ORCID Profile
0000-0002-0674-8824
Current Organisations
Deakin University
,
Barwon Health
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Publisher: Wiley
Date: 25-02-2020
DOI: 10.1111/JNE.12838
Publisher: Elsevier BV
Date: 07-2020
Publisher: Wiley
Date: 15-07-2019
DOI: 10.1111/JNE.12757
Abstract: The early-life environment is important in programming brain development, and metabolic disruptions at this time can have long-lasting effects. Previously, we have shown that rats overfed for the first 3 weeks of their neonatal life maintain obesity into adulthood. Neonatal overfeeding also leads to primed hypothalamic and hippoc al microglia that are hyper-responsive to an immune challenge in adulthood. However, whether this microglial priming contributes to the obese phenotype and whether it is possible to reverse either the obesity or the microglial priming are not clear. In the present study, we hypothesised that an intervention with minocycline during the juvenile period (postnatal day 21-42) would normalise both the microglial priming and obesity. To induce obesity in neonatal Wistar rats, we manipulated the litter sizes in which they were suckled, yielding litters of 12 (control-fed) or four (neonatally overfed). After weaning, we administered minocycline i.p. every second day for a 3-week period and examined body composition and microglial profiles 24 hours following an immune challenge with lipopolysaccharide. As demonstrated previously, neonatal overfeeding resulted in prolonged weight gain. However, minocycline failed to reverse this effect. Minocycline did reverse microglial priming in feeding-related regions of the hypothalamus, with minimal effects on pro-inflammatory cytokines and on microglial number and morphology in the hippoc us. Thus, the programming effect of neonatal overfeeding on microglial priming can be ameliorated by minocycline later in life. However, the persistent obesity seen after neonatal overfeeding is likely not driven by changes in hypothalamic inflammation and microglial activity.
Publisher: Bioscientifica
Date: 07-2017
DOI: 10.1530/JOE-16-0631
Abstract: Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill health. Neonatally overfed rats have an early increase in leptin that is maintained long term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here, we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in arcuate nucleus (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinaemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short term, but this is partly resolved by adulthood indicating an adaptation to the metabolic mal-programming effects of neonatal overfeeding.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2018
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000431378
Abstract: Fertility rates have been declining worldwide, with a growing number of young women suffering from infertility. Infectious and inflammatory diseases are important causes of infertility, and recent evidence points to the critical role of the early-life microbial environment in developmental programming of adult reproductive fitness. Our laboratory and others have demonstrated that acute exposure to an immunological challenge early in life has a profound and prolonged impact on male and female reproductive development. This review presents evidence that perinatal exposure to immunological challenge by a bacterial endotoxin, lipopolysaccharide, acts at all levels of the hypothalamic-pituitary-gonadal axis, resulting in long-lasting changes in reproductive function, suggesting that disposition to infertility may begin early in life.
Publisher: Frontiers Media SA
Date: 13-05-2014
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.BBI.2018.12.008
Abstract: Microglia are highly sensitive to dietary influence, becoming activated acutely and long-term by high fat diet. However, their role in regulating satiety and feeding in healthy in iduals remains unclear. Here we show that microglia are essential for the normal regulation of satiety and metabolism in rats. Short-term microglial depletion in a Cx3cr1-Dtr rat led to a dramatic weight loss that was largely accounted for by an acute reduction in food intake. This weight loss and anorexia were not likely due to a sickness response since the rats did not display peripheral or central inflammation, withdrawal, anxiety-like behavior, or nausea-associated pica. Hormonal and hypothalamic anatomical changes were largely compensatory to the suppressed food intake, which occurred in association with disruption of the gustatory circuitry at the paraventricular nucleus of the thalamus. Thus, microglia are important in supporting normal feeding behaviors and weight, and regulating preference for palatable food. Inhibiting this circuitry is able to over-ride strong compensatory drives to eat, providing a potential target for satiety control.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.BBI.2014.06.014
