ORCID Profile
0000-0003-2268-8654
Current Organisations
The University of Newcastle College of Health Medicine and Wellbeing
,
The University of Newcastle
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Publisher: Oxford University Press (OUP)
Date: 10-10-2017
Abstract: Normal ovarian development is crucial for female reproductive success and longevity. Interruptions to the delicate process of initial folliculogenesis may lead to ovarian dysfunction. We have previously demonstrated that an early life immune challenge in the rat, induced by administration of lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5, depletes ovarian follicle reserve long term. Here, we hypothesized that this neonatal immune challenge leads to an increase in peripheral and ovarian inflammatory signaling, contributing to an acute depletion of ovarian follicles. Morphological analysis of neonatal ovaries indicated that LPS administration significantly depleted PND 5 primordial follicle populations and accelerated follicle maturation. LPS exposure upregulated circulating interleukin 6, tumor necrosis factor alpha (TNFa), and C-reactive protein on PND 5, and upregulated ovarian mRNA expression of Tnfa, mitogen-activated protein kinase 8 (Mapk8/Jnk1), and growth differentiation factor 9 (Gdf9) (P < 0.05). Mass spectrometry and cell signaling pathway analysis indicated upregulation of cellular pathways associated with acute phase signaling, and cellular survival and assembly. Apoptosis assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling indicated significantly increased positive staining in the ovaries of LPS-treated neonates. These findings suggest that increased proinflammatory signaling within the neonatal ovary may be responsible for the LPS-induced depletion of the primordial follicle pool. These findings also have implications for female reproductive health, as the ovarian reserve is a major determinate of female reproductive longevity.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.BBR.2018.08.016
Abstract: Maternal immune activation induced by Poly(I:C) administration is one of the most commonly used animal models of schizophrenia at present. Previous work from our team has demonstrated that some, but not all of the features often reported for maternal immune activation exposure in rodents can be observed in rats exposed to maternal immune activation at mid or late gestation. To determine whether previous findings in our laboratory were due to these time points simply being less sensitive neurodevelopmental periods for rats with regard to maternal immune activation effects, we aimed to investigate whether maternal immune activation at an often-reported sensitive period (mid-late gestation, day 14) resulted in more behavioural features reflective of face validity for schizophrenia. We examined the behavioural outcomes of mid-late maternal immune activation on a battery of behavioural tests aimed at assessing validity for positive, negative and cognitive symptoms of schizophrenia. We found that rats exposed to maternal immune activation, compared to controls, exhibited enhanced sensitivity to the locomotor-stimulating effects of hetamine and reduced exploration of novel objects. These findings present a unique profile of effects, different to what has already been established for the same time point in rats, and different to what we had found at earlier and later time points. This work, among others in the literature, highlights the varying nature of models of maternal immune activation and we submit that it is essential for laboratories to characterise their models of maternal immune activation on behaviour rather than assuming that the effects from one laboratory apply in their own.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BIOPSYCHO.2016.01.011
Abstract: Although the scientific community appears to know a lot about MMN, about its neural generators and the computational processes that underlie its generation, do we have sufficient knowledge to understand what causes the reduction of MMN litude in schizophrenia? Here we attempt to integrate the evidence presented in this series of papers for the special issue on MMN in schizophrenia together with evidence from other new relevant research and ask--what have we learnt? While MMN research was the purview for decades of psychophysiologists interested in event-related potentials derived from scalp recorded EEG, it is now part of mainstream neuroscience research attracting the interest of basic auditory neuroscientists, neurobiologists and computational modellers. The confluence of these developments together with increasing clinical research has certainly advanced our understanding of the causes of reduced MMN in schizophrenia as this integrative review attempts to demonstrate--but much remains to be learnt. Future advances will rely on the application of multiple methodologies and approaches in order to arrive at better understanding of the neurobiology of MMN and implications for schizophrenia.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BIOPSYCHO.2015.07.006
Abstract: The mismatch negativity (MMN) component of the auditory event-related potential, elicited in response to unexpected stimuli in the auditory environment, has great value for cognitive neuroscience research. It is changed in several neuropsychiatric disorders such as schizophrenia. The ability to measure and manipulate MMN-like responses in animal models, particularly rodents, would provide an enormous opportunity to learn more about the neurobiology underlying MMN. However, the MMN in humans is a very specific phenomenon: how do we decide which features we should focus on emulating in an animal model to achieve the highest level of translational validity? Here we discuss some of the key features of MMN in humans and summarise the success with which they have been translated into rodent models. Many studies from several different labs have successfully shown that the rat brain is capable of generating deviance detection responses that satisfy of the criteria for the human MMN.
