visual-evoked-potential-recording-rat-model-experimental-optic-nerve

Visual Evoked Potential Recording in a Rat Model of Experimental Optic Nerve Demyelination

The visual evoked potential (VEP) recording is widely used in clinical practice to assess the severity of optic neuritis in its acute phase, and to ...

Macquarie University

The University of Sydney

To investigate the relationship between size of demyelinated lesion, extent of axonal loss, and degree of latency delay of visual evoked potentials (VEPs) in a rat model of experimental demyelination.

Latency delay of visual evoked potential is a real measurement of demyelination in a rat model of optic neuritis.

The aims of this study were to evaluate and improve the reproducibility of visual evoked potential (VEP) measurement in rats and to develop a mini-Ganzfeld stimulator for rat VEP recording. VEPs of Sprague-Dawley rats were recorded on one randomly selected eye on three separate days within a week, and the recordings were repeated three times on the first day to evaluate the intrasession repeatability and intersession reproducibility. The VEPs were recorded with subdermal needle and implanted skull screw electrodes, respectively, to evaluate the effect of electrode configuration on VEP reproducibility. We also designed a mini-Ganzfeld stimulator for rats, which provided better eye isolation than the conventional visual stimuli such as flash strobes and large Ganzfeld systems. The VEP responses from mini-Ganzfeld were compared with PS33-PLUS photic strobe and single light-emitting diode (LED). The latencies of P1, N1, P2, N2, and P3 and the amplitude of each component were measured and analysed. Intrasession and intersession within-subject standard deviations (Sw), coefficient of variation, repeatability (R95) and intraclass correlation coefficient (ICC) were calculated. The VEPs recorded using the implanted skull electrodes showed significantly larger amplitude and higher reproducibility compared to the needle electrodes (P<0.05). The mini-Ganzfeld stimulator showed superior repeatability and reproducibility in VEP recording. The intra/intersession ICCs of latency were 0.85/0.70 for mini-Ganzfeld, 0.72/0.62 for PS33-PLUS and only 0.59/0.42 for single LED. The latencies of the early peaks (N1 and P2) demonstrated better reproducibility than the later waves. The mean intrasession and intersession ICCs were 0.96 and 0.86 for the early peaks. Using a combination of skull screw electrodes, mini-Ganzfeld stimulator and early peak analysis, we achieved a high reproducibility in the rat VEP measurement. The latencies of the early peaks of rat VEPs were more consistent, which may be due to their generation in the primary visual cortex via the retino-geniculate fibres.

Improving reproducibility of VEP recording in rats: electrodes, stimulus source and peak analysis.

Focus on molecules: Sphingosine 1 Phosphate (S1P).

The visual evoked potential (VEP) is a frequently used noninvasive measurement of visual function. However, high-amplitude variability has limited its potential for evaluating axonal damage in both laboratory and clinical research. This study was conducted to improve the reliability of VEP amplitude measurement in rats by using electroencephalogram (EEG)-based signal correction.

Normalization of visual evoked potentials using underlying electroencephalogram levels improves amplitude reproducibility in rats.

Axonal loss in a rat model of optic neuritis is closely correlated with visual evoked potential amplitudes using electroencephalogram-based scaling.

Tropomyosin-receptor-kinase B (TrkB receptor) activation plays an important role in the survival of retinal ganglion cells (RGCs). This study reports a novel finding that, SH2 domain-containing phosphatase-2 (Shp-2) binds to the TrkB receptor in RGCs and negatively regulates its activity under glaucomatous stress. This enhanced binding of TrkB and Shp2 is mediated through caveolin. Caveolin 1 and 3 undergo hyper-phosphorylation in RGCs under stress and bind to the Shp2 phosphatase. Shp2 undergoes activation under glaucomatous stress conditions in RGCs in vivo with a concurrent loss of TrkB activity. Inhibiting the Shp2 phosphatase restored TrkB activity in cells exposed to excitotoxic and oxidative stress. Collectively, these findings implicate a molecular basis of Shp2 mediated TrkB deactivation leading to RGC degeneration observed in glaucoma.

Shp-2 regulates the TrkB receptor activity in the retinal ganglion cells under glaucomatous stress.

A preferential loss of retinal ganglion cells (RGCs) is observed in glaucoma and optic neuritis. Loss of tropomyosin-related kinase receptor B (TrkB)-mediated signaling has been implicated in this degeneration. Our study indicates that 7,8-dihydroxyflavone (7,8 DHF) robustly upregulates the TrkB signaling in the primary rat RGCs and the retinal neuronal precursor RGC-5 cell line by promoting phosphorylation of TrkB receptor, leading to enhanced TrkB receptor tyrosine kinase activity. The flavonoid derivative 7,8 DHF acts a potent TrkB agonist and upregulates the downstream AKT and MAPK/ERK survival signaling pathways in a TrkB-dependent manner in both primary rat RGCs as well as the RGC-5 cell line. Excitotoxicity and oxidative injury have been alleged in the specific RGC degeneration in various forms of glaucoma. A novel finding of this study is that treatment with 7,8 DHF protects these cells significantly from excitotoxic and oxidative stress-induced apoptosis and cell death. 7,8 DHF also promotes neuritogenesis by stimulating neurite outgrowth, suggesting a possible therapeutic strategy for protection of RGCs in various optic neuropathies.

