechanism designed to efficiently clear the invading pathogen from the body. Recent literature has demonstrated that changes in energy status can profoundly affect the fever response to an acute immune challenge. The purpose of the present study was to investigate whether the exacerbating effect of diet induced obesity (DIO) on the LPS-induced fever response demonstrated previously would generalize to other sickness behaviors and, further, whether incremental changes in body weight would influence these responses. Results showed that DIO male Wistar rats exhibited a higher number of sickness symptoms for a longer period after lipopolysaccharide (LPS) injection (100µg/kg) than lean rats. Similarly, they showed a more prolonged fever and a delayed recovery from LPS-induced suppression of social interaction. No difference in locomotor activity was observed between obese and lean groups. Comparisons among groups that varied in body weight showed that an 11% increase in body weight was sufficient to increase the number and duration of sickness symptoms displayed after an LPS-injection and that the severity of sickness symptoms increased with increasing body weight. Together these data suggest that DIO can have profound effects on multiple behavioral responses to an acute immune challenge placing obese organisms at higher risk of the consequences of prolonged inflammation.
Assuntos
Comportamento de Doença/fisiologia , Obesidade/imunologia , Obesidade/fisiopatologia , Comportamento Social , Animais , Dieta Hiperlipídica/efeitos adversos , Comportamento de Doença/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/imunologia , Masculino , Ratos , Ratos WistarRESUMO
Leptin is an important modulator of both inflammation and energy homeostasis, making it a key interface between the inflammatory response to pathogenic stimuli and the energy status of the host. In previous studies we demonstrated that sickness responses to systemic immune challenge, including fever, are significantly exacerbated in diet induced obese animals. To investigate whether this exacerbation is functionally linked to the obesity associated increase in circulating levels of leptin, a species-specific leptin antiserum (LAS) was used to neutralize endogenous leptin in diet-induced obese adult male Wistar rats treated with a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) (100µg/kg). LAS significantly reduced the magnitude of the later phases of the fever response, and attenuated the circulating levels of IL-6, IL-1ra and bioactivity of leptin in the obese animals. In addition, the antiserum significantly attenuated the hypothalamic expression of IL-1ß, IκBα, COX2, SOCS3 and IL-6 in both lean and obese rats 10h after the LPS injection and NF-IL6 in the hypothalamus of obese rats only. The relatively late rise in brain IL-6 suggested a role in mediating the extended fever response in obese animals and we tested this by neutralizing brain IL-6 using an IL6-AS injected intracerebroventricularly (4µl, icv). The IL6-AS significantly but transiently (between 9h and 12h post LPS) reduced the late fever response of obese rats. These results demonstrate that leptin plays an important part in modulating the late portion of the fever response to LPS, likely through the induction of hypothalamic IL-6 in obese animals.
Assuntos
Febre/metabolismo , Hipotálamo/metabolismo , Interleucina-6/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica , Febre/sangue , Febre/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-6/sangue , Lipopolissacarídeos , Masculino , Obesidade/sangue , Obesidade/etiologia , Ratos , Ratos Wistar , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
The increasing prevalence of diabetes is of particular concern in women of childbearing age because of the short and long-term consequences of maternal diabetes for the health of the offspring, such as a greater risk of developing metabolic impairments and cognitive deficits. In addition, maternal diet during pregnancy and lactation might contribute to preventing or ameliorating adverse offspring outcomes. Recently, we described that access to snacks exacerbates glucose intolerance in mildly hyperglycemic pregnant dams. Therefore, we hypothesized that these offspring would show greater impairment in metabolic and behavioral outcomes across the lifespan. Neonatal STZ treatment was employed to induce maternal mild hyperglycemia in females. After mating, normo- and hyperglycemic dams were given access either to standard chow or standard show plus snacks. Male and female offspring were evaluated on postnatal days (PND) 30, 90, and 360. Offspring behavior was assessed in the marble burying task, the open-field test, the elevated-plus maze, and sucrose preference. Glucose tolerance and morphometric analyses were also carried out. Maternal hyperglycemia increased body weight and fat deposition only on PND 30, while retroperitoneal fat deposition was reduced in the offspring of snack-fed dams. However, maternal snack intake reduced offspring body weight and length on PND 90. Fasting glucose was increased in females born to hyperglycemic, snack-fed dams on PND 90. Glucose clearance was altered by both maternal conditions in male offspring on PND 30, however, this sex difference was reversed on PND 90, with maternal hyperglycemia impairing glucose clearance only in females. In addition, maternal hyperglycemia reduced anxiety-like behavior in female offspring on PND 30, especially in the offspring of snack-fed dams, while maternal snack intake reduced sucrose preference in both males and females in adulthood. These results suggest that the effects of maternal hyperglycemia during pregnancy and lactation on offspring outcomes were not exacerbated by snack intake. Although additive effects of the two maternal conditions were hypothesized, the absence of such effects could be related to the mild maternal hyperglycemia induced by STZ treatment even when combined with snack intake. While maternal hyperglycemia alone impaired some offspring outcomes, its association with snack intake did not aggravate those impairments but rather resulted in outcomes more similar to those of offspring born to normoglycemic dams. Finally, females were found to be more susceptible to both the effects of maternal hyperglycemia and snack intake on metabolism and behavior.
