ORCID Profile
0000-0001-8832-4824
Current Organisation
RMIT University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Animal Physiology - Systems | Physiology | Nutrition and Dietetics | Central Nervous System | Central nervous system | Animal Physiology—Systems | Animal Nutrition | Nutritional Physiology | Animal neurobiology | Biomedical imaging | Neurosciences
ANZSRC Socio-Economic Objective (SEO)
Beef Cattle | Endocrine Organs and Diseases (excl. Diabetes) | Livestock | Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Biological Sciences | Nutrition | Biological sciences | Immune System and Allergy |
Related Links
Publications
Microglial regulation of satiety and cognition
Publisher: Wiley
Date: 25-02-2020
DOI: 10.1111/JNE.12838
One size does not fit all – Patterns of vulnerability and resilience in the COVID-19 pandemic and why heterogeneity of disease matters
Publisher: Elsevier BV
Date: 07-2020
Efficacy of post-insult minocycline administration to alter long-term hypoxia-ischemia-induced damage to the serotonergic system in the immature rat brain
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.NEUROSCIENCE.2011.03.033
Abstract: Neuroinflammation is a key mechanism contributing to long-term neuropathology observed after neonatal hypoxia-ischemia (HI). Minocycline, a second-generation tetracycline, is a potent inhibitor of neuroinflammatory mediators and is successful for at least short-term amelioration of neuronal injury after neonatal HI. However the long-term efficacy of minocycline to prevent injury to a specific neuronal network, such as the serotonergic (5-hydroxytryptamine, 5-HT) system, is not known. In a post-natal day 3 (P3) rat model of preterm HI we found significant reductions in 5-HT levels, 5-HT transporter expression and numbers of 5-HT-positive dorsal raphé neurons 6 weeks after insult compared to control animals. Numbers of activated microglia were significantly elevated in the thalamus and dorsal raphé although the greatest numbers were observed in the thalamus. Brain levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were also significantly elevated on P45 in the thalamus and frontal cortex. Post-insult administration of minocycline for 1 week (P3-P9) attenuated the P3 HI-induced increases in numbers of activated microglia and levels of TNF-α and IL-1β on P45 with concurrent changes in serotonergic outcomes. The parallel prevention of P3 HI-induced serotonergic changes suggests that inhibition of neuroinflammation within the first week after P3 HI injury was sufficient to prevent long-term neuroinflammation as well as serotonergic system damage still evident at 6 weeks. Thus early, post-insult administration of minocycline may target secondary neuroinflammation and represent a long-term therapy to preserve the integrity of the central serotonergic network in the preterm neonate.
Novel pharmacological strategies to treat cognitive dysfunction in chronic obstructive pulmonary disease
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.PHARMTHERA.2021.108017
Abstract: Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and currently the 3rd largest cause of death in the world, with approximately 3.23 million deaths per year. Globally, the financial burden of COPD is approximately €82 billion per year and causes substantial morbidity and mortality. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and viral and bacterial-induced acute exacerbations (AECOPD). Recent clinical studies have shown that cognitive dysfunction is present in up to 60% of people with COPD, with impairments in executive function, memory, and attention, impacting on important outcomes such as quality of life, hospitalisation and survival. The high prevalence of cognitive dysfunction in COPD may also help explain the insufficient adherence to therapeutic plans and strategies, thus worsening disease progression in people with COPD. However, the mechanisms underlying the impaired neuropathology and cognition in COPD remain largely unknown. In this review, we propose that the observed pulmonary oxidative burden and inflammatory response of people with COPD 'spills over' into the systemic circulation, resulting in damage to the brain and leading to cognitive dysfunction. As such, drugs targeting the lungs and comorbidities concurrently represent an exciting and unique therapeutic opportunity to treat COPD and cognitive impairments, which may lead to the production of novel targets to prevent and reverse the debilitating and life-threatening effects of cognitive dysfunction in COPD.
Hypothalamic effects of neonatal diet: reversible and only partially leptin dependent
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.
Neurohypophysial peptides: gatekeepers in the amygdala
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.TEM.2005.08.001
Abstract: A recent paper by Huber, Veinante and Stoop reports electrophysiological studies in slices of the amygdala in which the authors are able to demonstrate a cellular and spatial dissociation between the sites of action of oxytocin and vasopressin. These studies are important for determining how these brain peptides might gate autonomic responses to fear and other emotional stimuli.
Des-Acyl Ghrelin and Ghrelin O-Acyltransferase Regulate Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Response to Acute Stress
Publisher: The Endocrine Society
Date: 04-08-2016
DOI: 10.1210/EN.2016-1306
Abstract: Ghrelin exists in two forms in circulation, acyl ghrelin and des-acyl ghrelin, both of which have distinct and fundamental roles in a variety of physiological functions. Despite this fact, a large proportion of papers simply measure and refer to plasma ghrelin without specifying the acylation status. It is therefore critical to assess and state the acylation status of plasma ghrelin in all studies. In this study we tested the effect of des-acyl ghrelin administration on the hypothalamic-pituitary-adrenal axis and on anxiety-like behavior of mice lacking endogenous ghrelin and in ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no endogenous acyl ghrelin and high endogenous des-acyl ghrelin. Our results show des-acyl ghrelin produces an anxiogenic effect under nonstressed conditions, but this switches to an anxiolytic effect under stress. Des-acyl ghrelin influences plasma corticosterone under both nonstressed and stressed conditions, although c-fos activation in the paraventricular nucleus of the hypothalamus is not different. By contrast, GOAT KO are anxious under both nonstressed and stressed conditions, although this is not due to corticosterone release from the adrenals but rather from impaired feedback actions in the paraventricular nucleus of the hypothalamus, as assessed by c-fos activation. These results reveal des-acyl ghrelin treatment and GOAT deletion have differential effects on the hypothalamic-pituitary-adrenal axis and anxiety-like behavior, suggesting that anxiety-like behavior in GOAT KO mice is not due to high plasma des-acyl ghrelin.
Differential involvement of rat medial prefrontal cortex dopamine receptors in modulation of hypothalamic‐ pituitary‐adrenal axis responses to different stressors
Publisher: Wiley
Date: 08-2004
Early life immune challenge—effects on behavioural indices of adult rat fear and anxiety
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.BBR.2005.06.032
Abstract: Neonatal exposure to an immune challenge has been shown to alter many facets of adult physiology including fever responses to a similar infection. However, there is a paucity of information regarding its effects on adult behaviours. Male Sprague-Dawley rats were administered a single injection of the bacterial endotoxin lipopolysaccharide (LPS) at 14 days old and were compared, when they reached adulthood, with neonatally saline-treated controls in several behavioural tests of unconditioned fear and anxiety. There was no effect of the neonatal treatment on performance in either the elevated plus maze, modified Porsolt's forced swim test or the open field test. However, neonatally LPS-treated rats did show significantly reduced exploration of novel objects introduced to the open field arena, indicating an effect of the neonatal immune challenge on behaviours relating to anxiety in the adult.
