Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats

Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24 h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24 h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v) + glucose 3% (w/v), and glucose 3% (w/v)) for 15 days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development.     

Maternal deprivation has sexually dimorphic long-term effects on hypothalamic cell-turnover, body weight and circulating hormone levels

Maternal deprivation (MD) has numerous outcomes, including modulation of neuroendocrine functions. We previously reported that circulating leptin levels are reduced and hypothalamic cell-turnover is affected during MD, with some of these effects being sexually dimorphic. As leptin modulates the development of hypothalamic circuits involved in metabolic control, we asked whether MD has long-term consequences on body weight, leptin levels and the expression of neuropeptides involved in metabolism. Rats were separated from their mother for 24 h starting on postnatal day (PND) 9 and sacrificed at PNDs 13, 35 and 75. In both sexes MD reduced body weight, but only until puberty, while leptin levels were unchanged at PND 35 and significantly reduced at PND 75. Adiponectin levels were also reduced at PND 75 in females, while testosterone levels were reduced in males. At PND 13, MD modulated cell-turnover markers in the hypothalamus of males, but not females and increased nestin, a marker of immature neurons, in both sexes, with males having higher levels than females and a significantly greater rise in response to MD. There was no effect of MD on hypothalamic mRNA levels of the leptin receptor or metabolic neuropeptides or the mRNA levels of leptin and adiponectin in adipose tissue. Thus, MD has long-term effects on the levels of circulating hormones that are not correlated with changes in body weight. Furthermore, these endocrine outcomes are different between males and females, which could be due to the fact that MD may have sexually dimorphic effects on hypothalamic development.     

Early life conditions,reproductive and sexuality-related life history outcomes among human males: A systematic review and meta-analysis

In order to investigate the association between early life conditions and reproductive and sexuality-related life history outcomes among men, we conducted a meta-analysis that compiled the results of 198 articles. A total of 331 effect sizes drawn from 573 samples were included. The meta-analysis revealed that low family socioeconomic status was associated with early sexual debut (r = 0.07), early first birth (r = 0.14), and early marriage (r = 0.03). There was no significant association between family socioeconomic status and pubertal timing or number of sexual partners. Parental absence was associated with early sexual debut (r = ? 0.12), greater number of sexual partners (r = ? 0.19), early first birth (r = ? 0.14), and early marriage (r = ? 0.13). There was no significant association between parental absence and pubertal timing. Small body size before puberty was associated with delayed pubertal timing (r = ? 0.10). There was no significant association between adult body size and number of offspring, and between body size at birth and pubertal timing. Small adult body size, greater number of siblings, and older parents were associated with non-heterosexual orientation (rs = 0.12, 0.03, and 0.03 respectively). Factors such as sampling procedure, data collection method, and age cut-off used to measure family structure change influenced the association between some predictors (e.g., family socioeconomic status) and outcomes (e.g., first birth). The findings are discussed in relation to the utility of life history theory for understanding human male reproductive and sexuality-related outcomes.     

Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats

Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect.     

Role of premature leptin surge in obesity resulting from intrauterine undernutrition

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to “developmental origins of health and disease.”     

Maternal Obesity Induced by Diet in Rats Permanently Influences Central Processes Regulating Food Intake in Offspring

Hypothalamic systems which regulate appetite may be permanently modified during early development. We have previously reported hyperphagia and increased adiposity in the adult offspring of rodents fed an obesogenic diet prior to and throughout pregnancy and lactation. We now report that offspring of obese (OffOb) rats display an amplified and prolonged neonatal leptin surge, which is accompanied by elevated leptin mRNA expression in their abdominal white adipose tissue. At postnatal Day 30, before the onset of hyperphagia in these animals, serum leptin is normal, but leptin-induced appetite suppression and phosphorylation of STAT3 in the arcuate nucleus (ARC) are attenuated; the level of AgRP-immunoreactivity in the hypothalamic paraventricular nucleus (PVH), which derives from neurones in the ARC and is developmentally dependent on leptin, is also diminished. We hypothesise that prolonged release of abnormally high levels of leptin by neonatal OffOb rats leads to leptin resistance and permanently affects hypothalamic functions involving the ARC and PVH. Such effects may underlie the developmental programming of hyperphagia and obesity in these rats.     