Publisher: S. Karger AG
Date: 2018
DOI: 10.1159/000493320
Abstract: b i Objectives: /i /b Gastrointestinal (GI) inflammation and GI integrity deficits are common comorbidities of neuropsychiatric disorders. Ongoing research suggests that these aberrations may be contributing to heightened immune signals that have the potential to disrupt neuronal homeostasis and exacerbate behavioural deficits. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the maternal immune activation (MIA) model, produced GI inflammation and integrity disruptions in association with anxiety-like behaviour. b i Methods: /i /b Pregnant Wistar rats were exposed to the viral mimetic polyriboinosinic:polyribocytidilic acid (polyI:C) on gestational days (GD) 10 and 19. Evidence of ANS activation, GI inflammation, and GI barrier integrity was assessed in both neonatal (postnatal day, P7) and adult (P84) offspring. Anxiety-like behaviour was assessed at P100. b i Results: /i /b Neonatal MIA offspring exhibited an altered intestinal inflammatory profile and evidence of an increase in lymphoid aggregates. MIA neonates also displayed disruptions to GI barrier tight junction protein mRNA. In addition, adult MIA offspring exhibited an increase in anxiety-like behaviours. b i Conclusion: /i /b These results indicate that the MIA rat model, which is well documented to produce behavioural, neurochemical, and neuroanatomical abnormalities, also produces GI inflammation and integrity disruptions. We suggest that this model may be a useful tool to elucidate biological pathways associated with neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.SCHRES.2017.03.042
Abstract: One of the most robust electrophysiological features of schizophrenia is reduced mismatch negativity, a component of the event related potential (ERP) induced by rare and unexpected stimuli in an otherwise regular pattern. Emerging evidence suggests that mismatch negativity (MMN) is not the only ERP index of deviance detection in the mammalian brain and that sensitivity to deviant sounds in a regular background can be observed at earlier latencies in both the human and rodent brain. Pharmacological studies in humans and rodents have previously found that MMN reductions similar to those seen in schizophrenia can be elicited by N-methyl-d-aspartate (NMDA) receptor antagonism, an observation in agreement with the hypothesised role of NMDA receptor hypofunction in schizophrenia pathogenesis. However, it is not known how NMDA receptor antagonism affects early deviance detection responses. Here, we show that NMDA antagonism impacts both early and late deviance detection responses. By recording EEG in awake, freely-moving rats in a drug-free condition and after varying doses of NMDA receptor antagonist MK-801, we found the hypothesised reduction of deviance detection for a late, negative potential (N55). However, the litude of an early component, P13, as well as deviance detection evident in the same component, were increased by NMDA receptor antagonism. These findings indicate that late deviance detection in rats is similar to human MMN, but the surprising effect of MK-801 in increasing ERP litudes as well as deviance detection at earlier latencies suggests that future studies in humans should examine ERPs over early latencies in schizophrenia and after NMDA antagonism.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.PNPBP.2015.09.006
Abstract: Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) density in the fibre tracts below the cortex in people with schizophrenia. The current study assesses IWMN pathology in a model of maternal immune activation (MIA) a risk factor for schizophrenia. Experimental MIA was produced by an injection of polyinosinic:polycytidylic acid (PolyI:C) into pregnant rats on gestational day (GD) 10 or GD19. A separate control group received saline injections. The density of neuronal nuclear antigen (NeuN(+)) and somatostatin (SST(+)) IWMNs was determined in the white matter of the corpus callosum in two rostrocaudally adjacent areas in the 12week old offspring of GD10 (n=10) or GD19 polyI:C dams (n=18) compared to controls (n=20). NeuN(+) IWMN density trended to be higher in offspring from dams exposed to polyI:C at GD19, but not GD10. A subpopulation of these NeuN(+) IWMNs was shown to express SST. PolyI:C treatment of dams induced a significant increase in the density of SST(+) IWMNs in the offspring when delivered at both gestational stages with more regionally widespread effects observed at GD19. A positive correlation was observed between NeuN(+) and SST(+) IWMN density in animals exposed to polyI:C at GD19, but not controls. This is the first study to show that MIA increases IWMN density in adult offspring in a similar manner to that seen in the brain in schizophrenia. This suggests the MIA model will be useful in future studies aimed at probing the relationship between IWMNs and schizophrenia.