Blocked, delayed, or obstructed: What causes poor white matter development in intrauterine growth restricted infants?
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.PNEUROBIO.2017.03.009
Abstract: Poor white matter development in intrauterine growth restricted (IUGR) babies remains a major, untreated problem in neonatology. New therapies, guided by an understanding of the mechanisms that underlie normal and abnormal oligodendrocyte development and myelin formation, are required. Much of our knowledge of the mechanisms that underlie impaired myelination come from studies in adult demyelinating disease, preterm brain injury, or experimental models of hypoxia-ischemia. However, relatively less is known for IUGR which is surprising because IUGR is a leading cause of perinatal mortality and morbidity, second only to premature birth. IUGR is also a significant risk factor for the later development of cerebral palsy, and is a greater risk compared to some of the more traditionally researched antecedents - asphyxia and inflammation. Recent evidence suggests that the white matter injury and reduced myelination in the brains of some preterm babies is due to impaired maturation of oligodendrocytes thereby resulting in the reduced capacity to synthesize myelin. Therefore, it is not surprising that the hypomyelination observable in the central nervous system of IUGR infants has similarly lead to investigations identifying a delay or blockade in the progress of maturation of oligodendrocytes in these infants. This review will discuss current ideas thought to account for the poor myelination often present in the neonate's brain following IUGR, and discuss novel interventions that are promising as treatments that promote oligodendrocyte maturation, and thereby repair the myelination deficits that otherwise persist into infancy and childhood and lead to neurodevelopmental abnormalities.
Perinatal nutrition programs neuroimmune function long-term: mechanisms and implications
Publisher: Frontiers Media SA
Date: 2013
Acylated ghrelin suppresses the cytokine response to lipopolysaccharide and does so independently of the hypothalamic-pituitary-adrenal axis
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.
Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation
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.
Gender inequality in publishing during the COVID-19 pandemic
Publisher: Elsevier BV
Date: 2021
Neonatal overfeeding induces early decline of the ovarian reserve: Implications for the role of leptin
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.
Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats
Publisher: Society for Neuroscience
Date: 02-07-2008
Overfeeding during a critical postnatal period exacerbates hypothalamic-pituitary-adrenal axis responses to immune challenge: a role for adrenal melanocortin 2 receptors
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.
Hyperleptinemia in neonatally overfed female rats does not dysregulate feeding circuitry
Publisher: Frontiers Media SA
Date: 25-10-2017
What’s in a name? How about being listed in the “Psychiatry” category in Clarivate’s Journal Citation Index!
Publisher: Elsevier BV
Date: 05-2019
Ovarian follicles are resistant to monocyte perturbations—implications for ovarian health with immune disruption
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.
High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory
Publisher: Elsevier BV
Date: 10-2017
Glial remodeling enhances short-term memory performance in Wistar rats
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.
Early life stress and metabolism
Publisher: Elsevier BV
Date: 08-2019
Ghrelin and hypothalamic NPY/AgRP expression in mice are affected by chronic early-life stress exposure in a sex-specific manner
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.PSYNEUEN.2017.09.006
Abstract: Early-life stress (ES) is a risk factor for metabolic disorders (e.g. obesity) with a notoriously higher prevalence in women compared to men. However, mechanisms underlying these effects remain elusive. The development of the hypothalamic feeding and metabolic regulatory circuits occurs mostly in the early sensitive postnatal phase in rodents and is tightly regulated by the metabolic hormones leptin and ghrelin. We have previously demonstrated that chronic ES reduces circulating leptin and alters adipose tissue metabolism early and later in life similarly in both sexes. However, it is unknown whether chronic ES might also affect developmental ghrelin and insulin levels, and if it induces changes in hypothalamic feeding circuits, possibly in a sex-dependent manner. We here show that chronic ES, in the form of exposure to limited nesting and bedding material from postnatal day (P)2 to P9 in mice, affects ghrelin levels differently, depending on the form of ghrelin (acylated vs desacylated), on age (P9 vs P14) and on sex, while insulin levels were similarly increased in both sexes after ES at P9. Even though ghrelin levels were more strongly affected in ES-exposed females, hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) fiber density at P14 were similarly altered in both sexes by ES. In the paraventricular nucleus of the hypothalamus, both NPY and AgRP fiber density were increased, while in the arcuate nucleus of the hypothalamus, NPY was increased and AgRP unaltered. Additionally, the hypothalamic mRNA expression of ghrelin's receptor (i.e. growth hormone secretagogue receptor) was not affected by ES. Taken together, the specific alterations found in these important regulatory circuits after ES might contribute to an altered energy balance and feeding behavior in adulthood and thereby to an increased vulnerability to develop metabolic disorders.
Acupuncture: A Promising Approach for Comorbid Depression and Insomnia in Perimenopause
Publisher: Informa UK Limited
Date: 10-2021
DOI: 10.2147/NSS.S332474
Neonatal overfeeding alters adult anxiety and stress responsiveness
Publisher: Elsevier BV
Date: 09-2009
Thalamic paraventricular nucleus lesions facilitate central amygdala neuronal responses to acute psychological stress
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/J.BRAINRES.2003.10.054
Abstract: The thalamic paraventricular nucleus (PVT) is activated by stress and projects to forebrain structures directly implicated in processing stress-related information. Accordingly, it seems likely the PVT plays an important role in modulating stress responses. We examined effects of excitotoxic PVT lesions on forebrain Fos expression patterns normally elicited by an acute psychological stressor. PVT lesions significantly increased stress-induced Fos in a key stress-processing region, the central amygdala.
The Role of Ghrelin in Neuroprotection after Ischemic Brain Injury
Publisher: MDPI AG
Date: 19-03-2013
Microglial ablation in rats disrupts the circadian system
Publisher: Wiley
Date: 16-11-2021
The role of microglia in the second and third postnatal weeks of life in rat hippocampal development and memory.
Publisher: Elsevier BV
Date: 08-2020
Monocyte perturbation modulates the ovarian response to an immune challenge
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.
Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice
Publisher: Portland Press Ltd.
Date: 26-07-2016
DOI: 10.1042/CS20160077
Abstract: The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo). We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced blood-brain barrier (BBB) disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity and expression of 3-nitrotyrosine. Collectively, these results demonstrate that post-stroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischaemia/reperfusion-induced brain injury and swelling, and BBB disruption, by reducing oxidative and/or nitrosative damage.
Validation of quantitative magnetic resonance as a non-invasive measure of body composition in an Australian microbat
Publisher: CSIRO Publishing
Date: 28-02-2021
DOI: 10.1071/AM19060
Abstract: Body composition (the total amount of fat mass, lean mass, minerals and water that constitute the body) is an important measure for understanding an animal’s physiology, ecology and behaviour. Traditional measures of body composition require the animal to either be placed under anaesthetic, which is invasive and can be high-risk, or be euthanised, preventing the ability to perform repeated measures on the same in idual. We aimed to validate quantitative magnetic resonance (QMR) as a non-invasive measure of body composition by comparing QMR scans with chemical carcass analysis (CCA) in Gould’s wattled bats (Chalinolobus gouldii). In addition, we compared a commonly used microbat body condition index (residuals of mass by forearm length) to CCA. We found that QMR is an accurate method of estimating body condition in Gould’s wattled bats after calibration with regression equations, and the condition index could accurately predict lean and water mass but was a poor predictor of fat mass. Using accurate, non-invasive, repeatable measures of body condition may have important implications for ecological research in the face of changing environments.
