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Brain injury can cause many distinct types of visual impairment in children, but these deficits are difficult to quantify due to co-morbid deficits in communication and cognition. Clinicians must instead rely on low-resolution, subjective judgements of simple reactions to handheld stimuli, which limits treatment potential. We have developed an interactive assessment program called the Visual Ladder, which uses gaze-based responses to intuitive, game-like tasks to address the lack of broad-spectrum quantified data on the visual abilities of children with brain injury. Here, we present detailed metrics on eye movements, field asymmetries, contrast sensitivity, and other critical visual abilities measured longitudinally using the Ladder in hospitalized children with varying types and degrees of brain injury, many of whom were previously considered untestable. Our findings show which abilities are most likely to exhibit recovery and reveal how distinct patterns of task outcomes defined unique diagnostic clusters of visual impairment.
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Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.
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Perfilación de la Expresión Génica , Neuronas , Animales , Ratas , Biomarcadores , Células Epiteliales , Pigmentos RetinianosRESUMEN
Autism spectrum disorder (ASD) is the assorted uneven conditions of the human brain that lead to developmental disabilities. This cross-sectional study aimed to identify the substantial risk factors of ASD among children in Bangladesh. The data were collected using convenience sampling through a questionnaire filled up by the trained interviewers. Mann-Whitney U and Kruskal-Wallis H tests were applied as bivariate analysis, and generalized beta regression was performed to determine the significant risk factors of autism spectrum disorder. The odds ratio (OR) along with 95% confidence interval (CI) were the measuring parameters of the risk factors of ASD. The result revealed that later birth order children have more risk of ASD (OR = 1.13, CI: 1.014-1.264, p = 0.027) compared to the children whose birth order is first. Premature birth of the child (OR: 0.87, CI: 0.76-1.00, p = 0.05) and father's age (OR: 0.86, CI: 0.76-0.97, p = 0.020) substantially affects ASD. The maternal history of specific illness (diabetes, thyroiditis, and hypertension) during pregnancy also significantly affect ASD (OR: 1.34, CI: 1.14-1.61, p = 0.002). The results of this study would assist policymakers in taking necessary steps to reduce the incidence of this disorder by targeting the potential risk factors.
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Trastorno del Espectro Autista , Femenino , Embarazo , Humanos , Niño , Adolescente , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/etiología , Estudios Transversales , Bangladesh/epidemiología , Factores de Riesgo , Orden de Nacimiento , Factores SocioeconómicosRESUMEN
Genetic disorders which present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis (XLRS), an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuro-glial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention.Significance StatementDevelopmental disorders make it difficult to distinguish pathophysiology due to ongoing disease from pathophysiology due to disrupted development. Here, we investigated a mouse model for X-linked retinoschisis (XLRS), a well-defined monogenic degenerative disease caused by mutations in the Rs1 gene, which codes for the protein retinoschisin. We evaluated the spontaneous activity of explanted retinas lacking retinoschisin at key stages of development using the unbiased approach of ubiquitously expressing GCaMP6f in all retinal neurons, vasculature and glia. In mice lacking RS1, we found an array of novel phenotypes which present around eye-opening, are linked to glutamatergic neurotransmission, and affect visual processing. These data identify novel pathophysiology linked to RS1, and define a window where treatments might be best targeted.
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Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between -6.5 and -7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.