Effect of arousing stimuli on circulating corticosterone and the circadian rhythms of luteinizing hormone (LH) surges and locomotor activity in estradiol-treated ovariectomized (ovx + EB) Syrian hamsters

In most proestrous hamsters, novel wheel exposure phase advances activity rhythms and blocks the preovulatory LH surge, which occurs 2 h earlier the next day. Because wheel immobilization does not prevent these effects we hypothesized that arousal alone blocks and phase advances the LH surge. Ovariectomized (ovx) hamsters received a jugular vein cannula and estradiol benzoate (EB) or vehicle was injected sc. The next day (Day 1), at zeitgeber time (ZT) 4–5 (ZT 12 = lights off), after obtaining a blood sample, each hamster was exposed to constant darkness (DD), and either remained in her home cage or was transferred to a new cage and exposed to a running wheel or a 2-hour arousal paradigm. Blood samples were obtained in dim red light and activity was recorded hourly until ~ ZT 10–11 on Days 1 and 2. For the next 1–2 weeks, activity was monitored in DD. Plasma LH and corticosterone were assessed by RIA. Novel wheel exposure or arousal at ZT 4 greatly attenuated the Day 1 LH surge in ovx + EB hamsters, and phase advanced the Day 2 LH surge by about 2 h. In proestrous hamsters, novel wheel exposure led to a prolonged (> 2 h) increase in corticosterone levels only when LH surges were blocked. Phase advances in activity rhythms were enhanced by estradiol and arousal. The results suggest that estradiol modulates the effectiveness of non-photic stimuli. The role of the increased activity of the hypothalamic–pituitary–adrenal axis associated with novel wheel-induced attenuation of LH surges in ovx + EB hamsters remains to be determined.     

Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice

Orexins are hypothalamic neuropeptides, which are involved in several physiological functions of the central nervous system, including anxiety and stress. Several studies provide biochemical and behavioral evidence about the anxiogenic action of orexin A. However, we have little evidence about the underlying neuromodulation. Therefore, the aim of the present study was to investigate the involvement of neurotransmitters in the orexin A-induced anxiety-like behavior in elevated plus maze (EPM) test in mice. Accordingly, mice were pretreated with a non-selective muscarinic cholinergic antagonist, atropine; a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; a non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol 30 min prior to the intracerebroventricular administration of orexin A. The EPM test started 30 min after the i.c.v. injection of the neuropeptide. Our results show that orexin A decreases significantly the time spent in the arms (open/open + closed) and this action is reversed by bicuculline, phenoxybenzamine and propranolol, but not by atropine, haloperidol or nitro-l-arginine. Our results provide evidence for the first time that the orexin A-induced anxiety-like behavior is mediated through GABA-A-ergic, α- and β-adrenergic neurotransmissions, whereas muscarinic cholinergic, dopaminergic and nitrergic neurotransmissions may not be implicated.     

Relation between leptin and estradiol levels in Egyptian lactating Arab mares during foaling heat

Sixteen Arab lactating mares belonging to Al-Zahraa Arab Horse Stud underwent two ultrasound examinations at 3 weeks interval starting from the day of demonstration of foaling heat. In addition, daily blood samples were collected from parturition until after exhibiting first postpartum estrus (day 11) with daily observation of estrous signs. Both leptin and estradiol hormones were assayed. Mean day of foaling heat was 8.9 ± 0.9 day. Most mares came in foaling heat during days 9 and 10 had high conception rate compared to those who came in estrus earlier or later. Estradiol levels were high after day of foaling then decrease after expression of foaling heat. But leptin levels increase from day 8 to day 10 compared to other days before and after the first ovulation. A significant positive correlation was found between estradiol and leptin (r = 0.58, p < 0.025). The positive correlation between leptin and estradiol led us to suggest that leptin hormone plays an important role in ovulation of the first postpartum estrus in mares.     