Ghrelin Plays a Role in Various Physiological and Pathophysiological Brain Functions
Publisher: Springer New York
Date: 2014
Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-α
Publisher: American Physiological Society
Date: 2007
DOI: 10.1152/AJPREGU.00398.2006
Abstract: Early life events and childhood infections have been associated with the development and onset of inflammatory bowel disease in adulthood. However, the consequences of neonatal infection in the development and severity of colitis are not established. We investigated the effects of a neonatal (postnatal day 14) or juvenile (postnatal day 28) immune challenge with LPS on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced damage and weight loss, as well as on food intake and body temperature in adult rats. Neonatally (n)LPS-treated rats developed more severe colitis than control animals, reflected in a greater loss of weight and a significantly increased macroscopic tissue damage score. These findings were associated with a hypothermic response after TNBS treatment in nLPS rats, but not in neonatally saline-treated rats receiving TNBS. These differences were not seen after TNBS in rats that had received LPS on postnatal day 28. Plasma corticosterone was measured as an index of adult hypothalamic-pituitary-adrenal (HPA) axis activation as was TNF-α, a proinflammatory cytokine associated with inflammatory bowel disease. Four days after TNBS treatment, plasma corticosterone was unaltered in all groups however, TNF-α was significantly increased in adult TNBS-treated rats that had LPS as neonates compared with all other groups. In conclusion, neonatal, but not later, exposure to LPS produces long-term exacerbations in the development of colitis in adults. This change is independent of HPA axis activation 4 days after TNBS treatment but is associated with increased circulating TNF-α, suggestive of an exaggerated immune response in adults exposed to neonatal infection.
Early Life Programming of Obesity: The Impact of the Perinatal Environment on the Development of Obesity and Metabolic Dysfunction in the Offspring.
Publisher: Bentham Science Publishers Ltd.
Date: 2012
DOI: 10.2174/157339912798829214
Abstract: It is now well accepted that early life events can contribute substantially to the likelihood of an in idual becoming obese, although many of the mechanisms for this are not well understood. Maternal over- and under-nutrition as well as the postnatal nutritional environment can contribute significantly to obesity throughout life. This review will provide an overview of early life events associated with neuroendocrine programming of obesity and metabolic dysfunction. In particular this review will focus on the long-term impact of perinatal nutrition, as well as the perinatal role of leptin, insulin, and glucocorticoids in programming the hypothalamic circuitry responsible for appropriate regulation of feeding and metabolism throughout life.
Neuroimmunology of the female brain across the lifespan: Plasticity to psychopathology
Publisher: Elsevier BV
Date: 07-2019
Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways
Publisher: Society for Neuroscience
Date: 09-06-2010
Microglia: Key players in neurodevelopment and neuronal plasticity
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.
Peripheral Inflammation Exacerbates Damage After Global Ischemia Independently of Temperature and Acute Brain Inflammation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2007
DOI: 10.1161/STROKEAHA.106.476507
Abstract: Background and Purpose— Concomitant infection can exacerbate damage caused by cerebral ischemia. However, the interaction between and relative importance of the febrile and inflammatory components of the immune response is still unknown. Methods— Male Sprague-Dawley rats were subjected to a 2-vessel occlusion with hypotension, immediately followed by intraperitoneal injection of lipopolysaccharide or pyrogen-free saline. Results— Inflammation immediately after 2-vessel occlusion exacerbated hippoc al cell loss at 3 days and enhanced anxiety-related behaviors in the elevated plus maze and open field. These effects were not associated with differences in body temperature changes or with hippoc al pro-inflammatory cytokine production or hippoc al microglial activation. Conclusion— We show a previously undocumented dissociation between lipopolysaccharide-exacerbated damage after global ischemia in the rat and the temperature and acute brain immune response, indicating that the mechanism for enhanced lipopolysaccharide damage is hippoc al cytokine and temperature independent in this case.
Chronic predator stress in female mice reduces primordial follicle numbers: Implications for the role of ghrelin
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.
Neonatal overfeeding by small‐litter rearing sensitises hippocampal microglial responses to immune challenge: Reversal with neonatal repeated injections of saline or minocycline
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.
Role of catecholaminergic inputs to the medial prefrontal cortex in local and subcortical expression of Fos after psychological stress
Publisher: Wiley
Date: 07-09-2004
DOI: 10.1002/JNR.20242
Abstract: A wide variety of stressors elicit Fos expression in the medial prefrontal cortex (mPFC). No direct attempts, however, have been made to determine the role of the inputs that drive this response. We examined the effects of lesions of mPFC catecholamine terminals on local expression of Fos after exposure to air puff, a stimulus that in the rat acts as an acute psychological stressor. We also examined the effects of these lesions on Fos expression in a variety of subcortical neuronal populations implicated in the control of adrenocortical activation, one classic hallmark of the stress response. Lesions of the mPFC that were restricted to dopaminergic terminals significantly reduced numbers of Fos-immunoreactive (Fos-IR) cells seen in the mPFC after air puff, but had no significant effect on stress-induced Fos expression in the subcortical structures examined. Lesions of the mPFC that affected both dopaminergic and noradrenergic terminals also reduced numbers of Fos-IR cells observed in the mPFC after air puff. Additionally, these lesions resulted in a significant reduction in stress-induced Fos-IR in the ventral bed nucleus of the stria terminalis. These results demonstrate a role for catecholaminergic inputs to the mPFC, in the generation of both local and subcortical responses to psychological stress.
Neonatal immune challenge does not affect body weight regulation in rats
Publisher: American Physiological Society
Date: 08-2007
DOI: 10.1152/AJPREGU.00262.2007
Abstract: The perinatal environment plays a crucial role in programming many aspects of adult physiology. Myriad stressors during pregnancy, from maternal immune challenge to nutritional deficiency, can alter long-term body weight set points of the offspring. In light of the increasing concern over body weight issues, such as obesity and anorexia, in modern societies and accumulating evidence that developmental stressors have long-lasting effects on other aspects of physiology (e.g., fever, pain), we explored the role of immune system activation during neonatal development and its impact on body weight regulation in adulthood. Here we present a thorough evaluation of the effects of immune system activation (LPS, 100 μg/kg ip) at postnatal days 3, 7, or 14 on long-term body weight, adiposity, and body weight regulation after a further LPS injection (50 μg/kg ip) or fasting and basal and LPS-induced circulating levels of the appetite-regulating proinflammatory cytokine leptin. We show that neonatal exposure to LPS at various times during the neonatal period has no long-term effects on growth, body weight, or adiposity. We also observed no effects on body weight regulation in response to a short fasting period or a further exposure to LPS. Despite reductions in circulating leptin levels in response to LPS during the neonatal period, no long-term effects on leptin were seen. These results convincingly demonstrate that adult body weight and weight regulation are, unlike many other aspects of adult physiology, resistant to programming by a febrile-dose neonatal immune challenge.