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Visual deficits in children that result from brain injury, including cerebral/cortical visual impairment (CVI), are difficult to assess through conventional methods due to their frequent co-occurrence with cognitive and communicative disabilities. Such impairments hence often go undiagnosed or are only determined through subjective evaluations of gaze-based reactions to different forms, colors, and movements, which limits any potential for remediation. Here, we describe a novel approach to grading visual health based on eye movements and evidence from gaze-based tracking behaviors. Our approach-the "Visual Ladder"-reduces reliance on the user's ability to attend and communicate. The Visual Ladder produces metrics that quantify spontaneous saccades and pursuits, assess visual field responsiveness, and grade spatial visual function from tracking responses to moving stimuli. We used the Ladder to assess fourteen hospitalized children aged 3 to 18 years with a diverse range of visual impairments and causes of brain injury. Four children were excluded from analysis due to incompatibility with the eye tracker (e.g., due to severe strabismus). The remaining ten children-including five non-verbal children-were tested multiple times over periods ranging from 2 weeks to 9 months, and all produced interpretable outcomes on at least three of the five visual tasks. The results suggest that our assessment tasks are viable in non-communicative children, provided their eyes can be tracked, and hence are promising tools for use in a larger clinical study. We highlight and discuss informative outcomes exhibited by each child, including directional biases in eye movements, pathological nystagmus, visual field asymmetries, and contrast sensitivity deficits. Our findings indicate that these methodologies will enable the rapid, objective classification and grading of visual impairments in children with CVI, including non-verbal children who are currently precluded from most vision assessments. This would provide a much-needed differential diagnostic and prognostic tool for CVI and other impairments of the visual system, both ocular and cerebral.
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In mammals with binocular vision, integration of the left and right visual scene relies on information in the center visual field, which are relayed from each retina in parallel and merge in the primary visual cortex (V1) through the convergence of ipsi- and contralateral geniculocortical inputs as well as transcallosal projections between two visual cortices. The developmental assembly of this binocular circuit, especially the transcallosal pathway, remains incompletely understood. Using genetic methods in mice, we found that several days before eye-opening, retinal and callosal activities drive massive apoptosis of GABAergic chandelier cells (ChCs) in the binocular region of V1. Blockade of ChC elimination resulted in a contralateral eye-dominated V1 and deficient binocular vision. As pre-vision retinal activities convey the left-right organization of the visual field, their regulation of ChC density through the transcallosal pathway may prime a nascent binocular territory for subsequent experience-driven tuning during the post-vision critical period.
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Plasticidad Neuronal/fisiología , Neuronas/fisiología , Retina/fisiología , Visión Binocular/fisiología , Corteza Visual/fisiología , Animales , Apoptosis/fisiología , Período Crítico Psicológico , Ratones , Ratones Transgénicos , Corteza Visual/crecimiento & desarrollo , Campos Visuales/fisiología , Vías Visuales/crecimiento & desarrollo , Vías Visuales/fisiologíaRESUMEN
The contrast sensitivity function (CSF) is an informative measure of visual health, but the practical difficulty of measuring it has impeded detailed analyses of its relationship to different visual disorders. Furthermore, most existing tasks cannot be used in populations with cognitive impairment. We analyzed detailed CSFs measured with a nonverbal procedure called "Gradiate," which efficiently infers visibility from eye movements and manipulates stimulus appearance in real time. Sixty observers of varying age (38 with refractive error) were presented with moving stimuli. Stimulus spatial frequency and contrast advanced along 15 radial sweeps through CSF space in response to stimulus-congruent eye movements. A point on the CSF was recorded when tracking ceased. Gradiate CSFs were reliable and in high agreement with independent low-contrast acuity thresholds. Overall CSF variation was largely captured by two orthogonal factors ("radius" and "slope") or two orthogonal shape factors when size was normalized ("aspect ratio" and "curvature"). CSF radius was highly predictive of LogMAR acuity, as were aspect ratio and curvature together, but only radius was predictive of observer age. Our findings suggest that Gradiate holds promise for assessing spatial vision in both verbal and nonverbal populations and indicate that variation between detailed CSFs can reveal useful information about visual health.
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Sensibilidad de Contraste/fisiología , Movimientos Oculares/fisiología , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Percepción de Movimiento/fisiología , Procesamiento Espacial , Agudeza Visual/fisiología , Adulto JovenRESUMEN
Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts of nerves as a pathogenic mechanism and HDAC6 as a therapeutic target for CMT2A.
