ORCID Profile
0000-0001-9885-3607
Current Organisation
University of Western Australia
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Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.NEUROSCIENCE.2013.05.045
Abstract: The velocity of impact between an object and the human head is a critical factor influencing brain injury outcomes but has not been explored in any detail in animal models. Here we provide a comprehensive overview of the interplay between impact velocity and injury severity in a well-established weight-drop impact acceleration (WDIA) model of diffuse brain injury in rodents. We modified the standard WDIA model to produce impact velocities of 5.4, 5.85 and 6.15 m/s while keeping constant the weight and the drop height. Gradations in impact velocity produced progressive degrees of injury severity measured behaviourally, electrophysiologically and anatomically, with the former two methods showing greater sensitivity to changes in impact velocity. There were impact velocity-dependent reductions in sensorimotor performance and in cortical depth-related depression of sensory cortex responses however axonal injury (demonstrated by immunohistochemistry for β-amyloid precursor protein and neurofilament heavy-chain) was discernible only at the highest impact velocity. We conclude that the WDIA model is capable of producing graded axonal injury in a repeatable manner, and as such will prove useful in the study of the biomechanics, pathophysiology and potential treatment of diffuse axonal injury.
Publisher: Mary Ann Liebert Inc
Date: 15-02-2016
Abstract: Progesterone (P4) has been suggested as a neuroprotective agent for traumatic brain injury (TBI) because it ameliorates many post-TBI sequelae. We examined the effects of P4 treatment on the short-term (4 days post-TBI) and long-term (8 weeks post-TBI) aftermath on neuronal processing in the rodent sensory cortex of impact acceleration-induced diffuse TBI. We have previously reported that in sensory cortex, diffuse TBI induces a short-term hypoexcitation that is greatest in the supragranular layers and decreases with depth, but a long-term hyperexcitation that is exclusive to the supragranular layers. Now, adult male TBI-treated rats administered P4 showed, in the short term, even greater suppression in neural responses in supragranular layers but a reversal of the TBI-induced suppression in granular and infragranular layers. In long-term TBI there were only inconsistent effects of P4 on the TBI-induced hyperexcitation in supragranular responses but infragranular responses, which were not affected by TBI alone, were elevated by P4 treatment. Intriguingly, the effects in the injured brain were almost identical to P4 effects in the normal brain, as seen in sham control animals treated with P4: in the short term, P4 effects in the normal brain were identical to those exercised in the injured brain and in the long term, P4 effects in the normal brain were rather similar to what was seen in the TBI brain. Overall, these results provide no support for any protective effects of P4 treatment on neuronal encoding in diffuse TBI, and this was reflected in sensorimotor and other behavior tasks also tested here. Additionally, the effects suggest that mechanisms used for P4 effects in the normal brain are also intact in the injured brain.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Mary Ann Liebert Inc
Date: 15-11-2014
Publisher: MDPI AG
Date: 24-03-2017
DOI: 10.3390/GENES8040108
Publisher: Mary Ann Liebert Inc
Date: 06-2016
Abstract: We have previously demonstrated that traumatic brain injury (TBI) induces significant long-term neuronal hyperexcitability in supragranular layers of sensory cortex, coupled with persistent sensory deficits. Hence, we aimed to investigate whether brain plasticity induced by environmental enrichment (EE) could attenuate abnormal neuronal and sensory function post-TBI. TBI (n = 22) and sham control (n = 21) animals were randomly assigned housing in either single or enriched conditions for 7-9 weeks. Then, in terminal experiments, extracellular recordings were obtained from barrel cortex neurons in response to whisker motion, including those mimicking motion in awake animals undertaking different tasks. Long-term EE exposure (6 weeks) attenuated TBI-induced hyperexcitability in layers 2-3, such that neuronal activity in TBI animals exposed to EE was restored to control levels. Little to no EE-induced changes in population neuronal responses occurred in input layer 4 and output layer 5. However, single-cell responses demonstrated EE-induced hypoexcitation in L4 post-TBI. EE was also able to fully ameliorate sensory hypersensitivity post-TBI, although it was not found to improve motor function. Long-term enrichment post-TBI induces changes at both the population and single-cell level in the sensory cortex, where EE may act to restore the excitation/inhibition balance in supragranular cortical layers.