Protective effects of 7,8-dihydroxyflavone on retinal ganglion and RGC-5 cells against excitotoxic and oxidative stress.

To investigate anterograde degenerative changes along the visual pathway in a rat model of optic nerve axotomy.

Anterograde degeneration along the visual pathway after optic nerve injury.

Optic neuropathy refers to dysfunction and/or degeneration of axons of the optic nerve with subsequent optic nerve atrophy. A common feature of different optic neuropathies is retinal ganglion cell (RGC) apoptosis and axonal damage. Glaucoma and optic neuritis are the two major degenerative causes of optic nerve damage. Here, we review the anatomy and pathology of the optic nerve, and etiological categories of optic neuropathies, and discuss rodent models that can mimic these conditions. Electrophysiology can reveal signature features of RGC damage using the pattern electroretinogram (PERG), scotopic threshold response (STR) and photopic negative response (PhNR). The amplitude of the visual evoked potential (VEP) also reflects RGC axonal damage. The neurotrophin-mediated survival pathways, as well as the extrinsic and intrinsic cell apoptotic pathways, play a critical role in the pathogenesis of RGC loss. Finally, promising neuroprotective approaches based on the molecular signaling are analyzed for the treatment of optic neuropathies.

Optic neuropathies: characteristic features and mechanisms of retinal ganglion cell loss.

The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.

TrkB Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders.

Nighttime physician staffing in an intensive care unit.

To evaluate the effects of acute arterial blood pressure (ABP) and venous pressure changes on IOP in rats with experimental glaucoma.

The dynamic response of intraocular pressure and ocular pulse amplitude to acute hemodynamic changes in normal and glaucomatous eyes.

To investigate the neuroprotective effects of sphingosine-1-phosphate (S1P) analogue fingolimod (FTY720) in experimental glaucoma in rats.

FTY720 protects retinal ganglion cells in experimental glaucoma.

Brain-derived neurotrophic factor (BDNF) stimulation of its high-affinity receptor TrkB results in activation of pro-survival cell-signalling pathways that can afford neuroprotection to the retina. Reduction in retrograde axonal transport of neurotrophic factors such as BDNF from the brain to the neuronal cell bodies in the retina has been suggested as a critical factor underlying progressive and selective degeneration of ganglion cell layer and optic nerve in glaucoma. We investigated the role of BDNF in preserving inner retinal homeostasis in normal and glaucoma states using BDNF(+/-) mice and compared it with wild type controls. This study demonstrated that BDNF(+/-) animals were more susceptible to functional, morphological and molecular degenerative changes in the inner retina caused by age as well as upon exposure to experimental glaucoma caused by increased intraocular pressure. Glaucoma induced a down regulation of BDNF/TrkB signalling and an increase in levels of neurotoxic amyloid β 1-42 in the optic nerve head which were exacerbated in BDNF(+/-) mice. Similar results were obtained upon analysing the human optic nerve head tissues. Our data highlighted the role of BDNF in maintaining the inner retinal integrity under normal conditions and the detrimental effects of its insufficiency on the retina and optic nerve in glaucoma.

BDNF impairment is associated with age-related changes in the inner retina and exacerbates experimental glaucoma.

Glycogen synthase kinase 3β (GSK3β) is involved in several biochemical processes in neurons regulating cellular survival, gene expression, cell fate determination, metabolism and proliferation. GSK3β activity is inhibited through the phosphorylation of its Ser-9 residue. In this study we sought to investigate the role of BDNF/TrkB signalling in the modulation of GSK3β activity. BDNF/TrkB signalling regulates the GSK3β activity both in vivo in the retinal tissue as well as in the neuronal cells under culture conditions. We report here for the first time that BDNF can also regulate GSK3β activity independent of its effects through the TrkB receptor signalling. Knockdown of BDNF lead to a decline in GSK3β phosphorylation without having a detectable effect on the TrkB activity or its downstream effectors Akt and Erk1/2. Treatment with TrkB receptor agonist had a stimulating effect on the GSK3β phosphorylation, but the effect was significantly less pronounced in the cells in which BDNF was knocked down. The use of TrkB receptor antagonist similarly, manifested itself in the form of downregulation of GSK3β phosphorylation, but a combined TrkB inhibition and BDNF knockdown exhibited a much stronger negative effect. In vivo, we observed reduced levels of GSK3β phosphorylation in the retinal tissues of the BDNF(+/-) animals implicating critical role of BDNF in the regulation of the GSK3β activity. Concluding, BDNF/TrkB axis strongly regulates the GSK3β activity and BDNF also exhibits GSK3β regulatory effect independent of its actions through the TrkB receptor signalling.

Yuyi You

Department of Ophthalmology,
Australian School of Advanced Medicine,
Department of Ophthalmology, Australian School of Advanced Medicine

Macquarie University

Visual Evoked Potential Recording in a Rat Model of Experimental Optic Nerve Demyelination

Yuyi You

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Ophthalmology,Australian School of Advanced Medicine,Department of Ophthalmology, Australian School of Advanced Medicine

Macquarie University

Visual Evoked Potential Recording in a Rat Model of Experimental Optic Nerve Demyelination

Department of Ophthalmology,
Australian School of Advanced Medicine,
Department of Ophthalmology, Australian School of Advanced Medicine