Abstract: The early life period is one of significant vulnerability to programming effects from the environment. Given the sensitivity of microglial cells to early life programming and to adult diet, we hypothesized overfeeding during the neonatal period would acutely alter microglial profiles within the developing brain, predisposing the in idual to a lasting central pro-inflammatory profile that contributes to overactive immune responses long-term. We tested this idea by manipulating litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of 4 (neonatally overfed) or 12 (control). This manipulation induces obesity and susceptibility to lipopolysaccharide (LPS) long-term. We then examined microglial and central pro-inflammatory profiles during development and in adulthood as well as susceptibility to neuroimmune challenge with LPS. Neonatally overfed rats have evidence of microgliosis in the paraventricular nucleus of the hypothalamus (PVN) as early as postnatal day 14. They also show changes in hypothalamic gene expression at this time, with suppressed hypothalamic interleukin 1β mRNA. These effects persist into adulthood, with basal PVN microgliosis and increased hypothalamic toll-like receptor 4, nuclear factor κB, and interleukin 6 gene expression. These neonatally overfed rats also have dramatically exacerbated microglial activation in the PVN 24h after an adult LPS challenge, coupled with changes in inflammatory gene expression. Thus, it appears neonatal overfeeding sensitizes PVN microglia, contributing to a basal pro-inflammatory profile and an altered response to a neuroimmune challenge throughout life. It remains to be seen if these effects can be reversed with early interventions.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2017
Publisher: Frontiers Media SA
Date: 2013
Publisher: Informa UK Limited
Date: 27-03-2011
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.BBI.2018.07.011
Abstract: Ghrelin, one of the major metabolic hormones involved in controlling energy balance, has recently been shown to have other properties including regulating the hypothalamic-pituitary-adrenal (HPA) axis response to psychological stress and being a potent anti-inflammatory agent. Ghrelin's HPA axis and anti-inflammatory actions have previously been identified as principally due to the acylated form (AG). However, our recent work has also suggested a role for des-acylated ghrelin (DAG) in these functions. Here we hypothesized ghrelin's anti-inflammatory activity is mediated by the HPA axis and this effect is differentially executed by AG and DAG. We gave adult male Wistar rats a concomitant injection of AG or DAG and lipopolysaccharide (LPS) and measured their effects on circulating cytokines, stress hormones and neuronal activation of the paraventricular nucleus of the hypothalamus (PVN). AG, but not DAG significantly suppressed the pro- and anti-inflammatory cytokine response induced by LPS in vivo. DAG also had no effects on any components of the HPA axis. AG, despite stimulating neuronal activation in the PVN in vivo and stimulating ACTH release from the pituitary in vitro, did not affect the HPA axis response to LPS. These findings suggest AG's anti-inflammatory effects are independent of its actions on the HPA axis and have implications for the potential use of this peptide for treatment of inflammatory conditions without compromising HPA axis activity.
Publisher: Wiley
Date: 30-07-2016
DOI: 10.1002/HIPO.22620
Abstract: Adolescence is a period of significant brain plasticity that can be affected by environmental factors, including the degree of physical activity. Here we hypothesized that adolescent rats would be more sensitive to the beneficial metabolic and anti-inflammatory effects of voluntary exercise than adult rats, whose more mature brains have less capacity for plasticity. We tested this by giving adolescent and adult Wistar rats four weeks' voluntary access to running wheels. At the end of this period we assessed metabolic effects, including weight and circulating leptin and ghrelin, as well as performance in a novel object recognition test of memory and central changes in neuronal proliferation, survival, synaptic density, and inflammatory markers in hippoc us. We found exercise reduced fat mass and circulating leptin levels in both adults and adolescents but suppressed total weight gain and lean mass in adults only. Exercise stimulated neuronal proliferation in the suprapyramidal blade of the dentate gyrus in both adults and adolescents without altering the number of mature neurons during this time frame. Exercise also increased dentate microglial numbers in adolescents alone and microglial numbers in this region were inversely correlated with performance in the novel object recognition test. Together these data suggest that adolescent hippoc al microglia are more sensitive to the effects of exercise than those of adults, but this leads to no apparent improvement in recognition memory. © 2016 Wiley Periodicals, Inc.