Hormonal and nutritional regulation of postnatal hypothalamic development
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.
Neural and humoral changes associated with the adjustable gastric band: insights from a rodent model
Publisher: Springer Science and Business Media LLC
Date: 27-03-2012
DOI: 10.1038/IJO.2012.25
Abstract: Bariatric surgical procedures, including the laparoscopic adjustable gastric band (LAGB), are currently the only effective treatments for morbid obesity, however, there is no clear understanding of the mechanisms underpinning the efficacy of LAGB. The aim of this study is to examine changes in activation of the sensory neuronal pathways and levels of circulating gut hormones associated with inflation of an AGB. The trajectory within the central nervous system of polysynaptic projections of sensory neurons innervating the stomach was determined using the transsynaptically transported herpes simplex virus (HSV). Populations of HSV-infected neurons were present in the brainstem, hypothalamus and cortical regions associated with energy balance. An elevation of Fos protein was present within the nucleus of the solitary tract, a region of the brainstem involved in the control of food intake, following acute and chronic band inflation. Two approaches were used to test (1) the impact of inflation of the band alone (on a standard caloric background) or (2) the impact of a standard caloric meal (on the background of the inflated band) on circulating gut hormones. Importantly, there was a significant elevation of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) following oral gavage of a liquid meal in animals with pre-inflated bands. There was no impact of inflation of the band alone on circulating GLP-1, PYY or ghrelin in animals on a standard caloric background. These data are consistent with the notion that the LAGB exerts its effects on satiety, reduced food intake and reduced body weight by the modulation of both neural and hormonal responses with the latter involving an elevation of meal-related levels of GLP-1 and PYY. These data are contrary to the view that the surgery is purely 'restrictive'.
Obesity after neonatal overfeeding is independent of hypothalamic microgliosis
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.
Diet-induced obesity causes ghrelin resistance in reward processing tasks
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.PSYNEUEN.2015.08.004
Abstract: Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1mg/kg in 10ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33μg/μl in 0.5μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing.
Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production
Publisher: Springer Science and Business Media LLC
Date: 06-07-2018
Obesity and neuroinflammation: A pathway to cognitive impairment
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BBI.2014.04.001
Abstract: Obesity is a growing problem worldwide and is associated with a range of comorbidities, including cognitive dysfunction. In this review we will address the evidence that obesity and high fat feeding can lead to cognitive dysfunction. We will also examine the idea that obesity-associated systemic inflammation leads to inflammation within the brain, particularly the hypothalamus, and that this is partially responsible for these negative cognitive outcomes. Thus, obesity, and high fat feeding, lead to systemic inflammation and excess circulating free fatty acids. Circulating cytokines, free fatty acids and immune cells reach the brain at the level of the hypothalamus and initiate local inflammation, including microglial proliferation. This local inflammation likely causes synaptic remodeling and neurodegeneration within the hypothalamus, altering internal hypothalamic circuitry and hypothalamic outputs to other brain regions. The result is disruption to cognitive function mediated by regions such as hippoc us, amygdala, and reward-processing centers. Central inflammation is also likely to affect these regions directly. Thus, central inflammation in obesity leads not just to disruption of hypothalamic satiety signals and perpetuation of overeating, but also to negative outcomes on cognition.
Perinatal and Postnatal Determinants of Brain Development: Recent Studies and Methodological Advances
Publisher: Springer New York
Date: 2016
Early-Life Immune Challenge: Defining a Critical Window for Effects on Adult Responses to Immune Challenge
Publisher: Springer Science and Business Media LLC
Date: 04-01-2006
Abstract: Many aspects of mammalian physiology are functionally immature at birth and continue to develop throughout at least the first few weeks of life. Animals are therefore vulnerable during this time to environmental influences such as stress and challenges to the immune system that may permanently affect adult function. The adult immune system is uniquely sensitive to immune challenges encountered during the neonatal period, but it is unknown where the critical window for this programming lies. We subjected male Sprague-Dawley rats at postnatal day (P)7, P14, P21, and P28 to either a saline or lipopolysaccharide (LPS) injection and examined them in adulthood for differences in responses to a further LPS injection. Adult febrile and cyclooxygenase-2 responses to LPS were attenuated in rats given LPS at P14 and P21, but not in those treated at P7 or P28, while P7-LPS rats displayed lower adult body weights than those treated at other times. P28-LPS rats also tended to display enhanced anxiety in the elevated plus maze. In further experiments, we examined maternal-pup interactions, looking at the mothers' preference in two pup-retrieval tasks, and found no differences in maternal attention to LPS-treated pups. We therefore demonstrate a 'critical window' for the effects of a neonatal immune challenge on adult febrile responses to inflammation and suggest that there are other critical time points during development for the programming of adult physiology. We also show that the neonatal LPS effects on the adult immune system are not likely due to overt differences in maternal attention.
Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: Possible role of the bed nucleus of the stria terminalis
Publisher: Wiley
Date: 2004
DOI: 10.1002/CNE.20376
Abstract: The medial prefrontal cortex (mPFC) has been strongly implicated in control of the paraventricular nucleus of the hypothalamus (PVN) response to stress. Because of the paucity of direct projections from the mPFC to the PVN, we sought to investigate possible brain regions that might act as a relay between the two during psychological stress. Bilateral ibotenic acid lesions of the rat mPFC enhanced the number of Fos-immunoreactive cells seen in the PVN after exposure to the psychological stressor, air puff. Altered neuronal recruitment was seen in only one of the candidate relay populations examined, the ventral bed nucleus of the stria terminalis (vBNST). Furthermore, bilateral ibotenic acid lesions of the BNST caused a significant attenuation of the PVN response to air puff. To better characterize the structural relationships between the mPFC and PVN, retrograde tracing studies were conducted examining Fos expression in cells retrogradely labeled with cholera toxin b subunit (CTb) from the PVN and the BNST. Results obtained were consistent with an important role for both the mPFC and BNST in the mpPVN CRF cell response to air puff. We suggest a set of connections whereby a direct PVN projection from the ipsilateral vBNST is involved in the mpPVN response to air puff and this may, in turn, be modulated by an indirect projection from the mPFC to the BNST.
Eating behavior and stress: a pathway to obesity
Publisher: Frontiers Media SA
Date: 13-05-2014
Perinatal programming of neuroendocrine mechanisms connecting feeding behavior and stress
Publisher: Frontiers Media SA
Date: 2013
Conditional microglial depletion in rats leads to reversible anorexia and weight loss by disrupting gustatory circuitry
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.