Plasma leptin level predicts hematoma growth and early neurological deterioration after acute intracerebral hemorrhage

Higher plasma leptin levels have been associated with poor clinical outcomes after intracerebral hemorrhage. Nevertheless, their links with hematoma growth and early neurological deterioration are unknown. Therefore, we aimed to investigate the relationship between plasma leptin levels, hematoma growth, and early neurological deterioration in patients with acute intracerebral hemorrhage. We prospectively studied 102 consecutive patients with acute spontaneous basal ganglia hemorrhage presenting within 6 h from symptoms onset. Significant hematoma growth was defined as hematoma enlargement >33% at 24 h. Early neurological deterioration was defined as an increase of ≥4 points in National Institute of Health Stroke Scale score at 24 h from symptoms onset. We measured plasma leptin levels on admission using an enzyme-linked immunosorbent assay in a blinded fashion. In multivariate logistic regression analysis, plasma leptin level emerged as the independent predictor of hematoma growth (odds ratio, 1.182; 95% confidence interval, 1.061–2.598; P = 0.008) and early neurological deterioration (odds ratio, 1.193; 95% confidence interval, 1.075–2.873; P = 0.004). Using receiver operating characteristic curves, we calculated areas under the curve for hematoma growth (area under curve, 0.844; 95% confidence interval, 0.759–0.908) and early neurological deterioration (area under curve, 0.857; 95% confidence interval, 0.774–0.918). The predictive performance of leptin was similar to, but did not obviously improve that of hematoma volume. Thus, leptin may help in the prediction of hematoma growth and early neurological deterioration after intracerebral hemorrhage.     

Metabolic response of short term calorie restriction and supplementation with Hoodia gordonii

Hoodia gordonii is a supplement of natural origin which is known for its appetite suppressant activity. Owing to its anorectic activity, the aim of this study was to evaluate the effect of H. gordonii supplementation on metabolic changes and appetite regulatory peptides during calorie restriction. Male albino rats were divided into three groups (n = 12 in each) — Control, Calorie Restricted (CR, 25% for 5 days), Calorie Restricted and H. gordonii supplemented (CR + HG, organic solvent extract given orally for 5 days at a dose of 100 mg/kg bwt.). The regulatory peptides i.e. ghrelin, leptin, CCK, NPY, insulin, IGF-1, corticosterone, thyroid hormones, adiponectin, serotonin were determined. On comparison with CR rats, modulations were noticed in the appetite regulatory peptides and biochemical variables of the CR + HG rats. A significant decline in ghrelin and increase in CCK was observed. The CR group exhibited a significant decrease in leptin, IGF-1, plasma and whole brain serotonin with a significant increase in the ghrelin and thyroxin levels. These changes indicate altered metabolic responses and hunger suppression which seem to be caused by H. gordonii with CR along with the changes occurring due to CR itself. It is concluded that H. gordonii can modulate hunger during CR and may be used for better adherence to dietary restriction regime.     

Prolactin administration during early postnatal life decreases hippocampal and olfactory bulb neurogenesis and results in depressive-like behavior in adulthood

Tight regulation of hormone and neurochemical milieu during developmental periods is critical for adequate physiological functions. For instance, activation of peptide systems during early life stress induces morphological changes in the brain resulting in depression and anxiety disorders. Prolactin (PRL) exerts different actions within the brain; it regulates neurogenesis and modulates neuroendocrine functions in the adult. However, PRL effects during early postnatal life are hardly known. Therefore, we examined whether neonatal administration of PRL influences cell survival in the hippocampal dentate gyrus (DG) and in the olfactory bulb (OB) and whether such influence results in behavioral consequences in adulthood. PRL-treated rat pups (13 mg/kg; PND1 to PND14), injected with BrdU at postnatal day 5 (PND5), showed a decrease in the density of DG BrdU/DCX and BrdU/NeuN-positive cells that survive at PND15. Similarly, PRL treatment decreased the density of BrdU + cells in the OB compared with VEH. Fluorojade B analysis showed no significant changes in the amount of cell death in the DG between the groups. Postnatal PRL administration induced a passive coping strategy in the forced swimming test in male and female adult rats when compared with control and vehicle groups. Corticosterone endogenous levels at PND12 were not affected by PRL or VEH treatment. Altogether, these results suggest that opposed to its effects in the adult, postnatal PRL treatment affects neurogenesis and results in psychopathology later in life. High PRL levels, as observed in neonates under several pathological states, might contribute to detrimental effects on the developing brain.     