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Benzamidas/farmacología , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Quinolinas/farmacología , Tubulina (Proteína)/metabolismo , Acetilación/efectos de los fármacos , Animales , Enfermedad de Charcot-Marie-Tooth/metabolismo , Ratones , Ratones Mutantes , Actividad Motora/efectos de los fármacosRESUMEN
Adequate supply of choline, an essential nutrient, is necessary to support proper brain development. Whether prenatal choline availability plays a role in development of the visual system is currently unknown. In this study, we addressed the role of in utero choline supply for the development and later function of the retina in a mouse model. We lowered choline availability in the maternal diet during pregnancy and assessed proliferative and differentiation properties of retinal progenitor cells (RPCs) in the developing prenatal retina, as well as visual function in adult offspring. We report that low choline availability during retinogenesis leads to persistent retinal cytoarchitectural defects, ranging from focal lesions with displacement of retinal neurons into subretinal space to severe hypocellularity and ultrastructural defects in photoreceptor organization. We further show that low choline availability impairs timely differentiation of retinal neuronal cells, such that the densities of early-born retinal ganglion cells, amacrine and horizontal cells, as well as cone photoreceptor precursors, are reduced in low choline embryonic d 17.5 retinas. Maintenance of higher proportions of RPCs that fail to exit the cell cycle underlies aberrant neuronal differentiation in low choline embryos. Increased RPC cell cycle length, and associated reduction in neurofibromin 2/Merlin protein, an upstream regulator of the Hippo signaling pathway, at least in part, explain aberrant neurogenesis in low choline retinas. Furthermore, we find that animals exposed to low choline diet in utero exhibit a significant degree of intraindividual variation in vision, characterized by marked functional discrepancy between the 2 eyes in individual animals. Together, our findings demonstrate, for the first time, that choline availability plays an essential role in the regulation of temporal progression of retinogenesis and provide evidence for the importance of adequate supply of choline for proper development of the visual system.-Trujillo-Gonzalez, I., Friday, W. B., Munson, C. A., Bachleda, A., Weiss, E. R., Alam, N. M., Sha, W., Zeisel, S. H., Surzenko, N. Low availability of choline in utero disrupts development and function of the retina.
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Deficiencia de Colina/embriología , Retina/anomalías , Animales , Ciclo Celular/fisiología , Diferenciación Celular/fisiología , Colina/administración & dosificación , Colina/metabolismo , Deficiencia de Colina/fisiopatología , Dieta , Regulación hacia Abajo , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Neurogénesis/fisiología , Embarazo , Retina/embriología , Retina/fisiopatología , Células Fotorreceptoras Retinianas Conos/ultraestructura , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/fisiología , Células Madre/citología , Células Madre/fisiologíaRESUMEN
Changes in neuronal activity alter blood flow to match energy demand with the supply of oxygen and nutrients. This functional hyperemia is maintained by interactions between neurons, vascular cells, and glia. However, how changing neuronal activity prevalent at the onset of neurodegenerative disease affects neurovascular elements is unclear. Here, in mice with photoreceptor degeneration, a model of neuron-specific dysfunction, we combined assessment of visual function, neurovascular unit structure, and the blood-retina barrier permeability. We found that the rod loss paralleled remodeling of the neurovascular unit, comprised of photoreceptors, retinal pigment epithelium, and Muller glia. When significant visual function was still present, blood flow became disrupted and blood-retina barrier began to fail, facilitating cone loss and vision decline. Thus, in contrast to the established view, vascular deficit in neuronal degeneration is not a late consequence of neuronal dysfunction, but is present early in the course of disease. These findings further establish the importance of vascular deficit and blood retina barrier function in neuron-specific loss, and highlight it as a target for early therapeutic intervention.