Preweaning over- and underfeeding alters onset of puberty in the rat without affecting kisspeptin
Publisher: Oxford University Press (OUP)
Date: 05-2012
DOI: 10.1095/BIOLREPROD.111.097758
Abstract: The perinatal nutritional environment can permanently influence body weight, potentially leading to changes in puberty onset and reproductive function. We hypothesized that perinatal under- or overfeeding would alter puberty onset and influence concentrations of a neuropeptide crucial for successful puberty, kisspeptin. We manipulated Wistar rat litter sizes to derive small (SL), control (CL), and large (LL) litters containing 4, 12, and 20 rat pups respectively. This manipulation results in an overweight phenotype in SL rats and a lean phenotype in LL that persists throughout life. To investigate whether successful puberty onset is affected by neonatal under- or overfeeding, we examined indices of growth and development, including the onset of puberty, as well as the central expression of Kiss1 mRNA in these pups. Male LL rats reached puberty later than those from CL. These males also had reduced plasma testosterone and elevated 17beta-estradiol concentrations at puberty. The age at puberty onset was not affected in SL males despite accelerated growth. In females, puberty onset was not significantly delayed by having a lean phenotype, and steroid hormones were not affected. The age at onset was, however, younger in the SL females. Kiss1 mRNA in the hypothalamus was not affected by neonatal nutrition either at puberty or 7 days later. Our findings show early life underfeeding in males and overfeeding in females significantly affects puberty onset, altering steroid hormone concentrations in males, but this is not related to changes in hypothalamic kisspeptin.
The role of microglia and monocytes in the generation and resolution of the immune response in female and male rats
Publisher: Elsevier BV
Date: 2023
Neonatal overfeeding alters hypothalamic microglial profiles and central responses to immune challenge long-term
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.
Psychoneuroimmunology goes East: Development of the PNIRS affiliate and its expansion into PNIRS
Publisher: Elsevier BV
Date: 08-2020
Neonatal overfeeding disrupts pituitary ghrelin signalling in female rats long-term; Implications for the stress response
Publisher: Public Library of Science (PLoS)
Date: 10-03-2017
Neonatal overfeeding attenuates acute central pro-inflammatory effects of short-term high fat diet
Publisher: Frontiers Media SA
Date: 13-01-2015
Neonatal immune challenge alters nociception in the adult rat
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2005
DOI: 10.1016/J.PAIN.2005.09.022
Abstract: Intense pain or intense peripheral inflammation experienced during development can have pronounced effects upon adult pain sensation. However, little is known about the more commonly encountered mild systemic inflammation, such as that experienced with mild illness. Neonatal exposure to lipopolysaccharide (LPS), an established model of immune system activation, has been shown to affect febrile and cyclooxygenase-2 (COX-2) responses to a similar exposure in adulthood. Adult LPS also elicits a range of sickness behaviours, including enhanced responses to painful stimuli. We, therefore, hypothesized that adult sensation and pain responses could be affected by a neonatal LPS challenge. Male and female Sprague-Dawley rats were administered LPS at postnatal day 14 and were tested in adulthood for nociceptive responses to thermal and mechanical stimuli using, respectively, a plantar test apparatus and von Frey filaments, before and after adult LPS. Expression of dorsal root ganglion and lumbar spinal cord COX-2 was also examined. Animals treated as neonates with saline showed the expected hypersensitivity to painful stimuli after adult LPS as well as enhanced spinal cord COX-2. Neonatally LPS-treated rats, however, showed a significantly different profile. They displayed enhanced baseline nociception and elevated basal spinal cord COX-2 compared with neonatally saline-treated rats. Also, rather than the expected hyperalgesia after adult LPS, no changes in nociceptive responses and a reduction in spinal cord COX-2 expression were observed. These findings have important implications for the understanding of pain and its management and highlight the importance of the neonatal period in the development of pain pathways.
Effects of Global Cerebral Ischemia in the Pregnant Rat
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2008
DOI: 10.1161/STROKEAHA.107.497016
Abstract: Background and Purpose— Stroke during pregnancy is an emerging concern. Although females undergo many physiological, endocrine, and neurological alterations during pregnancy, the consequences of such changes on outcome after stroke are unclear. It is predicted that increases in steroid hormones observed during pregnancy may confer protective effects against the neurological and pathological sequelae of stroke. Methods— We therefore investigated behavioral and histological consequences of a global cerebral ischemia (2-vessel occlusion 2VO), and how these outcomes correlated with pregnancy-related changes in hormones in Sprague-Dawley rats. Results— After the 2VO, pregnant rats exhibited poorer memory in a contextual fear conditioning test of learning and memory than sham-treated controls, whereas nonpregnant rats did not. They also showed enhanced CA1 hippoc al neuronal injury. This susceptibility to damage is despite significant pregnancy-associated hypothermia and is probably not associated with alterations in 17β-estradiol or corticosterone levels. Conclusion— These findings are the first to show enhanced neuronal damage in pregnant animals after global cerebral ischemia. They also suggest that the mechanism may be independent of changes in estrogen, corticosterone, and body temperature.
Food for thought: how nutrition impacts cognition and emotion
Publisher: Springer Science and Business Media LLC
Date: 06-12-2017
DOI: 10.1038/S41538-017-0008-Y
Abstract: More than one-third of American adults are obese and statistics are similar worldwide. Caloric intake and diet composition have large and lasting effects on cognition and emotion, especially during critical periods in development, but the neural mechanisms for these effects are not well understood. A clear understanding of the cognitive–emotional processes underpinning desires to over-consume foods can assist more effective prevention and treatments of obesity. This review addresses recent work linking dietary fat intake and omega-3 polyunsaturated fatty acid dietary imbalance with inflammation in developing, adult, and aged brains. Thus, early-life diet and exposure to stress can lead to cognitive dysfunction throughout life and there is potential for early nutritional interventions (e.g., with essential micronutrients) for preventing these deficits. Likewise, acute consumption of a high-fat diet primes the hippoc us to produce a potentiated neuroinflammatory response to a mild immune challenge, causing memory deficits. Low dietary intake of omega-3 polyunsaturated fatty acids can also contribute to depression through its effects on endocannabinoid and inflammatory pathways in specific brain regions leading to synaptic phagocytosis by microglia in the hippoc us, contributing to memory loss. However, encouragingly, consumption of fruits and vegetables high in polyphenolics can prevent and even reverse age-related cognitive deficits by lowering oxidative stress and inflammation. Understanding relationships between diet, cognition, and emotion is necessary to uncover mechanisms involved in and strategies to prevent or attenuate comorbid neurological conditions in obese in iduals.