Publisher: Wiley
Date: 10-09-2022
DOI: 10.1111/PSYP.14175
Abstract: Reduced mismatch negativity (MMN), a robust finding in schizophrenia, has prompted interest in MMN as a preclinical biomarker of schizophrenia. The rat brain can generate human‐like mismatch responses (MMRs) which therefore enables the exploration of the neurobiology of reduced MMRs. Given epidemiological evidence that two developmental factors, maternal infection and adolescent cannabis use, increase the risk of schizophrenia, we determined the effect of these two developmental risk factors on rat MMR litude in different auditory contexts. MMRs were assessed in awake adult male and female Wistar rats that were offspring of pregnant dams treated with either a viral infection mimetic (poly I:C) inducing maternal immune activation (MIA) or saline control. In adolescence, subgroups of the prenatal treatment groups were exposed to either a synthetic cannabinoid (adolescent cannabinoid exposure: ACE) or vehicle. The context under which MMRs were obtained was manipulated by employing two different oddball paradigms, one that manipulated the physical difference between rare and common auditory stimuli, and another that manipulated the probability of the rare stimulus. The design of the multiple stimulus sequences across the two paradigms also allowed an investigation of context on MMRs to two identical stimulus sequences. Male offspring exposed to each of the risk factors for schizophrenia (MIA, ACE or both) showed a reduction in MMR, which was evident only in the probability paradigm, with no effects seen in the physical difference. Our findings highlight the importance of contextual factors induced by paradigm manipulations and sex for modeling schizophrenia‐like MMN impairments in rats.
Publisher: Elsevier BV
Date: 05-03-2008
DOI: 10.1016/J.BBR.2007.09.032
Abstract: Developmental vitamin D (DVD) deficiency has been proposed as an environmental risk factor for a number of brain disorders. The absence of this vitamin during foetal development in the rat is known to alter behaviour in the adult, and many of these alterations are informative with respect to the clinical features of schizophrenia. Here we investigated whether DVD deficiency had a similar effect on 129/SvJ and C57BL/6J mice. Female mice were fed a diet deficient in vitamin D for 6 weeks prior to conception until birth, after which dams and their offspring were fed a normal diet (i.e. containing vitamin D). Control mice were fed a normal diet throughout the experiment. The adult offspring underwent a comprehensive behavioural test battery at 10 weeks of age. We found that DVD-deficient mice of both strains exhibited significantly higher levels of exploration, as measured by the frequency of head dipping on the hole board test. In addition, DVD-deficient 129/SvJ mice, but not C57BL/6J mice, displayed spontaneous hyperlocomotion. There was no effect of maternal diet on parameters assessed by the SHIRPA primary screen, or on tests of sensorimotor gating, social behaviour, anxiety or depression. Some of these findings resemble the rat phenotype (hyperlocomotion) but there are also novel effects of DVD deficiency on mouse behaviour (increased exploration). This study confirms that the developmental absence of this vitamin affects brain function in another species (mouse), and lends further weight to the hypothesis that DVD deficiency in humans may contribute to adverse neuropsychiatric outcomes.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.BEEM.2011.05.009
Abstract: Vitamin D is a member of the superfamily of nuclear steroid transcription regulators and as such, exerts transcriptional control over a large number of genes. Several other steroids, such as thyroid hormones, vitamin A, androgens and the glucocorticoids, are known as 'neurosteroids' and their role in brain development and function is well defined. It has only been in the last decade or so that vitamin D has been thought to function as a neurosteroid. In this review we have collated a erse array of data describing the presence of vitamin D metabolites and the receptor in the brain, the evidence that vitamin D may be an important modulator of brain development, and the potential role of vitamin D in neurological and neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.PSYNEUEN.2009.04.015
Abstract: There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the "Biological Plausibility" of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.
