Comparison of Neuroprotective Effects of Monomethylfumarate to the Sigma 1 Receptor Ligand (+)-Pentazocine in a Murine Model of Retinitis Pigmentosa.

Purpose: Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photoreceptor cell loss in Pde6βrd10/J (rd10) mice, a model of retinitis pigmentosa. Beneficial effects are abrogated in rd10 mice lacking NRF2, implicating NRF2 as essential to Sig1R-mediated cone neuroprotection. Here we asked whether activation of NRF2 alone is sufficient to rescue cones in rd10 mice.

Pharmacological Inhibition of Spermine Oxidase Reduces Neurodegeneration and Improves Retinal Function in Diabetic Mice.

Diabetic retinopathy (DR) is a significant cause of blindness in working-age adults worldwide. Lack of effective strategies to prevent or reduce vision loss is a major problem. Since the degeneration of retinal neurons is an early event in the diabetic retina, studies to characterize the molecular mechanisms of diabetes-induced retinal neuronal damage and dysfunction are of high significance.

Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity.

Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation.

Activation of Sigma 1 Receptor Extends Survival of Cones and Improves Visual Acuity in a Murine Model of Retinitis Pigmentosa.

Purpose: Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod function and subsequently cones. Activation of sigma 1 receptor (Sig1R) has been shown to preserve cone function through 6 weeks in the rd10 mouse model of RP, when mice were treated systemically with the Sig1R ligand (+)-pentazocine (PTZ). This study determined the extent to which cone function is preserved in rd10 mice when Sig1R is activated.

Hyperhomocysteinemia-induced death of retinal ganglion cells: The role of Müller glial cells and NRF2.

Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid homocysteine (Hcy), is implicated in glaucoma, a disease characterized by increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here we analyzed the role of NRF2, a master regulator of the antioxidant response, in Hhcy-induced RGC death in vivo and in vitro.

A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse.

Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma.

Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa.

Purpose: Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R-/- mice have late-onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration.

Detailed electroretinographic findings in rd8 mice.

Purpose: Previous work has suggested that the retinal degeneration mutant rd8 mouse lacks an electroretinographic (ERG) phenotype until about 9 months of age. We evaluated the ERG phenotype of these mice by measuring both conventional ERG responses and scotopic threshold responses.

Methods: Groups of 4-month-old wild-type (WT) and mutant (rd8) mice were anesthetized and tested for mass retinal responses (ERGs) to several types of visual stimuli.

The Role of Sigma1R in Mammalian Retina.

This review article focuses on studies of Sigma 1 Receptor (Sigma1R) and retina . It provides a brief overview of the earliest pharmacological studies performed in the late 1990s that provided evidence of the presence of Sigma1R in various ocular tissues. It then describes work from a number of labs concerning the location of Sigma1R in several retinal cell types including ganglion, Müller glia , and photoreceptors .

Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury.

Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies.

Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease.

Aims: Sickle retinopathy (SR) is a major cause of blindness in sickle cell disease (SCD). The genetic mutation responsible for SCD is known, however; oxidative stress and inflammation also figure prominently in the development and progression of pathology. Development of therapies for SR is hampered by the lack of (a) animal models that accurately recapitulate human SR and (b) strategies for noninvasive yet effective retinal drug delivery.

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration.

Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β(rd10) (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration.

Multifocal Electroretinography in the Presence of Temporal and Spatial Correlations and Eye Movements.

Releasing patients from the fixation task, and permitting them to view natural stimuli such as movies, would provide increased comfort, and potentially additional signs of retinal function, when recording multifocal electroretinograms (mfERGs). Techniques must be developed to handle the difficulties that arise from these alternative stimulation strategies. Multifocal stimuli were presented to volunteer human subjects with and without fixation.

Mthfr as a modifier of the retinal phenotype of Crb1(rd8/rd8) mice.

Mutations in crumb homologue 1 (CRB1) in humans are associated with Leber's congenital amaurosis (LCA) and retinitis pigmentosa (RP). There is no clear genotype-phenotype correlation for human CRB1 mutations in RP and LCA. The high variability in clinical features observed in CRB1 mutations suggests that environmental factors or genetic modifiers influence severity of CRB1 related retinopathies.