Publisher: Oxford University Press (OUP)
Date: 10-10-2017
Abstract: Normal ovarian development is crucial for female reproductive success and longevity. Interruptions to the delicate process of initial folliculogenesis may lead to ovarian dysfunction. We have previously demonstrated that an early life immune challenge in the rat, induced by administration of lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5, depletes ovarian follicle reserve long term. Here, we hypothesized that this neonatal immune challenge leads to an increase in peripheral and ovarian inflammatory signaling, contributing to an acute depletion of ovarian follicles. Morphological analysis of neonatal ovaries indicated that LPS administration significantly depleted PND 5 primordial follicle populations and accelerated follicle maturation. LPS exposure upregulated circulating interleukin 6, tumor necrosis factor alpha (TNFa), and C-reactive protein on PND 5, and upregulated ovarian mRNA expression of Tnfa, mitogen-activated protein kinase 8 (Mapk8/Jnk1), and growth differentiation factor 9 (Gdf9) (P < 0.05). Mass spectrometry and cell signaling pathway analysis indicated upregulation of cellular pathways associated with acute phase signaling, and cellular survival and assembly. Apoptosis assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling indicated significantly increased positive staining in the ovaries of LPS-treated neonates. These findings suggest that increased proinflammatory signaling within the neonatal ovary may be responsible for the LPS-induced depletion of the primordial follicle pool. These findings also have implications for female reproductive health, as the ovarian reserve is a major determinate of female reproductive longevity.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.MCE.2016.05.001
Abstract: Early life nutrition is crucial for reproduction. Overweight and obese girls are more likely to experience early menarche, increasing the risk of adult disease. We have previously demonstrated neonatal overfeeding in the rat leads to accelerated growth, early puberty and increased circulating levels of leptin, an adipocyte-derived hormone that regulates puberty. However, the long-term consequences of accelerated puberty and metabolic dysfunction on ovarian reserve are unknown. Here we show that neonatal overfeeding reduced the number of ovarian follicles in adult rats specifically, the primordial follicle pool was reduced compared to controls. The reduction of ovarian reserve coincided with a diminished release of pituitary gonadotropins at ovulation and altered expression of ovarian markers important for follicular recruitment and survival. These changes were associated with increased levels of ovarian leptin and its receptor. Postnatal administration of leptin antagonist did not reverse the weight gain induced by early life overfeeding, but rescued the decline in the primordial follicle pool and abolished the differences in circulating leptin and gonadotropins. Our findings suggest that the acute effects of elevated circulating leptin may be responsible for the long-term reproductive outcomes after neonatal overfeeding, leading to premature ovarian ageing and changes in reproductive efficiency.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.MCE.2017.11.014
Abstract: A poor nutritional environment during early development has long been known to increase disease susceptibility later in life. We have previously shown that rats that are overfed as neonates (i.e. suckled in small litters (4 pups) relative to control conditions (12 pups)) show dysregulated hypothalamic-pituitary-adrenal axis responses to immune stress in adulthood, particularly due to an altered capacity of the adrenal to respond to an immune challenge. Here we hypothesised that neonatal overfeeding similarly affects the sympathomedullary system, testing this by investigating the biochemical function of tyrosine hydroxylase (TH), the first rate-limiting enzyme in the catecholamine synthesis. We also examined changes in adrenal expression of the leptin receptor and in mitogen-activated protein kinase (MAPK) signalling. During the neonatal period, we saw age-dependent changes in TH activity and phosphorylation, with neonatal overfeeding stimulating increased adrenal TH specific activity at postnatal days 7 and 14, along with a compensatory reduction in total TH protein levels. This increased TH activity was maintained into adulthood where neonatally overfed rats exhibited increased adrenal responsiveness 30 min after an immune challenge with lipopolysaccharide, evident in a concomitant increase in TH protein levels and specific activity. Neonatal overfeeding significantly reduced the expression of the leptin receptor in neonatal adrenals at postnatal day 7 and in adult adrenals, but did not affect MAPK signalling. These data suggest neonatal overfeeding alters the capacity of the adrenal to synthesise catecholamines, both acutely and long term, and these effects may be independent of leptin signalling.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Springer New York