High plasma leptin levels are associated with impaired diastolic function in patients with coronary artery disease

Background and aimsObese subjects have elevated leptin levels, which have been associated with increased risk of cardiovascular events. Because leptin has direct cellular effects on various tissues, we tested the hypothesis that leptin levels are associated with cardiac structure or function in patients with coronary artery disease (CAD).Methods and resultsThe study population consisted of 1 601 CAD patients, of whom 42% had type 2 diabetes mellitus. Plasma leptin was measured in fasted state and an echocardiography performed. Leptin levels were not related to LV dimensions or LV ejection fraction (NS for all), but higher leptin levels were associated with elevated E/E’ (9.43 vs. 11.94 in the lowest and the highest leptin quartile, respectively; p = 0.018 for trend). Correspondingly, a decreasing trend was observed in E/A (1.15 vs. 1.06; p = 0.037). These associations were independent of obesity and other relevant confounding variables.ConclusionWe conclude that elevated plasma leptin levels are associated with impaired left ventricular diastolic function in patients with CAD independently of obesity and other confounding variables. Leptin may be one of the mechanistic links explaining the development of congestive heart failure in obese subjects.     

The role of free fatty acids in the inflammatory and cardiometabolic profile in adolescents with metabolic syndrome engaged in interdisciplinary therapy

The purpose of the present study was to evaluate if interdisciplinary therapy can influence the cardiometabolic and serum free fatty acid profile. The second aim was to evaluate if there is an association between serum free fatty acids, inflammation and cardiometabolic biomarkers in obese adolescents with and without metabolic syndrome submitted to a long-term interdisciplinary therapy. The study involved 108 postpuberty obese adolescents, who were divided according to metabolic syndrome (MetS) diagnosis: MetS (n = 32) and Non-MetS (n = 76). The interdisciplinary therapy consisted of a 1-year period of nutrition, psychology, physical exercise and clinical support. After therapy, both groups improved metabolic, inflammatory (leptin, adiponectin, leptin/adiponectin ratio, adiponectin/leptin ratio and C-reactive protein) and cardiometabolic profile (PAI-1 and ICAM). Metabolic syndrome prevalence reduced from 28.70% to 12.96%. Both groups reduced myristic acid (C14:0) and increased docosahexaenoic acid (DHA, C22:6n3), heneicosapentaenoic acid (HPA, C21:5n3) and arachidonic acid (C20:4n6). After adjustment for metabolic syndrome and the number of metabolic syndrome parameters, multiple regression analysis showed that changes in VCAM and PAI-1 were negatively associated with changes in cis-linoleic acid (C18:2n6c). Additionally, changes in trans-linoleic acid (C18:2n6t) were also positively associated with these biomarkers. Moreover, leptin and leptin/adiponectin ratio were negatively associated with changes in docosapentaenoic acid (DPA, C22:5n3) and stearidonic acid (SDA, C18:4n3). Adiponectin/leptin ratio was positively associated with docosapentaenoic acid (DPA, C22:5n3). Changes in adiponectin were positively correlated with changes in omega 3, such as heneicosapentaenoic acid (HPA, C21:5n3) and docosapentaenoic acid (DPA, C22:5n3). Results support that interdisciplinary therapy can control inflammatory and cardiometabolic profile in obese adolescents. Moreover, serum fatty acids can be influenced by lifestyle changes and are able to modulate these biomarkers.     

Neonatal exposure to bisphenol A advances pubertal development in female rats

Neonatal exposure to bisphenol A (BPA) is hypothesized to advance pubertal development. However, the effects of neonatal BPA exposure on pubertal development has not been described. In this study, female Sprague‐Dawley rats were exposed to 0.05, 0.5, 5, or 10 mg·kg^?1·day^?1 BPA, or corn oil vehicle alone from postnatal day 1 (PND1) to PND10 via subcutaneous injection. We evaluated day of vaginal opening (DVO), ovarian morphology, serum hormone concentrations, and hypothalamic expression of Gnrh1 and Kiss1 in female rats at PND35. DVO was significantly advanced in rats exposed to 5 and 10 mg·kg^?1·day^?1 BPA. Serum hormone concentrations increased as BPA dose increased. Additionally, hypothalamic Gnrh1 and Kiss1 expression were increased with BPA exposure; rats exposed to 10 mg·kg^?1·day^?1 BPA had significantly upregulated hypothalamic Gnrh1 and Kiss1 expressions in terms of both messenger RNA and protein levels. Our results suggest that exposure to a 10 mg·kg^?1·day^?1 dose of BPA might advance pubertal development significantly. In addition, within the range of 0 to 10 mg·kg^?1·day^?1, neonatal exposure to BPA may affect pubertal development in a dose‐dependent manner.