Publisher: Mary Ann Liebert Inc
Date: 09-2015
Abstract: Traumatic brain injury (TBI) is a leading cause of death worldwide. In recent studies, we have shown that experimental TBI caused an immediate (24-h post) suppression of neuronal processing, especially in supragranular cortical layers. We now examine the long-term effects of experimental TBI on the sensory cortex and how these changes may contribute to a range of TBI morbidities. Adult male Sprague-Dawley rats received either a moderate lateral fluid percussion injury (n=14) or a sham surgery (n=12) and 12 weeks of recovery before behavioral assessment, magnetic resonance imaging, and electrophysiological recordings from the barrel cortex. TBI rats demonstrated sensorimotor deficits, cognitive impairments, and anxiety-like behavior, and this was associated with significant atrophy of the barrel cortex and other brain structures. Extracellular recordings from ipsilateral barrel cortex revealed normal neuronal responsiveness and diffusion tensor MRI showed increased fractional anisotropy, axial diffusivity, and tract density within this region. These findings suggest that long-term recovery of neuronal responsiveness is owing to structural reorganization within this region. Therefore, it is likely that long-term structural and functional changes within sensory cortex post-TBI may allow for recovery of neuronal responsiveness, but that this recovery does not remediate all behavioral deficits.
Publisher: Wiley
Date: 21-06-2013
Abstract: In this review we discuss the consequences to the brain's cortex, specifically to the sensory cortex, of traumatic brain injury. The thesis underlying this approach is that long-term deficits in cognition seen after brain damage in humans are likely underpinned by an impaired cortical processing of the sensory information needed to drive cognition or to be used by cognitive processes to produce a response. We take it here that the impairment to sensory processing does not arise from damage to peripheral sensory systems, but from disordered brain processing of sensory input.
Publisher: MDPI AG
Date: 22-10-2014
Publisher: Proceedings of the National Academy of Sciences
Date: 28-08-2020
Abstract: Hypertrophic cardiomyopathy affects 1:500 of the general population. Current drug therapy is used to manage symptoms in patients. There is an unmet need for treatments that can prevent the cardiomyopathy. Here we identify biomarkers of hypertrophic cardiomyopathy resulting from causing cardiac troponin I mutation Gly203Ser, and present a safe, nontoxic, preventative approach for the treatment of associated cardiomyopathy.
Publisher: Public Library of Science (PLoS)
Date: 07-05-2013
Publisher: Elsevier BV
Date: 02-1998
Publisher: Wiley
Date: 12-06-2016
DOI: 10.1113/JP271681
Publisher: SAGE Publications
Date: 30-06-2017
Abstract: Traumatic brain injury (TBI) initiates a cascade of pathophysiological changes that are both complex and difficult to treat. Progesterone (P4) is a neuroprotective treatment option that has shown excellent preclinical benefits in the treatment of TBI, but these benefits have not translated well in the clinic. We have previously shown that P4 exacerbates the already hypoactive upper cortical responses in the short-term post-TBI and does not reduce upper cortical hyperactivity in the long term, and we concluded that there is no tangible benefit to sensory cortex firing strength. Here we examined the effects of P4 treatment on temporal coding resolution in the rodent sensory cortex in both the short term (4 d) and long term (8 wk) following impact-acceleration–induced TBI. We show that in the short-term postinjury, TBI has no effect on sensory cortex temporal resolution and that P4 also sharpens the response profile in all cortical layers in the uninjured brain and all layers other than layer 2 (L2) in the injured brain. In the long term, TBI broadens the response profile in all cortical layers despite firing rate hyperactivity being localized to upper cortical layers and P4 sharpens the response profile in TBI animals in all layers other than L2 and has no long-term effect in the sham brain. These results indicate that P4 has long-term effects on sensory coding that may translate to beneficial perceptual outcomes. The effects seen here, combined with previous beneficial preclinical data, emphasize that P4 is still a potential treatment option in ameliorating TBI-induced disorders.