Date: 2017
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 12-02-2016
DOI: 10.1038/SREP21097
Abstract: Early life diet can critically program hypothalamic-pituitary-adrenal (HPA) axis function. We have previously shown rats that are overfed as neonates have exacerbated pro-inflammatory responses to immune challenge with lipopolysaccharide (LPS), in part by altering HPA axis responses, but how this occurs is unknown. Here we examined neonatal overfeeding-induced changes in gene expression in each step of the HPA axis. We saw no differences in glucocorticoid or mineralocorticoid receptor expression in key regions responsible for glucocorticoid negative feedback to the brain and no differences in expression of key HPA axis regulatory genes in the paraventricular nucleus of the hypothalamus or pituitary. On the other hand, expression of the adrenal melanocortin 2 receptor (MC2R) is elevated after LPS in control rats, but significantly less so in the neonatally overfed. The in vitro adrenal response to ACTH is also d ened in these rats, while the in vivo response to ACTH does not resolve as efficiently as it does in controls. These data suggest neonatal diet affects the efficiency of the adrenally-mediated response to LPS, potentially influencing how neonatally overfed rats combat bacterial infection.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Frontiers Media SA
Date: 25-10-2017
Publisher: Oxford University Press (OUP)
Date: 11-03-2021
Abstract: Monocytes and macrophages are the most abundant immune cell populations in the adult ovary, with well-known roles in ovulation and corpus luteum formation and regression. They are activated and proliferate in response to immune challenge and are suppressed by anti-inflammatory treatments. It is also likely they have a functional role in the healthy ovary in supporting the maturing follicle from the primordial through to the later stages however, this role has been unexplored until now. Here, we utilized a Cx3cr1-Dtr transgenic Wistar rat model that allows a conditional depletion of circulating monocytes, to investigate their role in ovarian follicle health. Our findings show that circulating monocyte depletion leads to a significant depletion of ovarian monocytes and monocyte-derived macrophages. Depletion of monocytes was associated with a transient reduction in circulating anti-Müllerian hormone (AMH) at 5 days postdepletion. However, the 50–60% ovarian monocyte/macrophage depletion had no effect on ovarian follicle numbers, follicle atresia, or apoptosis, within 5–21 days postdepletion. These data reveal that the healthy adult ovary is remarkably resistant to perturbations of circulating and ovarian monocytes despite acute changes in AMH. These data suggest that short-term anti-inflammatory therapies that transiently impact on circulating monocytes are unlikely to disrupt ovarian follicle health, findings that have significant implications for fertility planning relative to the experience of an immune challenge or immunosuppression.
Publisher: Frontiers Media SA
Date: 09-10-2018
Publisher: Bioscientifica
Date: 08-2022
DOI: 10.1530/JOE-21-0404
Abstract: Early life microglia are essential for brain development, and developmental disruption in microglial activity may have long-term implications for the neuroendocrine control of reproduction. We and others have previously shown that early life immune activation compromises the long-term potential for reproductive function in females. However, the supportive role of microglia in female reproductive development is still unknown. Here, we examined the long-term programming effects of transient neonatal microglial and monocyte ablation on hypothalamic–pituitary–gonadal (HPG) axis function in female rats. We employed a Cx3cr1-Dtr transgenic Wistar rat model to acutely ablate microglia and monocytes, commencing on either postnatal day (P) 7 or 14, since the development of the HPG axis in female rodents primarily occurs during the first two to three postnatal weeks. After an acutely diminished expression of microglia and monocyte genes in the brain and ovaries, respectively, microglia had repopulated the brain by P21, albeit that cellular complexity was still reduced in both groups at this time. Removal of microglia and monocytes on P7, but not P14 reduced circulating luteinising hormone levels in adulthood and ovarian gonadotropin receptors mRNA. These changes were notably associated with fewer primary and antral follicles in these rats. These data suggest that transient ablation of microglia and monocytes at the start of the second but not the third postnatal week has long-term effects on ovarian health. The findings highlight the important developmental role of a healthy immune system for female potential reproductive capacity and the importance of critical developmental periods to adult ovarian health.