Assuntos
Diabetes Mellitus , Intolerância à Glucose , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Recém-Nascido , Feminino , Masculino , Humanos , Lanches , Longevidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Peso Corporal , Glucose , Sacarose , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
Providing nutrients to their developing young is perhaps the most energetically demanding task facing female mammals. In this paper we focus primarily on studies carried out in rats to describe the changes in the maternal brain that enable the dam to meet the energetic demands of her offspring. In rats, providing milk for their litter is associated with a dramatic increase in caloric intake, a reduction in energy expenditure and changes in the pattern of energy utilization as well as storage. These behavioral and physiological adaptations result, in part, from alterations in the central pathways controlling energy balance. Differences in circulating levels of metabolic hormones such as leptin, ghrelin and insulin as well as in responsiveness to these signals between lactating and nonlactating animals, contribute to the modifications in energy balance pathways seen postpartum. Suckling stimulation from the pups both directly, and through the hormonal state that it induces in the mother, plays a key role in facilitating these adaptations.
Assuntos
Ingestão de Alimentos/fisiologia , Lactação/fisiologia , Adaptação Fisiológica , Animais , Animais Lactentes , Núcleo Arqueado do Hipotálamo/fisiologia , Tronco Encefálico/fisiologia , Colecistocinina/sangue , Ingestão de Energia , Metabolismo Energético/fisiologia , Estrogênios/sangue , Feminino , Grelina/sangue , Glucocorticoides/sangue , Hipotálamo/fisiologia , Insulina , Leptina/sangue , Tamanho da Ninhada de Vivíparos , Mesencéfalo/fisiologia , Ocitocina/sangue , Período Pós-Parto , Prolactina/sangue , RatosRESUMO
Previous studies have shown that estrogen affects whether a hippocampus-mediated place (allocentric) or a striatum-mediated response (egocentric) memory system is employed by female rats when searching for a food reward in a maze. Because it has been suggested that reproductive experience alters some of the responses to E in the brain, two experiments were carried out to investigate whether reproductive experience would also alter the effect of E on place and response learning. In experiment 1, 152 ovariectomized nulliparous (n=77; no reproductive experience) and primiparous (n=74; having had and raised one litter of pups) Wistar rats were trained on an ambiguous t-maze task and tested for memory system bias. In experiment 2, 35 ovariectomized nulliparous (n=16) and primiparous (n=19) Wistar rats were trained on place and response plus-maze tasks. All rats were exposed to no, chronic low or chronic low with pulsatile high 17ß-estradiol (E2) replacement. Congruent with previous findings, low E2 nulliparous rats showed predominant use of response memory and faster response learning, whereas high E2 nulliparous rats showed a trend towards predominant place memory use. Interestingly, the facilitatory effect of low E2 on response task learning and memory seen in nulliparous rats was not observed in low E2 primiparous rats in either experiment. In conclusion, E2 levels do dictate the rate at which female rats learn a response task and utilize response memory, but only in those with no reproductive experience.
