Browsing by Author "Kellaway, Lauriston"

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    Effect of age and unilateral dopamine depletion on striatal NMDA receptor function
    (2005) Khoboko, Thabelo; Russell, Vivienne A; Kellaway, Lauriston
    Includes bibliographical references.
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    Investigating neural responses in models of neurocysticercosis
    (2020) Tomes, Hayley Sarah; Raimondo, Joseph Valentino; Kellaway, Lauriston
    Epilepsy is more frequent in sub-Saharan Africa than the rest of the world due to high levels of brain infections by larvae of the pig cestode Taenia solium, a condition termed neurocysticercosis. Despite the large nature of the problem, little is known about how neurocysticercosis modulates neuronal responses to result in the development of seizures. In this thesis I have used the cestode Taenia crassiceps to develop multiple in vitro and in vivo models of neurocysticercosis in rodents. Utilising patch-clamp electrophysiology in organotypic hippocampal brain slices and chronic, wireless electrocorticographic recordings in freely moving animals I have explored how cestode larvae affect neuronal excitability in the brain across a range of time scales. First I demonstrate that homogenate of Taenia crassiceps larvae has a strong, acute excitatory effect on neurons, which is sufficient to trigger seizurelike events. The excitatory component of the homogenate was found to strongly activate glutamate receptors and not acetylcholine receptors nor acid-sensing ion channels. An enzymatic assay showed that the larval homogenate contains high levels of glutamate, explaining its acute excitatory effects on neurons. In the second part of my thesis I demonstrate that longer-term incubation of Taenia crassiceps homogenate with organotypic brain slices over the course of a day does not affect the intrinsic properties of pyramidal neurons nor the excitability of the neuronal network. In the final part of my thesis I established an in vivo model of neurocysticercosis. I found that intradermal inoculation together with multiple intracerebral injections of Taenia crassiceps homogenate did not result in the development of seizures over 3 months of chronic electrocorticography recordings. In addition, the seizure-threshold to picrotoxin, an excitotoxin, was not altered by Taenia crassiceps homogenate injection. Immunohistological analysis of the tissue below the injection site revealed no difference in astrocytes nor the number of microglia. However, microglial processes were observed to be retracted in the Taenia crassiceps group reflecting a moderate neuroinflammatory response. Together the data in my thesis provides novel insight into the acute and chronic effects of Taenia crassiceps homogenate on the excitability of neuronal networks with relevance to our understanding of neurocysticercosis.
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    Methamphetamine and cocaine effects on dopamine neurons in a rat model of developmental stress and attention-deficit/hyperactivity disorder
    (2014) Womersley, Jacqueline Samantha; Russell, Vivienne A; Kellaway, Lauriston; Stein, Dan J
    Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by age-inappropriate levels of inattention, hyperactivity and impulsivity and is theorised to be caused by dopaminergic dysregulation. Developmental stress interrupts vulnerable periods of neural developmental and has also been found to induce disturbances in dopamine. ADHD and developmental stress are both associated with a higher risk of abusing psychostimulants; drugs that act on the dopaminergic system to elicit a sense of reward. Central to dopamine regulation is the dopamine transporter (DAT), which is responsible for the rapid reuptake of released dopamine and therefore the regulation of extracellul ar dopamine concentration. The aim of this study was to examine the effects of developmental stress and psychostimulant exposure on dopaminergic function, more specifically DAT, in a rat model of ADHD, the spontaneously hypertensive rat (SHR) versus Wistar Kyoto (WKY) and Sprague-Dawley (SD) control strains.
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    The relationship between Alzheimer's disease, inflammation, the APOE genotype and neuronal integrity
    (2013) Grace, Laurian Kerry; Combrinck, Marc; Kellaway, Lauriston
    Includes abstract. Includes bibliographical references.
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    TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis
    (BioMed Central Ltd, 2015) Francisco, Ngiambudulu; Hsu, Nai-Jen; Keeton, Roanne; Randall, Philippa; Sebesho, Boipelo; Allie, Nasiema; Govender, Dhirendra; Quesniaux, Valerie; Ryffel, Bernhard; Kellaway, Lauriston; Jacobs, Muazzam
    BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF / ) mice and compared outcomes of disease against TNF f/f control and global TNF / mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF / mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF / mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF / mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.