Publisher: MDPI AG
Date: 30-12-2020
DOI: 10.3390/NU13010089
Abstract: Maternal diet is critical for offspring development and long-term health. Here we investigated the effects of a poor maternal diet pre-conception and during pregnancy on metabolic outcomes and the developing hypothalamus in male and female offspring at birth. We hypothesised that offspring born to dams fed a diet high in fat and sugar (HFSD) peri-pregnancy will have disrupted metabolic outcomes. We also determined if these HFSD-related effects could be reversed by a shift to a healthier diet post-conception, in particular to a diet high in omega-3 polyunsaturated fatty acids (ω3 PUFAs), since ω3 PUFAs are considered essential for normal neurodevelopment. Unexpectedly, our data show that there are minimal negative effects of maternal HFSD on newborn pups. On the other hand, consumption of an ω3-replete diet during pregnancy altered several developmental parameters. As such, pups born to high-ω3-fed dams weighed less for their length, had reduced circulating leptin, and also displayed sex-specific disruption in the expression of hypothalamic neuropeptides. Collectively, our study shows that maternal intake of a diet rich in ω3 PUFAs during pregnancy may be detrimental for some metabolic developmental outcomes in the offspring. These data indicate the importance of a balanced dietary intake in pregnancy and highlight the need for further research into the impact of maternal ω3 intake on offspring development and long-term health.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.NEUROPHARM.2016.09.023
Abstract: Early life overweight is a significant risk factor for developmental programming of adult obesity due to changes in the availability of metabolic factors crucial for the maturation of brain appetite-regulatory circuitry. The appetite-stimulating hormone, ghrelin, has been recently identified as a major regulator of the establishment of hypothalamic feeding pathways. Ghrelin exists in circulation in two major forms, as acylated and des-acylated ghrelin. While most research has focused on acyl ghrelin, the role of neonatal des-acyl ghrelin in metabolic programming is currently unknown. Here we assessed the influences of early life overfeeding on the ghrelin system, including acyl and des-acyl ghrelin's ability to access the hypothalamus in male rats. Our data show that early life overfeeding influences the ghrelin system short-term, leading to an acute reduction in circulating des-acyl ghrelin and increased expression of the growth hormone secretagogue receptor (GHSR) in the arcuate nucleus of the hypothalamus (ARC). These changes are associated with increased neuronal activation in response to exogenous acyl, but not des-acyl, ghrelin in the ARC and the paraventricular nucleus of the hypothalamus (PVN). Interestingly, while we observed no differences in the accessibility of the ARC to acyl or des-acyl ghrelin, less exogenous acyl ghrelin reaches the PVN in the neonatally overfed. Importantly, the influences of neonatal overfeeding on the ghrelin system were not maintained into adulthood. Therefore, while early life overfeeding results in excess body weight and stimulates acute changes in the brain's sensitivity to metabolic signals, this developmental mal-programming is at least partially alleviated in adulthood.