Emerging roles of extracellular vesicles in the intercellular communication for exercise-induced adaptations
Publisher: American Physiological Society
Date: 08-2020
DOI: 10.1152/AJPENDO.00215.2020
Abstract: Complex organisms rely heavily on intercellular communication. The rapidly expanding field of extracellular vesicle biology has made it clear that the necessary intercellular communication occurs partly through their paracrine and endocrine actions. Extracellular vesicles are nanoscale lipid membranes (30–2,000 nm in diameter) that shuttle functional biological material between cells. They are released from numerous tissues and are isolated from nearly all biofluids and cell cultures. Although their biogenesis, cell targeting, and functional roles are incompletely understood, they appear to have crucial roles in physiological and disease processes. Their enormous potential to serve as sensitive biomarkers of disease and also new therapeutic interventions for diseases have gained them considerable attention in recent years. Regular physical exercise training confers systemic health benefits and consequently prevents many age-related degenerative diseases. Many of the molecular mechanisms responsible for the salubrious effects of exercise are known, yet a common underlying mechanism potentially responsible for the holistic health benefits of exercise has only recently been explored (i.e., via extracellular vesicle transport of biological material). Here, we provide an overview of extracellular vesicle biology before outlining the current evidence on the capacity for a single bout and chronic exercise to elicit changes in extracellular vesicle content and modulate their molecular cargo (e.g., small RNAs). We highlight areas for future research and emphasize their potential utility as biomarkers and therapeutic strategies of disease and its prevention.
A Chat(GPT) about the future of scientific publishing
Publisher: Elsevier BV
Date: 05-2023
Neonatal overfeeding increases capacity for catecholamine biosynthesis from the adrenal gland acutely and long-term in the male rat
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.
Ghrelin’s Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.BIOPSYCH.2014.10.021
Abstract: Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a erse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal nucleus, the hippoc us, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders.
Baby’s genes may bear the consequences of Mum’s distress
Publisher: Elsevier BV
Date: 10-2018
Long term alterations in neuroimmune responses of female rats after neonatal exposure to lipopolysaccharide
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.BBI.2005.08.004
Abstract: Male and female rats display significant gender-associated differences in their responses to an immune challenge, and gender-specific alterations in many aspects of physiology are seen after a variety of interventions during the neonatal period. It is well-established that neonatal exposure to an immune challenge can alter centrally mediated inflammatory responses in adult male rats and yet little is known about female responses after a similar challenge. We therefore asked if neonatal exposure to lipopolysaccharide (LPS) would alter febrile and hypothalamic cyclooxygenase (COX)-2 responses to an adult immune challenge in female rats. Female Sprague-Dawley rats were administered a single injection of the bacterial endotoxin LPS at postnatal day 14 and were examined as adults for febrile, COX-2 and activity changes to LPS, as well as responses to interleukin (IL)-1beta. Adult female rat responses were similar to those we have seen previously for the males in that febrile and hypothalamic COX-2 responses to adult LPS were attenuated in neonatally LPS-treated animals. Responses to adult IL-1beta were unaffected. Interestingly, females did not display the elevated basal hypothalamic COX-2 that was previously seen in males. Thus we demonstrate that, like in the males, neonatal exposure to LPS has a powerful effect on adult responses to further LPS challenge in the female rats.
High Maternal Omega-3 Supplementation Dysregulates Body Weight and Leptin in Newborn Male and Female Rats: Implications for Hypothalamic Developmental Programming
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.
Anxiety and hypothalamic–pituitary–adrenal axis responses to psychological stress are attenuated in male rats made lean by large litter rearing
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.PSYNEUEN.2011.01.006
Abstract: An excellent strategy to treat overactive responses to stress is to exploit the body's inherent stress-inhibitory mechanisms. Stress responses are known to differ between in iduals depending upon their level and distribution of adiposity and their experiences in early life. For instance, we have recently shown that female rats made obese by overfeeding during the neonatal period have exacerbated responses to psychological stress. The converse may be true for those that are underfed during this period. In this investigation we hypothesized that rats made lean by neonatal underfeeding would have reduced anxiety and attenuated hypothalamic-pituitary-adrenal (HPA) axis responses to psychological stress. Our findings show that male (but not female) rats, made smaller by being suckled in a large litter, show reduced anxiety-related behaviour compared with those from normal litters when tested in the elevated plus maze. These smaller males also have attenuated activation of the paraventricular nucleus of the hypothalamus in response to the psychological stress, restraint, and corticosterone responses to restraint that return more quickly to baseline than controls. These findings are exciting from the perspective of understanding and potentially exploiting the body's inherent stress-inhibitory mechanisms to treat overactive responses to stress. They also provide an indication that being lean may be able to ameliorate overactive stress responses. Understanding the mechanisms by which these stress responses are attenuated in lean animals will be important for future strategies to treat diseases associated with overactive HPA axes in humans.
Consequences of early life overfeeding for microglia – Perspectives from rodent models
Publisher: Elsevier BV
Date: 08-2020
Early life disruption to the ghrelin system with over-eating is resolved in adulthood in male rats
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.
Early life overfeeding impairs spatial memory performance by reducing microglial sensitivity to learning
Publisher: Springer Science and Business Media LLC
Date: 18-05-2016
Postnatal Overfeeding Leads to Obesity and Exacerbated Febrile Responses to Lipopolysaccharide Throughout Life
Publisher: Wiley
Date: 23-02-2012
DOI: 10.1111/J.1365-2826.2011.02269.X
Abstract: The perinatal environment can be crucial for programming long-term physiology, including the mechanisms regulating body weight, and postnatal overfeeding can lead to obesity throughout life. Inflammation-related complications are of particular concern in the obese. However, little is known about how postnatal overfeeding contributes to changes in the ability to respond to inflammation. In the present study, we investigate changes in the febrile and neurochemical response to immune challenge with lipopolysaccharide (LPS), in juvenile and adult, male and female Wistar rats made obese by overfeeding during the postnatal period. We demonstrate that febrile responses to LPS are exacerbated in these rats, with peak core temperatures being up to 0.5 °C higher compared to those in controls, and this is associated with an enhanced pro-inflammatory cytokine profile and enhanced hypothalamic-pituitary-adrenal (HPA) axis activation. Plasma pro-inflammatory cytokines concentrations were approximately three-fold greater in neonatally overfed rats after LPS and there were approximately twice as many neurones activated in the paraventricular nucleus of the hypothalamus as in controls, with a prolonged corticosterone response. We also observed elevated expression of toll-like receptors (TLR) 2 and 4 in adipose tissue and greater inhibitory factor κB phosphorylation in these obese animals. Despite similar changes in expression of adipose TLR3, there was no corresponding alteration in the response to a viral mimetic that acts at this receptor. We suggest that an elevated febrile response to LPS therefore occurs in cases of obesity and this is associated with altered HPA axis function and enhanced TLR2/4 expression in adipose tissue and an up-regulated downstream pro-inflammatory cascade.
Linking stress and infertility: A novel role for Ghrelin
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.