Assuntos
Comportamento Animal/fisiologia , Estradiol/farmacologia , Estrogênios/farmacologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Paridade/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Testes Neuropsicológicos , Ovariectomia/métodos , Paridade/efeitos dos fármacos , Gravidez , Ratos , Ratos WistarRESUMO
Introduction: Gestational diabetes (GDM) is associated with negative outcomes in mothers and their offspring, including greater risks of macrosomia at birth and the development of metabolic disorders. While these outcomes are well-established, the mechanisms by which this increased metabolic vulnerability is conferred on the offspring are comparatively lacking. One proposed mechanism is that maternal glycemic dysregulation alters the development of the hypothalamic regions related to metabolism and energy balance. Methods: To investigate this possibility, in this study, we first examined the effects of STZ-induced maternal glucose intolerance on the offspring on pregnancy day (PD) 19, and, in a second experiment, in early adulthood (postnatal day (PND) 60). Whether effects would be influenced by sex, or exposure of offspring to a high-fat diet was also investigated. The impact of maternal STZ treatment on POMC neuron number in the ARC of offspring at both time points was also examined. Results: As expected, STZ administration on PD 7 decreased maternal glucose tolerance, and increased risk for macrosomia, and loss of pups at birth. Offspring of STZ-treated mothers were also more vulnerable to developing metabolic impairments in adulthood. These were accompanied by sex-specific effects of maternal STZ treatment in the offspring, including fewer POMC neurons in the ARC of female but not male infants in late pregnancy and a higher number of POMC neurons in the ARC of both male and female adult offspring of STZ-treated dams, which was exacerbated in females exposed to a high-fat diet after weaning. Discussion: This work suggests that maternal hyperglycemia induced by STZ treatment, in combination with early-life exposure to an obesogenic diet, leads to adult metabolic alterations that correlate with the increased hypothalamic expression of POMC, showing that maternal glycemic dysregulation can impact the development of hypothalamic circuits regulating energy state with a stronger impact on female offspring.
Assuntos
Diabetes Gestacional , Intolerância à Glucose , Efeitos Tardios da Exposição Pré-Natal , Masculino , Recém-Nascido , Gravidez , Humanos , Feminino , Adulto , Macrossomia Fetal , Intolerância à Glucose/etiologia , Pró-Opiomelanocortina/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Dieta Hiperlipídica/efeitos adversosRESUMO
Ghrelin is considered one of the most potent orexigenic peptide hormones and one that promotes homeostatic and hedonic food intake. Research on ghrelin, however, has been conducted predominantly in males and particularly in male rodents. In female mammals the control of energy metabolism is complex and it involves the interaction between ovarian hormones like estrogen and progesterone, and metabolic hormones. In females, the role that ghrelin plays in promoting feeding and how this is impacted by ovarian hormones is not well understood. Basal ghrelin levels are higher in females than in males, and ghrelin sensitivity changes across the estrus cycle. Yet, responses to ghrelin are lower in female and seem dependent on circulating levels of ovarian hormones. In this review we discuss the role that ghrelin plays in regulating homeostatic and hedonic food intake in females, and how the effects of ghrelin interact with those of ovarian hormones to regulate feeding and energy balance.
Assuntos
Comportamento Alimentar , Grelina , Animais , Metabolismo Energético , Comportamento Alimentar/fisiologia , Feminino , Homeostase , Masculino , Mamíferos/metabolismoRESUMO
Lactating rats show changes in the secretion of hormones and brain signals that promote hyperphagia and facilitate the production of milk. Little is known, however, about the role of ghrelin in the mechanisms sustaining lactational hyperphagia. Here, we used Wistar female rats that underwent surgery to sever the galactophores to prevent milk delivery (GC rats) and decrease the energetic drain of milk delivery. We compared plasma acyl-ghrelin concentrations and growth hormone secretagogue receptor (GHSR) mRNA expression in different brain regions of GC rats with those of sham operated lactating and nonlactating rats. Additional lactating and nonlactating rats were implanted with cannulae aimed at the lateral ventricles and were used to compare feeding responses to central ghrelin or GHSR antagonist infusions to those of nonlactating rats receiving similar infusions on day 14-16 postpartum (pp). Results show lower plasma acyl-ghrelin concentrations on day 15 pp sham operated lactating rats compared to GC or nonlactating rats. These changes occur in association with increased GHSR mRNA expression in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA) of sham operated lactating rats. Despite lactational hyperphagia, infusions of ghrelin (0.25 or 1 µg) resulted in similar increases in food intake in lactating and nonlactating rats. In addition, infusions of the GHSR antagonist JMV3002 (4 µg in 1 µl of vehicle) produced greater suppression of food intake in lactating rats than in nonlactating rats. These data suggest that, despite lower plasma ghrelin, the energetic drain of lactation increases sensitivity to the orexigenic effects of ghrelin in brain regions important for food intake and energy balance, and these events are associated with lactational hyperphagia.