Publisher: Springer Science and Business Media LLC
Date: 07-02-2020
DOI: 10.1186/S12974-020-1729-4
Abstract: Microglia play a key role in neuronal circuit and synaptic maturation in the developing brain. In the healthy adult, however, their role is less clear: microglial hyperactivation in adults can be detrimental to memory due to excessive synaptic pruning, yet learning and memory can also be impaired in the absence of these cells. In this study, we therefore aimed to determine how microglia contribute to short-term memory in healthy adults. To this end, we developed a Cx3cr1 - Dtr transgenic Wistar rat with a diphtheria toxin receptor ( Dtr ) gene inserted into the fractalkine receptor ( Cx3cr1 ) promoter, expressed on microglia and monocytes. This model allows acute microglial and monocyte ablation upon application of diphtheria toxin, enabling us to directly assess microglia’s role in memory. Here, we show that short-term memory in the novel object and place recognition tasks is entirely unaffected by acute microglial ablation. However, when microglia repopulate the brain after depletion, learning and memory performance in these tasks is improved. This transitory memory enhancement is associated with an ameboid morphology in the newly repopulated microglial cells and increased astrocyte density that are linked with a higher density of mature hippoc al synaptic spines and differences in pre- and post-synaptic markers. These data indicate that glia play a complex role in the healthy adult animal in supporting appropriate learning and memory and that subtle changes to the function of these cells may strategically enhance memory.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2016
Publisher: The Endocrine Society
Date: 27-07-2017
DOI: 10.1210/ER.2016-1133
Abstract: Infertility affects a remarkable one in four couples in developing countries. Psychological stress is a ubiquitous facet of life, and although stress affects us all at some point, prolonged or unmanageable stress may become harmful for some in iduals, negatively impacting on their health, including fertility. For instance, women who struggle to conceive are twice as likely to suffer from emotional distress than fertile women. Assisted reproductive technology treatments place an additional physical, emotional, and financial burden of stress, particularly on women, who are often exposed to invasive techniques associated with treatment. Stress-reduction interventions can reduce negative affect and in some cases to improve in vitro fertilization outcomes. Although it has been well-established that stress negatively affects fertility in animal models, human research remains inconsistent due to in idual differences and methodological flaws. Attempts to isolate single causal links between stress and infertility have not yet been successful due to their multifaceted etiologies. In this review, we will discuss the current literature in the field of stress-induced reproductive dysfunction based on animal and human models, and introduce a recently unexplored link between stress and infertility, the gut-derived hormone, ghrelin. We also present evidence from recent seminal studies demonstrating that ghrelin has a principal role in the stress response and reward processing, as well as in regulating reproductive function, and that these roles are tightly interlinked. Collectively, these data support the hypothesis that stress may negatively impact upon fertility at least in part by stimulating a dysregulation in ghrelin signaling.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 10-01-2017
DOI: 10.1038/SREP40475
Abstract: Neonatal immune challenge with the bacterial mimetic lipopolysaccharide has the capacity to generate long-term changes in the brain. Neonatal rats were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg) on postnatal day (PND) 3 and again on PND 5. The activation state of tyrosine hydroxylase (TH) was measured in the locus coeruleus, ventral tegmental area and substantia nigra on PND 85. In the locus coeruleus there was an approximately four-fold increase in TH activity. This was accompanied by a significant increase in TH protein together with increased phosphorylation of all three serine residues in the N-terminal region of TH. In the ventral tegmental area, a significant increase in TH activity and increased phosphorylation of the serine 40 residue was seen. Neonatal lipopolysaccharide had no effect on TH activation in the substantia nigra. These results indicate the capacity of a neonatal immune challenge to generate long-term changes in the activation state of TH, in particular in the locus coeruleus. Overall, the current results demonstrate the enduring outcomes of a neonatal immune challenge on specific brain catecholaminergic regions associated with catecholamine synthesis. This highlights a novel mechanism for long-term physiological and behavioural alterations induced by this model.
Publisher: Hogrefe Publishing Group
Date: 07-2015
DOI: 10.1027/0269-8803/A000143
Abstract: Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva s les, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.
Publisher: Elsevier BV
Date: 05-2011
Publisher: Wiley
Date: 16-11-2021
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.MCE.2021.111418
Abstract: Our recent findings indicate that an acute depletion of monocytes has no sustained effects on ovarian follicle health. Here, we utilised a Cx3cr1-Dtr transgenic Wistar rat model to transiently deplete monocytes and investigated the impact of an acute immune challenge by lipopolysaccharide (LPS) on ovarian follicle health and ovulatory capacity relative to wt once the monocytes had repopulated. Monocyte depletion and repopulation exacerbated the effects of LPS in several domains. As such, monocyte perturbation decreased the numbers of secondary follicles in those challenged with LPS. Monocyte perturbation was also associated with reduced antral follicle numbers and circulating luteinising hormone (LH) levels, as well as potential changes in ovarian sensitivity to LH, exacerbated by LPS. These data suggest that monocyte depletion and repopulation induce a transient suppression of ovulatory capacity in response to a subsequent immune challenge, but this is likely to be restored once the pro-inflammatory environment is resolved.