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Barrera Hematorretinal/metabolismo , Muerte Celular , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Bastones/patología , Vasos Retinianos/patología , Retinitis Pigmentosa/metabolismo , Trastornos de la Visión/metabolismo , Animales , Barrera Hematorretinal/patología , Efecto Espectador , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Ependimogliales/patología , Ratones , Permeabilidad , Células Fotorreceptoras de Vertebrados/patología , Flujo Sanguíneo Regional , Epitelio Pigmentado de la Retina/patología , Vasos Retinianos/fisiopatología , Retinitis Pigmentosa/patología , Retinitis Pigmentosa/fisiopatología , Trastornos de la Visión/patología , Trastornos de la Visión/fisiopatología , Visión OcularRESUMEN
The contrast sensitivity function (CSF) is an informative measure of visual function, but current tools for assessing it are limited by the attentional, motor, and communicative abilities of the participant. Impairments in these abilities can prevent participants from engaging with tasks or following an experimenter's instructions. Here, we describe an efficient new tool for measuring contrast sensitivity, Curveball, and empirically validate it with a sample of healthy adults. The Curveball algorithm continuously infers stimulus visibility through smooth eye tracking instead of perceptual report, and rapidly lowers stimulus contrast in real time until a threshold is found. The procedure requires minimal instruction to administer and takes only five minutes to estimate a full CSF, which is comparable to the best existing methods available for healthy adults. Task repeatability was high: the coefficients of repeatability were 0.275 (in log10 units of RMS contrast) within the same session and 0.227 across different days. We also present evidence that the task is robust across illumination changes, well correlated with results from conventional psychophysical methods, and highly sensitive to improvements in visual acuity from refractive correction. Our findings indicate that Curveball is a promising means of accurately assessing contrast sensitivity in previously neglected populations.
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Sensibilidad de Contraste/fisiología , Seguimiento Ocular Uniforme/fisiología , Pruebas de Visión/instrumentación , Adulto , Algoritmos , Femenino , Humanos , Masculino , Psicofísica , Agudeza Visual/fisiología , Adulto JovenRESUMEN
Age-related macular degeneration (AMD) is a common cause of central visual loss in the elderly. Retinal pigment epithelial (RPE) cell loss occurs early in the course of AMD and RPE cell transplantation holds promise to slow disease progression. We report that subretinal transplantation of RPE stem cell (RPESC)-derived RPE cells (RPESC-RPE) preserved vision in a rat model of RPE cell dysfunction. Importantly, the stage of differentiation that RPESC-RPE acquired prior to transplantation influenced the efficacy of vision rescue. Whereas cells at all stages of differentiation tested rescued photoreceptor layer morphology, an intermediate stage of RPESC-RPE differentiation obtained after 4 weeks of culture was more consistent at vision rescue than progeny that were differentiated for 2 weeks or 8 weeks of culture. Our results indicate that the developmental stage of RPESC-RPE significantly influences the efficacy of RPE cell replacement, which affects the therapeutic application of these cells for AMD.
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Células Madre Adultas/citología , Diferenciación Celular , Degeneración Macular/terapia , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/trasplante , Animales , Técnicas de Cultivo de Célula , Células Cultivadas , Humanos , Degeneración Macular/patología , Ratas , Epitelio Pigmentado de la Retina/patología , Porcinos , Visión OcularRESUMEN
The outer blood-retina barrier is established through the coordinated terminal maturation of the retinal pigment epithelium (RPE), fenestrated choroid endothelial cells (ECs) and Bruch's membrane, a highly organized basement membrane that lies between both cell types. Here we study the contribution of choroid ECs to this process by comparing their gene expression profile before (P5) and after (P30) the critical postnatal period when mice acquire mature visual function. Transcriptome analyses show that expression of extracellular matrix-related genes changes dramatically over this period. Co-culture experiments support the existence of a novel regulatory pathway: ECs secrete factors that remodel RPE basement membrane, and integrin receptors sense these changes triggering Rho GTPase signals that modulate RPE tight junctions and enhance RPE barrier function. We anticipate our results will spawn a search for additional roles of choroid ECs in RPE physiology and disease.