Publisher: Public Library of Science (PLoS)
Date: 28-01-2014
Publisher: Elsevier BV
Date: 2016
Publisher: American Chemical Society (ACS)
Date: 22-12-2015
DOI: 10.1021/NN5061404
Abstract: Increased reactive oxygen species (ROS) production and elevated intracellular Ca(2+) following cardiac ischemia-reperfusion injury are key mediators of cell death and the development of cardiac hypertrophy. The L-type Ca(2+) channel is the main route for calcium influx in cardiac myocytes. Activation of the L-type Ca(2+) channel leads to a further increase in mitochondrial ROS production and metabolism. We have previously shown that the application of a peptide derived against the alpha-interacting domain of the L-type Ca(2+) channel (AID) decreases myocardial injury post reperfusion. Herein, we examine the efficacy of simultaneous delivery of the AID peptide in combination with the potent antioxidants curcumin or resveratrol using multifunctional poly(glycidyl methacrylate) (PGMA) nanoparticles. We highlight that drug loading and dissolution are important parameters that have to be taken into account when designing novel combinatorial therapies following cardiac ischemia-reperfusion injury. In the case of resveratrol low loading capacity and fast release rates hinder its applicability as an effective candidate for simultaneous therapy. However, in the case of curcumin, high loading capacity and sustained release rates enable its effective simultaneous delivery in combination with the AID peptide. Simultaneous delivery of the AID peptide with curcumin allowed for effective attenuation of the L-type Ca(2+) channel-activated increases in superoxide (assessed as changes in DHE fluorescence Empty NP = 53.1 ± 7.6% NP-C-AID = 7.32 ± 3.57%) and mitochondrial membrane potential (assessed as changes in JC-1 fluorescence Empty NP = 19.8 ± 2.8% NP-C-AID=13.05 ± 1.78%). We demonstrate in isolated rat hearts exposed to ischemia followed by reperfusion, that curcumin and the AID peptide in combination effectively reduce muscle damage, decrease oxidative stress and superoxide production in cardiac myocytes.
Publisher: Cold Spring Harbor Laboratory
Date: 20-09-2011
DOI: 10.1101/LM.2245911
Abstract: Long-term potentiation (LTP) is an important process underlying learning and memory in the brain. At CA3–CA1 synapses in the hippoc us, three discrete forms of LTP (LTP1, 2, and 3) can be differentiated on the basis of maintenance and induction mechanisms. However, the relative roles of pre- and post-synaptic expression mechanisms in LTP1, 2, and 3 are unknown. Neurotransmitter release in the expression of LTP1, 2, and 3 was measured via FM 1–43 destaining from CA3 terminals in hippoc al slices from male Wistar rats (7–8 wk). No difference in vesicle turnover rate was observed for LTP1 up to 160 min following induction by one train of theta-burst stimulation (1TBS). A presynaptic enhancement was found for LTP2 at 160 min after induction by 4TBS, and for LTP3 at both 80 and 160 min after induction by 8TBS. Inhibition of nitric oxide (NO) signaling blocked both LTP2 and LTP3 maintenance and the associated enhanced release. LTP2 maintenance and its presynaptic expression were dependent on protein synthesis, but not gene transcription. LTP3 maintenance was dependent on both translation and transcription, but like LTP2, the enhanced release only required translation. These data considerably strengthen the mechanistic separation of LTP1, 2, and 3, supporting a model of multiple, discrete forms of LTP at CA3–CA1 synapses rather than different temporal phases.
No related grants have been discovered for Victoria Johnstone.