Assuntos
Grelina , Hipotálamo , Lactação , Receptores de Grelina , Área Tegmentar Ventral , Animais , Feminino , Grelina/sangue , Hiperfagia , Hipotálamo/metabolismo , Lactação/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Grelina/metabolismo , Área Tegmentar Ventral/metabolismoRESUMO
Astroglial cells are key players in the development and maintenance of neurons and neuronal networks. Astroglia express steroid hormone receptors and show rapid responses to hormonal manipulations. However, despite important sex differences in the cortex and hippocampus, few studies have examined sex differences in astroglial cells in telencephalic development. To characterize the cortical astroglial translatome in male and female mice across postnatal development, we use translating ribosome affinity purification together with RNA sequencing and immunohistochemistry to phenotype astroglia at six developmental time points. Overall, we find two distinct astroglial phenotypes between early (P1-P7) and late development (P14-adult), independent of sex. We also find sex differences in gene expression patterns across development that peak at P7 and appear to result from males reaching a mature astroglial phenotype earlier than females. These developmental sex differences could have an impact on the construction of neuronal networks and windows of vulnerability to perturbations and disease.
Assuntos
Astrócitos/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Caracteres Sexuais , Animais , Células Cultivadas , Feminino , Masculino , Camundongos Endogâmicos C57BL , Neocórtex/metabolismoRESUMO
Most psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.
Assuntos
Receptores de Grelina , Área Tegmentar Ventral , Animais , Grelina , Masculino , Camundongos , Camundongos Knockout , Motivação , Receptores de Grelina/metabolismo , Secretagogos , Área Tegmentar Ventral/metabolismoRESUMO
Chronic exposure to high circulating glucocorticoid or ghrelin concentrations increases food intake, weight gain and adiposity, suggesting that ghrelin could contribute to the metabolic effects of chronic glucocorticoids. In male mice, however, blocking ghrelin receptor (GHSR) signaling increased the weight gain and adiposity induced by chronic corticosterone (CORT), rather than attenuating them. In the current study, we investigated the role of GHSR signaling in the metabolic effects of chronic exposure to high circulating CORT in female mice. To do this, female WT and GHSR KO mice were treated with either CORT in a 1% ethanol (EtOH) solution or 1% EtOH alone in their drinking water for 32 days (n = 5-8/group). Body weight, food, and water intake as well as vaginal cyclicity were assessed daily. As expected, CORT treatment-induced significant increases in body weight, food intake, adiposity and also impaired glucose tolerance. In contrast to results observed in male mice, WT and GHSR KO female mice did not differ on any of these parameters. Neither plasma levels of ghrelin, LEAP-2, the endogenous GHSR antagonist produced by the liver, nor their ratio were altered by chronic glucocorticoid exposure. In addition, CORT treatment disrupted vaginal cyclicity, produced a reduction in sucrose consumption and increased locomotor activity regardless of genotype. Chronic CORT also decreased exploration in WT but not GHSR KO mice. Collectively, these data suggest that most metabolic, endocrine, reproductive and behavioral effects of chronic CORT exposure are independent of GHSR signaling in female mice.
Assuntos
Corticosterona/administração & dosagem , Obesidade/etiologia , Receptores de Grelina/fisiologia , Transdução de Sinais/fisiologia , Adiposidade/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/sangue , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Grelina/sangue , Camundongos , Camundongos Knockout , Receptores de Grelina/deficiência , Receptores de Grelina/genética , Aumento de Peso/efeitos dos fármacosRESUMO
Metabolic disorders, like diabetes, as well as maternal diet, alter nutrient availability in utero, inducing adaptations in the offspring. Whether the effects of maternal hyperglycemia are modulated by diet, however, has yet to be explored. In the current study, we examined this issue by giving females rats, treated neonatally with STZ to induce mild hyperglycemia, and control littermates either ad libitum access to standard chow (Control n = 17; STZ n = 16) or standard chow and snacks (Control-snack n = 18; STZ-snack n = 19) (potato chips and a red fruit-flavored sucrose syrup solution 1.5%) throughout pregnancy and lactation. We hypothesized that the maternal glucose intolerance typically seen in female rats treated neonatally with STZ would be exacerbated by snack intake, and that the combination of snack intake and STZ treatment would lead to alterations in maternal behavior and offspring development. Maternal body weight and food intake were measured daily through pregnancy and lactation and litter weight throughout lactation. At birth, litter size, offspring weight, body length, and anogenital distance were obtained and offspring were classified according to their weight. Measures of nursing and retrieval behavior, as well as exploration in the open