Publisher: Frontiers Media SA
Date: 15-01-2019
Publisher: MDPI AG
Date: 15-07-2021
DOI: 10.3390/NU13072418
Abstract: The authors would like to correct a typographical error in their recently published paper [...]
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.BBR.2011.08.038
Abstract: Neonatal lipopolysaccharide (LPS) exposure increases anxiety-like behaviour in adulthood. Our current aim was to examine whether neonatal LPS exposure is associated with changes in microglial activation, and whether these alterations correspond with alterations in behaviour. In adulthood, LPS-treated animals exhibited significantly increased anxiety-like behaviour and hippoc al microglial activation. The efficacy of the LPS challenge was confirmed by increased neonatal plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. These findings suggest a neuroimmune pathway which may underpin the long-term behavioural and neuroendocrine changes following neonatal infection.
Publisher: Oxford University Press (OUP)
Date: 23-12-2009
Abstract: This article presents a narrative-based technique, which allows medical personnel to empower patients with diabetes and improve adherence. The study was undertaken in Maccabi Healthcare Services, among 123 patients diagnosed with diabetes. Four empathic narratives were constructed, referring to different factors influencing resistance to treatment, as were identified by the Resistance to Treatment Questionnaire. Each narrative contains statements typical for patients whose resistance to treatment is influenced by a particular factor. An Empathic Narratives Evaluation Questionnaire was designed for this study. It contained three items, assessing the correlation of a specific empathic narrative with the patient's attitude and their reasons for resistance to treatment. The patients were asked to indicate whether they recognize these narratives as describing their reasons for resistance. Three empathic narratives were read to each patient: two narratives were matched for the two major categories of resistance for each patient and one narrative related to a category of resistance that received the lowest score. The narratives were found to correspond to the core reasons for resistance to diabetes treatment. Significant difference was found also between the scores of the empathic narrative related to the second strongest reason for resistance to treatment and the empathic narrative related to the weakest reason for resistance to treatment. This finding supports testimonial validity of the narratives. Short narrative interventions demonstrated in this study can be used by health care professionals as a working tool that provides the possibility reducing the patient's reasons for resistance to treatment.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2012
DOI: 10.1007/S11064-012-0812-3
Abstract: Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthetic pathway for catecholamine synthesis. Stress triggers an increase in TH activity, resulting in increased release of catecholamines from both neurons and the adrenal medulla. In response to stress three phases of TH activation have been identified (acute, sustained and chronic) and each phase has a unique mechanism. The acute and chronic phases have been studied in vivo in a number of animal models, but to date the sustained phase has only been characterised in vitro. We aimed to investigate the effects of dual exposure to lipopolysaccharide (LPS) in neonatal rats on TH protein, TH phosphorylation at serine residues 19, 31 and 40 and TH activity in the adrenal gland over the sustained phase. Wistar rats were administered LPS (0.05 mg/kg, intraperitoneal injection) or an equivolume of non-pyrogenic saline on days 3 and 5 postpartum. Adrenal glands were collected at 4, 24 and 48 h after the drug exposure on day 5. Neonatal LPS treatment resulted in increases in TH phosphorylation of Ser40 at 4 and 24 h, TH phosphorylation of Ser31 at 24 h, TH activity at 4 and 24 h and TH protein at 48 h. We therefore have provided evidence for the first time that TH phosphorylation at Ser31 and Ser40 occurs for up to 24 h in vivo and leads to TH activation independent of TH protein synthesis, suggesting that the sustained phase of TH activation occurs in vivo.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.BIOCEL.2017.11.012
Abstract: Microglia are the primary innate immune cells in the CNS. Since their initial discovery and characterization, decades of research have revealed their unique roles not only in maintaining immune homeostasis, but also being indispensable to brain development and cognitive function. As such, microglia drive synaptogenesis, synaptic pruning, neurogenesis and neuronal activity. Microglia-specific mutations are implicated in several neurodevelopmental disorders, and dysregulation of microglial function is strongly linked to several pathologies, including cognitive decline and Alzheimer's disease. Importantly, developmental insults can lead to long-term changes in microglial function that may compromise the ability of the adult brain to fight infections and process cognitive information. Adult lifestyle or injury can also lastingly influence microglial morphology and function. Here we highlight key research on microglia's role in neuronal plasticity across the lifespan.