Effects of mild calorie restriction on anxiety and hypothalamic-pituitary-adrenal axis responses to stress in the male rat
Publisher: Wiley
Date: 03-2014
DOI: 10.1002/PHY2.265
Perinatal programming by inflammation
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.BBI.2017.02.007
Abstract: Since Levine and then Barker's seminal work mid to late last century demonstrating the importance of early life environment, intensive research has revealed the plasticity, vulnerability and resilience of the developing brain to environmental challenges. In particular, early exposure to infectious pathogens and inflammatory stimuli has a lasting impact on brain and behavior. These data establish clear effects on vulnerability to later disease and neuroinflammatory injury, cognitive function and emotionality, and even responses to pain and susceptibility to metabolic disorders. They also highlight the issues with defining rodent models of complex diseases like autism spectrum disorders and schizophrenia, as well as the complexity of experimental design, for instance when deciding the appropriate allocation of subjects to experimental groups when dealing with whole-litter manipulations in rodents. The studies presented in this special issue of Brain Behavior and Immunity are a collection of the very latest advances in the science of perinatal inflammation and its implications for perinatal programming of brain and behavior.
Western diet chow consumption in rats induces striatal neuronal activation while reducing dopamine levels without affecting spatial memory in the radial arm maze
Publisher: Frontiers Media SA
Date: 09-02-2017
Curcumin-nanodiamond-silk wound dressings for sensing infection
Publisher: SPIE
Date: 31-12-2019
DOI: 10.1117/12.2539576
Neonatal Programming by Neuroimmune Challenge: Effects on Responses and Tolerance to Septic Doses of Lipopolysaccharide in Adult Male and Female Rats
Publisher: Wiley
Date: 04-2010
Neonatal programming of innate immune function
Publisher: American Physiological Society
Date: 2011
DOI: 10.1152/AJPENDO.00516.2010
Abstract: The early life environment can be crucial in influencing the development of an animal's long-term physiology. There is now much evidence to suggest that perinatal challenges to an animal's immune system will result in changes in adult rat behavior, physiology, and molecular pathways following a single inflammatory event during development caused by the bacterial endotoxin lipopolysaccharide (LPS). In particular, it is now apparent that neonatal LPS administration can influence the adult neuroimmune response to a second LPS challenge through hypothalamic-pituitary-adrenal axis modifications, some of which are caused by alterations in peripheral prostaglandin synthesis. These pronounced changes are accompanied by a variety of alterations in a number of disparate aspects of endocrine physiology, with significant implications for the health and well-being of the adult animal. In this review, we discuss the newly elucidated mechanisms by which neonatal immune challenge can permanently alter an animal's endocrine and metabolic physiology and the implications this has for various disease states.
Being Suckled in a Large Litter Mitigates the Effects of Early‐Life Stress on Hypothalamic‐Pituitary‐Adrenal Axis Function in the Male Rat
Publisher: Wiley
Date: 20-08-2013
DOI: 10.1111/JNE.12056
Abstract: The perinatal environment influences stress responses in the long-term, as does body composition. Male rats suckled in large litters, where they have reduced access to milk and attention from the dam, are less anxious and have attenuated hypothalamic-pituitary-adrenal (HPA) axis responses to stress compared to rats from control litters. In the present study, we investigated whether this early-life environment can also ameliorate anxiety and HPA axis function in rats prone to be stress-sensitive. We conducted these experiments in male rats from control litters (n = 12) or large litters (n = 20). Half were given 24 h of maternal separation on postnatal day 10 to induce HPA axis hyperactivity the remainder staying undisturbed with their dam. When the rats reached adulthood, we examined behavioural indices of anxiety (elevated plus maze) and depression (Porsolt's forced swim test) under basal conditions and after 15 min of restraint stress. We also examined neuronal activation in the paraventricular nucleus of the hypothalamus (PVN) as an index of HPA axis function. Being suckled in a large litter led to a significantly attenuated PVN response to stress in adulthood. Maternal separation strongly exacerbated the stress-induced increase in PVN neuronal activation in control rats but did not affect the PVN response in large-litter rats. Immobility in the forced swim after restraint was also exacerbated in neonatally maternally separated control rats but not in those from large litters. Our findings show that being suckled in large litters mitigates the effects of early-life stress on HPA axis function and indices of depression in the rat.
Acylated Ghrelin Supports the Ovarian Transcriptome and Follicles in the Mouse: Implications for Fertility
Publisher: Frontiers Media SA
Date: 15-01-2019
Erratum: Xavier et al. High Maternal Omega-3 Supplementation Dysregulates Body Weight and Leptin in Newborn Male and Female Rats: Implications for Hypothalamic Developmental Programming. Nutrients 202
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 [...]
The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.NEUBIOREV.2017.10.014
Abstract: Obesity is an increasing problem in young people. Childhood obesity and overweight have increased rapidly on a global scale, and have tripled in the past 30 years, to affect approximately one in five children. Diets high in refined fats and sugar are a major contributor to the development of obesity, and the effects of such obesity-inducing hypercaloric diets on brain function may contribute to the high prevalence of anxiety disorders in people with obesity. Anxiety disorders typically emerge in childhood and adolescence, and symptoms often continue into adulthood. Based on this symptomology, we consider anxiety-related behavioral consequences of hypercaloric diets across development. We review research on the effects of hypercaloric dietary manipulations across the lifespan on emotion regulation and the neurobiological mechanisms that underpin these processes. Cumulatively, the findings reveal that gestation and the juvenile/adolescent developmental periods may be early-life windows of vulnerability for developing anxiety in later life due to the augmented effects of these diets on neuroendocrine stress systems and the maturation of neural circuitry supporting emotion regulation.
Systemic apomorphine alters HPA axis responses to interleukin-1β adminstration but not sound stress
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0306-4530(02)00065-3
Abstract: Apomorphine is a dopamine receptor agonist that was recently licensed for the treatment of erectile dysfunction. However, although sexual activity can be stressful, there has been little investigation into whether treatments for erectile dysfunction affect stress responses. We have examined whether a single dose of apomorphine, sufficient to produce penile erections (50 microg/kg, i.a.), can alter basal or stress-induced plasma ACTH levels, or activity of central pathways thought to control the hypothalamic-pituitary-adrenal axis in rats. An immune challenge (interleukin-1 beta, 1 microg/kg, i.a.) was used as a physical stressor while sound stress (100 dB white noise, 30 min) was used as a psychological stressor. Intravascular administration of apomorphine had no effect on basal ACTH levels but did substantially increase the number of Fos-positive amygdala and nucleus tractus solitarius catecholamine cells. Administration of apomorphine prior to immune challenge augmented the normal ACTH response to this stressor at 90 min and there was a corresponding increase in the number of Fos-positive paraventricular nucleus corticotropin-releasing factor cells, paraventricular nucleus oxytocin cells and nucleus tractus solitarius catecholamine cells. However, apomorphine treatment did not alter ACTH or Fos responses to sound stress. These data suggest that erection-inducing levels of apomorphine interfere with hypothalamic-pituitary-adrenal axis inhibitory feedback mechanisms in response to a physical stressor, but have no effect on the response to a psychological stressor. Consequently, it is likely that apomorphine acts on a hypothalamic-pituitary-adrenal axis control pathway that is unique to physical stressors. A candidate for this site of action is the nucleus tractus solitarius catecholamine cell population and, in particular, A2 noradrenergic neurons.
Understanding the role of P2X7 in affective disorders—are glial cells the major players?