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Membrana Basal/metabolismo , Lámina Basal de la Coroides/metabolismo , Matriz Extracelular/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Uniones Estrechas/metabolismo , Animales , Biotinilación , Barrera Hematorretinal/metabolismo , Adhesión Celular , Supervivencia Celular , Células Cultivadas , Coroides/metabolismo , Técnicas de Cocultivo , Electrorretinografía , Femenino , Integrinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Rastreo , Permeabilidad , Proteína-Lisina 6-Oxidasa/metabolismo , ARN Mensajero/metabolismo , Análisis de Secuencia de ARNRESUMEN
Obesity is a major risk factor for the development of chronic kidney disease, even independent of its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding of obesity-related kidney disease is glomerulopathy, with glomerular hypertrophy, mesangial matrix expansion, and focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition of AMP kinase, and endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure in glomerular endothelial cells, podocytes, and proximal tubular epithelial cells after 28 weeks of a high-fat diet in C57BL/6 mice. Treatment with SS-31, a tetrapeptide that targets cardiolipin and protects mitochondrial cristae structure, during high-fat diet preserved normal mitochondrial structure in all kidney cells, restored renal AMP kinase activity, and prevented intracellular lipid accumulation, endoplasmic reticulum stress, and apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, SS-31 prevented loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-ß) cytokines. Thus, mitochondria protection can overcome lipotoxicity in the kidney and represent a novel upstream target for therapeutic development.
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Dieta Alta en Grasa/efectos adversos , Glomerulonefritis/prevención & control , Túbulos Renales Proximales/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Oligopéptidos/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Capilares/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Glomerulonefritis/etiología , Túbulos Renales Proximales/ultraestructura , Metabolismo de los Lípidos/efectos de los fármacos , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Mitocondrias/ultraestructura , Obesidad/complicaciones , Oligopéptidos/farmacología , Podocitos/efectos de los fármacosRESUMEN
Age is the main risk factor for sporadic Alzheimer's disease. Yet, cognitive decline in aged rodents has been less well studied, possibly due to concomitant changes in sensory or locomotor function that can complicate cognitive tests. We tested mice that were 3, 11, and 23 months old in cognitive, sensory, and motor measures, and postmortem measures of gliosis and neural activity (c-Fos). Hippocampal synaptic function was also examined. While age-related impairments were detectable in tests of spatial memory, greater age-dependent effects were observed in tests of associative learning [active avoidance (AA)]. Gross visual function was largely normal, but startle responses to acoustic stimuli decreased with increased age, possibly due to hearing impairments. Therefore, a novel AA variant in which light alone served as the conditioning stimuli was used. Age-related deficits were again observed. Mild changes in vision, as measured by optokinetic responses, were detected in 19- versus 4-month-old mice, but these were not correlated to AA performance. Thus, deficits in hearing or vision are unlikely to account for the observed deficits in cognitive measures. Increased gliosis was observed in the hippocampal formation at older ages. Age-related changes in neural function and plasticity were observed with decreased c-Fos in the dentate gyrus, and decreased synaptic strength and paired-pulse facilitation in CA1 slices. This work, which carefully outlines age-dependent impairments in cognitive and synaptic function, c-Fos activity, and gliosis during normal aging in the mouse, suggests robust translational measures that will facilitate further study of the biology of aging.
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Diabetic retinopathy is characterized by progressive vision loss and the advancement of retinal micoraneurysms, edema and angiogenesis. Unfortunately, managing glycemia or targeting vascular complications with anti-vascular endothelial growth factor agents has shown only limited efficacy in treating the deterioration of vision in diabetic retinopathy. In light of growing evidence that mitochondrial dysfunction is an independent pathophysiology of diabetes and diabetic retinopathy, we investigated whether selectively targeting and improving mitochondrial dysfunction is a viable treatment for visual decline in diabetes. Measures of spatial visual behavior, blood glucose, bodyweight and optical clarity were made in mouse models of diabetes. Treatment groups were administered MTP-131, a water-soluble tetrapeptide that selectively targets mitochondrial cardiolipin and promotes efficient electron transfer, either systemically or in eye drops. Progressive visual decline emerged in untreated animals before the overt symptoms of metabolic and ophthalmic abnormalities were manifest, but with time, visual dysfunction was accompanied by compromised glucose clearance, and elevated blood glucose and bodyweight. MTP-131 treatment reversed the visual decline without improving glycemic control or reducing bodyweight. These data provide evidence that visuomotor decline is an early complication of diabetes. They also indicate that selectively treating mitochondrial dysfunction with MTP-131 has the potential to remediate the visual dysfunction and to complement existing treatments for diabetic retinopathy.