Publisher: Elsevier BV
Date: 07-2009
Publisher: Frontiers Media SA
Date: 02-06-2015
Publisher: Bioscientifica
Date: 06-2019
DOI: 10.1530/JOE-19-0109
Abstract: Chronic stress is a known suppressor of female reproductive function. However, attempts to isolate single causal links between stress and reproductive dysfunction have not yet been successful due to their multi-faceted aetiologies. The gut-derived hormone ghrelin regulates stress and reproductive function and may therefore be pivotal in the neuroendocrine integration of the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes. Here, we hypothesised that chronic stress disrupts ovarian follicle maturation and that this effect is mediated by a stress-induced increase in acyl ghrelin and activation of the growth hormone secretatogue receptor (GHSR). We gave C57BL/6J female mice 30 min daily chronic predator stress for 4 weeks, or no stress, and gave them daily GHSR antagonist ( d -Lys3-GHRP-6) or saline. Exposure to chronic predator stress reduced circulating corticosterone, elevated acyl ghrelin levels and led to significantly depleted primordial follicle numbers. GHSR antagonism stress-dependently altered the expression of genes regulating ovarian responsiveness to gonadotropins and was able to attenuate the stress-induced depletion of primordial follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation.
Publisher: Public Library of Science (PLoS)
Date: 06-03-2013
Publisher: Elsevier BV
Date: 11-2021
Publisher: Elsevier BV
Date: 11-2014
Publisher: Frontiers Media SA
Date: 08-09-2023
Publisher: Elsevier BV
Date: 02-2019
Publisher: Wiley
Date: 11-2017
DOI: 10.1111/JNE.12540
Abstract: The early-life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper-responsive to an immune challenge, as well as hippoc al microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippoc al microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control-fed). We then examined the hippoc al microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippoc us after immune challenge compared to control-fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippoc us and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippoc al immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long-term impact, highlighting the importance of considering these effects when interpreting experimental data.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Springer Science and Business Media LLC
Date: 31-05-2020
DOI: 10.1186/S12974-020-01832-2
Abstract: Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation. Depletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion vs. control) × 2 (LPS vs. saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice. Chronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice. These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.
Publisher: Wiley
Date: 05-03-2013
DOI: 10.1002/SYN.21640
Publisher: Springer Science and Business Media LLC
Date: 26-03-2022
DOI: 10.1007/S12035-022-02800-Y
Abstract: The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB
Publisher: Bio-Protocol, LLC
Date: 2016
Publisher: Wiley
Date: 11-2013
Publisher: Bioscientifica
Date: 05-2018
DOI: 10.1530/JOE-17-0722
Abstract: The hypothalamus is a key centre for regulation of vital physiological functions, such as appetite, stress responsiveness and reproduction. Development of the different hypothalamic nuclei and its major neuronal populations begins prenatally in both altricial and precocial species, with the fine tuning of neuronal connectivity and attainment of adult function established postnatally and maintained throughout adult life. The perinatal period is highly susceptible to environmental insults that, by disrupting critical developmental processes, can set the tone for the establishment of adult functionality. Here, we review the most recent knowledge regarding the major postnatal milestones in the development of metabolic, stress and reproductive hypothalamic circuitries, in the rodent, with a particular focus on perinatal programming of these circuitries by hormonal and nutritional influences. We also review the evidence for the continuous development of the hypothalamus in the adult brain, through changes in neurogenesis, synaptogenesis and epigenetic modifications. This degree of plasticity has encouraging implications for the ability of the hypothalamus to at least partially reverse the effects of perinatal mal-programming.
No related grants have been discovered for Luba Sominsky.