field and the elevated plus-maze were also recorded. As predicted, snack intake tended to aggravate the glucose intolerance of STZ-treated rats during pregnancy. Both Control and STZ-treated females that had access to snacks ate more calories and fat, but less carbohydrate and protein than females having access to chow alone. Overall, STZ-treated dams gave birth to fewer pups. Chow-fed STZ females gave birth to a greater proportion of large for pregnancy age pups, whereas dams in the Control-snack group gave birth to a greater proportion of small pups. The birth weight classification of pups born to STZ-snack rats, however, resembled that of the Control chow-fed females. Although all litters gained weight during lactation, litters from snack-fed dams gained less weight regardless of maternal hyperglycemia and did not show catch-up growth by weaning. Overall, STZ rats spent more time nest building, whereas the average inter milk ejection interval was higher in snack-fed females. STZ-snack dams retrieved the complete litter faster than dams in the other groups. Together, these data suggest that when mild hyperglycemic females are given access to snacks throughout pregnancy and lactation their intake is similar to that of Control females given snack access. The combination of hyperglycemia and snack access tended to decrease glucose tolerance in pregnancy, and normalized birth weight classification, but produced few other effects that were not seen as a function of snack intake or hyperglycemia alone. Since birth weight is a strong predictor of health issues, future studies will further investigate offspring behavioral and metabolic outcomes later in life.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Lanches , Animais , Peso Corporal , Feminino , Lactação , Gravidez , Ratos , Ratos Wistar , ReproduçãoRESUMO
Lactation is associated with suppression of reproductive function, the duration of which depends on the number of young suckled and food availability. Although previous studies have documented increasing responsivity to the positive feedback effects of estrogen on luteinizing hormone (LH) secretion with time postpartum, changes in the ability of estrogen to stimulate sexual behavior across these time points and the influence of food restriction on response to estrogen have not been investigated. Thus, we compared the ability of exogenous estrogen administration to stimulate proceptive and receptive behavior in ad libitum fed and food restricted rats on Days 15 and 20 postpartum. Because the ability of estrogen to induce sexual behavior depends on activation of both estrogen receptors and estrogen-induced progesterone receptors, a second study compared estrogen and progesterone-ir within the VMH and MPOA in similar groups. Finally, we investigated the role of the high levels of progesterone typical of lactation in the suppression of estrogen-induced sexual behavior by transient blockade of the progesterone receptor using RU486. As expected there was an increase across time in the ability of estrogen to stimulate sexual behavior that correlated with an increased ability of estrogen to induce progesterone receptors in the MPOA that was most evident in ad libitum fed rats. RU486 administration concomitant with estrogen administration increased solicitation behavior and was most effective in ad libitum fed rats suggesting an inhibitory role of progesterone on estrogen-induced sexual proceptivity in lactating rats.
Assuntos
Estrogênios/metabolismo , Lactação/fisiologia , Receptores de Progesterona/metabolismo , Comportamento Sexual Animal/fisiologia , Animais , Contagem de Células , Dieta , Receptor alfa de Estrogênio/metabolismo , Feminino , Antagonistas de Hormônios/farmacologia , Imuno-Histoquímica , Masculino , Mifepristona/farmacologia , Período Pós-Parto/fisiologia , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/fisiologia , Ratos , Ratos Wistar , Receptores de Progesterona/antagonistas & inibidores , Fatores de Tempo , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/fisiologiaRESUMO
Neuropeptide Y (NPY) is increased in the hypothalamus during lactation. To investigate the role of the NPY Y5 receptor during lactation, an antisense oligodeoxynucleotide (ODN) targeted to the NPY Y5 receptor, an equivalent scrambled ODN or vehicle, was chronically infused into the 3rd ventricle of lactating rats from day 8 postpartum. Y5 antisense ODN treatment reduced Y5 positive cell number in the paraventricular nucleus and resulted in significant reductions in food intake and litter growth. Litters from pair-fed vehicle treated dams gained significantly more weight than the litters of Y5 antisense ODN treated dams suggesting that decreased maternal food intake is not the only mechanism involved in suppressing litter weight gain. When mother-litter interaction was examined on day 13 pp, Y5 antisense ODN treated dams spent significantly less time on the nest and had significantly shorter nest bouts. These results suggest that in addition to regulating feeding behaviour, the Y5 receptor subtype may have previously unrecognised roles in the control of nesting behaviour during lactation with subsequent effects on litter growth rates.