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Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/fisiopatología , Mitocondrias/efectos de los fármacos , Oligopéptidos/uso terapéutico , Visión Ocular/efectos de los fármacos , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/fisiología , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/fisiopatología , Oligopéptidos/administración & dosificación , Soluciones Oftálmicas , Umbral Sensorial/efectos de los fármacos , Visión Ocular/fisiología , Percepción Visual/efectos de los fármacosRESUMEN
PURPOSE: To better understand how photoreceptors and their circuits support luminance-dependent spatial visual behavior. METHODS: Grating thresholds for optokinetic tracking were measured under defined luminance conditions in mice with genetic alterations of photoreceptor activity. RESULTS: The luminance conditions that enable cone- and rod-mediated behavior, and the luminance range over which rod and cone functions overlap, were characterized. The AII amacrine pathway was found to support low-resolution and high-contrast function, with the rod-cone pathway supporting high-resolution and low-contrast function. Rods alone were also shown to be capable of driving cone-like spatial visual function, but only when cones were genetically maintained in a physiological dark state. CONCLUSIONS: The study defined how luminance signals drive rod- and cone-mediated spatial visual behavior and revealed new and unexpected contributions for rods that depend on an interaction between cone and rod systems.
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Células Fotorreceptoras de Vertebrados/fisiología , Conducta Espacial/fisiología , Navegación Espacial/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Estimulación LuminosaRESUMEN
Distinct subclasses of retinal ganglion cells (RGCs) mediate vision and nonimage-forming functions such as circadian photoentrainment. This distinction stems from studies that ablated melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs) and showed deficits in nonimage-forming behaviors, but not image vision. However, we show that the ON alpha RGC, a conventional RGC type, is intrinsically photosensitive in mammals. In addition to their classical response to fast changes in contrast through rod/cone signaling, melanopsin expression allows ON alpha RGCs to signal prior light exposure and environmental luminance over long periods of time. Consistent with the high contrast sensitivity of ON alpha RGCs, mice lacking either melanopsin or ON alpha RGCs have behavioral deficits in contrast sensitivity. These findings indicate a surprising role for melanopsin and ipRGCs in vision.
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Sensibilidad de Contraste/fisiología , Células Ganglionares de la Retina/clasificación , Células Ganglionares de la Retina/fisiología , Opsinas de Bastones/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Sensibilidad de Contraste/genética , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Femenino , Antagonistas del GABA/farmacología , Glicinérgicos/farmacología , Técnicas In Vitro , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Picrotoxina/farmacología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/genética , Retina/citología , Células Ganglionares de la Retina/ultraestructura , Opsinas de Bastones/deficiencia , Opsinas de Bastones/genética , Opsinas de Bastones/ultraestructura , Estricnina/farmacologíaRESUMEN
We previously reported in adult mice that visuomotor experience during monocular deprivation (MD) augmented enhancement of visual-cortex-dependent behavior through the non-deprived eye (NDE) during deprivation, and enabled enhanced function to persist after MD. We investigated the physiological substrates of this experience-enabled form of adult cortical plasticity by measuring visual behavior and visually evoked potentials (VEPs) in binocular visual cortex of the same mice before, during, and after MD. MD on its own potentiated VEPs contralateral to the NDE during MD and shifted ocular dominance (OD) in favor of the NDE in both hemispheres. Whereas we expected visuomotor experience during MD to augment these effects, instead enhanced responses contralateral to the NDE, and the OD shift ipsilateral to the NDE were attenuated. However, in the same animals, we measured NMDA receptor-dependent VEP potentiation ipsilateral to the NDE during MD, which persisted after MD. The results indicate that visuomotor experience during adult MD leads to enduring enhancement of behavioral function, not simply by amplifying MD-induced changes in cortical OD, but through an independent process of increasing NDE drive in ipsilateral visual cortex. Because the plasticity is resident in the mature visual cortex and selectively effects gain of visual behavior through experiential means, it may have the therapeutic potential to target and non-invasively treat eye- or visual-field-specific cortical impairment.