Publisher: Public Library of Science (PLoS)
Date: 26-04-2012
Publisher: Elsevier BV
Date: 03-2020
Publisher: Frontiers Media SA
Date: 2013
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.BIOPSYCHO.2015.06.015
Abstract: Reductions in the size of the mismatch negativity (MMN), an event-related potential component elicited in response to unexpected stimuli, are arguably the most robust neurophysiological findings in schizophrenia. Several studies have now demonstrated that 'true' human-like deviance detection mismatch responses (MMRs) can be generated in the rodent brain and therefore that animal models can be used to examine the neurobiology of schizophrenia-like MMR impairments and investigate the efficacy of new treatments in addressing underlying neurobiological mechanisms. Two broad categories of animal models have been examined for schizophrenia-like MMRs: models involving N-methyl-D-aspartate receptor hypofunction, and models involving an insult or exposure during development. While these models have been shown to exhibit reductions in MMRs, it is still unclear whether or not these reductions involve changes to neural adaptation to repetitive stimuli or whether they reflect impairments in the response to unexpected deviations in regular patterns.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.PSYCHRES.2018.05.063
Abstract: Animal models of maternal immune activation study the effects of infection, an environmental risk factor for schizophrenia, on brain development. Microglia activation and cytokine upregulation may have key roles in schizophrenia neuropathology. We hypothesised that maternal immune activation induces changes in microglia and cytokines in the brains of the adult offspring. Maternal immune activation was induced by injecting polyriboinosinic:polyribocytidylic acid into pregnant rats on gestational day (GD) 10 or GD19, with brain tissue collected from the offspring at adulthood. We observed no change in Iba1, Gfap, IL1-β and TNF-α mRNA levels in the cingulate cortex (CC) in adult offspring exposed to maternal immune activation. Prenatal exposure to immune activation had a significant main effect on microglial IBA1-positive immunoreactive material (IBA1+IRM) in the corpus callosum post-hoc analyses identified a significant increase in GD19 offspring, but not GD10. No change in was observed in the CC. In contrast, maternal immune activation had a significant main effect on GFAP+IRM in the CC at GD19 (not GD10) post-hoc analyses only identified a strong trend towards increased GFAP+IRM in the GD19 offspring, with no white matter changes. This suggests late gestation maternal immune activation causes subtle alterations to microglia and astrocytes in the adult offspring.
Publisher: Cold Spring Harbor Laboratory
Date: 12-05-2019
DOI: 10.1101/636068
Abstract: Efficient sensory processing requires that the brain is able to maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. MMN has been found to be reduced in in iduals with schizophrenia in over 100 separate studies, an effect believed to be underpinned by glutamate N-methyl-D-aspartate receptor (NMDA-R) dysfunction, as it is observed that NMDA-R antagonists also reduce MMN in healthy volunteers. The aim of the current study is to examine this effect in rodents. Using single unit recording in specific auditory areas using methods not readily utilized in humans, we have previously demonstrated that neuronal indices of rodent mismatch responses recorded from thalamic and cortical areas of the brain can be decomposed into a relatively simple repetition suppression and a more sophisticated prediction error process. In the current study, we aimed to test how the NMDA-R antagonist, MK-801, affected both of these processes along the rat auditory thalamocortical pathway. We found that MK-801 had the opposite effect than expected, and enhanced thalamic repetition suppression and cortical prediction error. These single unit data correlate with the recordings of local field responses. Together with previous data, this study suggests that our understanding of the contribution of NMDA-R system to MMN generation is far from complete, and also has potential implications for future research in schizophrenia. In this study, we demonstrate that an NMDA-R antagonist, MK-801, differentially affects single neuron responses to auditory stimuli along the thalamocortical axis by increasing the response magnitude of unexpected events in the auditory cortex and intensifying the adaptation of responses to expected events in the thalamus. Thus, we provide evidence that NMDA-R antagonists alter the balance between prediction-error and repetition suppression processes that underlie the generation of mismatch responses in the brain, and these effects are differentially expressed at different levels of auditory processing. As effects of MK-801 were in the opposite direction to our expectations, it demonstrates that our understanding of role of NMDA-R in synaptic plasticity and the neural processes underpinning MMN generation are far from complete.
Publisher: Public Library of Science (PLoS)
Date: 03-08-2012
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.BBR.2012.02.007
Abstract: Evidence from epidemiology suggests that developmental vitamin D (DVD) deficiency is associated with an increased risk of schizophrenia. DVD deficiency in rats is associated with altered brain morphology and enhanced hyperlocomotion in response to MK-801 and hetamine. The aim of this study was to determine if similar phenotypes were associated with DVD deficiency in two strains of mice (C57BL/6J, 129/X1SvJ). Brains from neonatal (P0) and adult (P70) mice were imaged using MRI and the volumes of the cerebrum, hippoc us, striatum, septum, cortex and ventricles measured, as well as the widths of white matter tracts. Locomotor sensitivity to 5mg/kg d- hetamine, 0.5mg/kg MK-801 or saline was examined in a separate group of mice in an open field. DVD deficiency altered brain morphology in C57BL6/J mice, such that C57BL/6J female DVD-deficient neonatal mice had a smaller hippoc us compared to female controls. In addition, adult C57BL/6J male DVD-deficient mice had smaller lateral ventricles compared to controls, which may have been compressed by the enlarged striatum seen in these DVD-deficient mice. However, in contrast to the behavioural phenotypes found in DVD-deficient rats, there was no significant effect of maternal diet on hetamine or MK-801-induced locomotion in either strain. These data indicate that not only species, but also strain of mouse, moderates the impact of DVD deficiency on neuroanatomical and behavioural phenotypes in rodent animal models.
Location: Australia
No related grants have been discovered for Lauren Harms.