Publisher: Frontiers Media SA
Date: 08-07-2015
The power of effective study design in animal experimentation: Exploring the statistical and ethical implications of asking multiple questions of a data set
Publisher: Elsevier BV
Date: 08-2023
Endogenous ghrelin's role in hippocampal neuroprotection after global cerebral ischemia: does endogenous ghrelin protect against global stroke?
Publisher: American Physiological Society
Date: 06-2013
DOI: 10.1152/AJPREGU.00594.2012
Abstract: Ghrelin is a gastrointestinal hormone with a well-characterized role in feeding and metabolism. Recent evidence suggests that ghrelin may also be neuroprotective after injury in animal models of cerebral ischemia. Thus exogenous ghrelin treatment can improve cell survival, reduce infarct size, and rescue memory deficits in focal ischemia models, doing so by suppressing inflammation and apoptosis. Endogenous ghrelin plays a key a role in a number of physiological processes, including feeding, metabolism, stress, and anxiety. However, no study has examined whether endogenous ghrelin also contributes to neuroprotection after cerebral ischemia. Here, we aimed to determine whether endogenous ghrelin normally protects against neuronal cell death and cognitive impairments after global cerebral ischemia and whether such changes are linked with inflammation or apoptosis. We used a two-vessel occlusion (2VO) model of global cerebral ischemia in wild-type (wt) and ghrelin knockout (ghr−/−) C57/Bl6J mice. ghr−/− mice had improved cell survival in the Cornu Ammonis(CA)-2/3 region of the hippoc us—a region of significant growth hormone secretagogue receptor expression. They also displayed less cellular degeneration than wt mice after the 2VO (Fluoro-Jade) and had less cognitive impairment in the novel object-recognition test. These outcomes were despite evidence of more neuroinflammation and apoptosis in the ghr−/− and less of a postsurgery hypothermia. Finally, we found that mortality in the week following the 2VO was reduced more in ghr−/− mice than in wt. Overall, these experiments point to a neurodegenerative but antiapoptotic effect of endogenous ghrelin in this model of global ischemia, highlighting that further research is essential before we can apply ghrelin treatments to neurodegenerative insults in the clinic.
Maternal diet before and during pregnancy modulates microglial activation and neurogenesis in the postpartum rat brain
Publisher: Elsevier BV
Date: 11-2021
Diet, behavior and immunity across the lifespan
Publisher: Elsevier BV
Date: 11-2014
The glucocorticoid contribution to obesity
Publisher: Informa UK Limited
Date: 06-02-2011
DOI: 10.3109/10253890.2010.534831
Abstract: Obesity is fast becoming the scourge of our time. It is one of the biggest causes of death and disease in the industrialized world, and affects as many as 32% of adults and 17% of children in the USA, considered one of the world's fattest nations. It can also cost countries billions of dollars per annum in direct and indirect care, latest estimates putting the USA bill for obesity-related costs at $147 billion in 2008. It is becoming clear that the pathophysiology of obesity is vastly more complicated than the simple equation of energy in minus energy out. A combination of genetics, sex, perinatal environment and life-style factors can influence diet and energy metabolism. In this regard, psychological stress can have significant long-term impact upon the propensity to gain and maintain weight. In this review, we will discuss the ability of psychological stress and ultimately glucocorticoids (GCs) to alter appetite regulation and metabolism. We will specifically focus on (i) GC regulation of appetite and adiposity, (ii) the apparent sexual dimorphism in stress effects on obesity and (iii) the ability of early life stress to programme obesity in the long term.
High-fat diet worsens the impact of aging on microglial function and morphology in a region-specific manner
Publisher: Elsevier BV
Date: 02-2019
Effects of Neonatal Overfeeding on Juvenile and Adult Feeding and Energy Expenditure in the Rat
Publisher: Public Library of Science (PLoS)
Date: 14-12-2012
Ghrelin-Related Peptides Exert Protective Effects in the Cerebral Circulation of Male Mice Through a Nonclassical Ghrelin Receptor(s)
Publisher: The Endocrine Society
Date: 2015
DOI: 10.1210/EN.2014-1415
Ghrelin Regulates the Hypothalamic-Pituitary-Adrenal Axis and Restricts Anxiety After Acute Stress
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.BIOPSYCH.2012.03.010
Abstract: Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress. We used ghrelin knockout (ghr-/-) mice to examine the role of endogenous ghrelin in anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute stress. Ghr-/- mice are more anxious after acute restraint stress, compared with wild-type (WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus of the amygdala in ghr-/- mice compared with WT, and exogenous ghrelin reversed this effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal nucleus in WT but not ghr-/- mice. Ghr-/- mice exhibited a lower corticosterone response after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence of ghrelin. We found no differences in dexamethasone-induced Fos expression between ghr-/- and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic hormone replacement elevated plasma corticosterone in ghr-/-, compared with WT mice, indicating increased adrenal sensitivity. The adrenocorticotropic hormone response to acute stress was significantly reduced in ghr-/- mice, compared with control subjects. Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue receptor. Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus promotes an appropriate stress response. Thus, ghrelin regulates acute stress and offers potential therapeutic efficacy in human mood and stress disorders.
Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation
Publisher: Wiley
Date: 15-02-2018
DOI: 10.1002/HIPO.22834
Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats
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.
Rat Neonatal Immune Challenge Alters Adult Responses to Cerebral Ischaemia
Publisher: SAGE Publications
Date: 10-08-2005
Abstract: Infection, inflammation, and hyperthermia associated with cerebral ischaemia are known to contribute to enhanced neuronal cell loss and more severe behavioural deficits. Because neonatal exposure to an immune challenge has been shown to alter the severity of inflammatory and febrile responses to a further immune challenge experienced in adulthood, we hypothesised that this could also alter temperature responses and neuronal survival after ischaemia. Thus, male Sprague–Dawley rats were treated at postnatal day 14 with a single injection of the bacterial endotoxin lipopolysaccharide (LPS) and were examined as adults for temperature changes, behavioural deficits, and neuronal cell loss associated with global cerebral ischaemia after a two-vessel occlusion (2 VO). Neonatally LPS-treated rats showed behavioural differences in a novel object exploration paradigm, as well as altered temperature responses to the 2 VO compared with neonatally salinetreated controls. Interestingly, these neonatally LPS-treated rats also showed increased cell loss in the central nucleus of the amygdala, a region that is important in the processing of emotional responses, but that is not usually examined in animal models of cerebral ischaemia. No differences were seen in the CA1, CA3, or dentate gyrus regions of the hippoc us. This work shows the importance of examining brain regions other than the hippoc us in association with global ischaemia. We also highlight the importance of the early period of development in programming an animal's ability to deal with injury such as cerebral ischaemia in adulthood.
Postnatal programming of the innate immune response
Publisher: Oxford University Press (OUP)
Date: 10-06-2009
DOI: 10.1093/ICB/ICP025
The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease
Publisher: Elsevier BV
Date: 2021
Central and peripheral neuroimmune responses: hyporesponsiveness during pregnancy
Publisher: Wiley
Date: 14-01-2008
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