Retinal Ganglion Cell Loss and Mild Vasculopathy in Methylene Tetrahydrofolate Reductase (Mthfr)-Deficient Mice: A Model of Mild Hyperhomocysteinemia.

Purpose: Methylenetetrahydrofolate reductase (Mthfr) is a key enzyme in homocysteine-methionine metabolism. We investigated Mthfr expression in retina and asked whether mild hyperhomocysteinemia, due to Mthfr deficiency, alters retinal neurovascular structure and function.

Methods: Expression of Mthfr was investigated at the gene and protein level using quantitative (q) RT-PCR, in situ hybridization, immunoblotting, and immunohistochemistry (IHC).

Diabetes accelerates retinal ganglion cell dysfunction in mice lacking sigma receptor 1.

Purpose: Sigma receptor 1 (σR1) is a non-opioid transmembrane protein that may act as a molecular chaperone at the endoplasmic reticulum-mitochondrial membrane. Ligands for σR1, such as (+)-pentazocine [(+)-PTZ], confer marked retinal neuroprotection in vivo and in vitro. Recently we analyzed the retinal phenotype of mice lacking σR1 (σR1 KO) and observed normal retinal morphology and function in young mice (5-30 weeks) but diminished negative scotopic threshold responses (nSTRs), retinal ganglion cell (RGC) loss, and disruption of optic nerve axons consistent with inner retinal dysfunction by 1 year.

Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1).

Purpose: Sigma receptor 1 (σR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of σR1 on ocular development, structure, and function.

Methods: Wild-type (σR1⁺/⁺), heterozygous (σR1⁺/⁻), and homozygous (σR1⁻/⁻, knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement.

Arginase 2 deletion reduces neuro-glial injury and improves retinal function in a model of retinopathy of prematurity.

Background: Retinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are also affected. This study was undertaken to determine the role of the mitochondrial arginine/ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP.

Effects of fixational saccades on response timing in macaque lateral geniculate nucleus.

Even during active fixation, small eye movements persist that might be expected to interfere with vision. Numerous brain mechanisms probably contribute to discounting this jitter. Changes in the timing of responses in the visual thalamus associated with fixational saccades are considered in this study.

Lagged cells in alert monkey lateral geniculate nucleus.

Five lagged cells were recognized by extracellular recording in the lateral geniculate nucleus of an awake, behaving macaque monkey. Previous reports of lagged cells were all in the anesthetized cat. Both parvocellular and magnocellular lagged cells were observed.

Lagged cells.

The timing of the retinal input to the lateral geniculate nucleus is highly modified in lagged cells. Evidence is reviewed for how the responses of these cells are generated, how their structure and function differs from their nonlagged neighbors, and what their projections to cortex might do.

Temporal receptive field estimation using wavelets.

A standard goal of many neurophysiological investigations is to obtain enough insight into a neuron's behavior that it becomes possible to predict responses to arbitrary stimuli. Techniques have been developed to solve this system identification problem, and the numerical method presented here adds to this toolbox. Stimuli and responses, beginning as functions of time, are transformed to complex-valued functions of both time and temporal frequency, giving amplitude and phase at each frequency and time point.

Eye position compensation improves estimates of response magnitude and receptive field geometry in alert monkeys.

Studies of visual function in behaving subjects require that stimuli be positioned reliably on the retina in the presence of eye movements. Fixational eye movements scatter stimuli about the retina, inflating estimates of receptive field dimensions, reducing estimates of peak responses, and blurring maps of receptive field subregions. Scleral search coils are frequently used to measure eye position, but their utility for correcting the effects of fixational eye movements on receptive field maps has been questioned.

Temporal properties of inputs to direction-selective neurons in monkey V1.

Motion in the visual scene is processed by direction-selective neurons in primary visual cortex. These cells receive inputs that differ in space and time. What are these inputs? A previous single-unit recording study in anesthetized monkey V1 proposed that the two major streams arising in the primate retina, the M and P pathways, differed in space and time as required to create direction selectivity.

Development of response timing and direction selectivity in cat visual thalamus and cortex.

Single-unit recordings were made in the dorsal lateral geniculate nucleus (LGN) and visual cortex of kittens that were 4-13 weeks of age. Responses to visual stimuli were analyzed to determine the relationship between two related facets of the behaviors of the cells: direction selectivity (DS) and timing. DS depends on timing differences within the receptive field.