Development and regeneration of neuronal circuits in the vertebrate retina

Thesis (Ph.D.)--University of Washington, 2016-08

UV wavelengths experienced during development affect larval newt visual sensitivity and predation efficiency

International audience

Factores de riesgo asociados a retinopatía del prematuro en menor o igual a 1750 gramos al nacer, que requirió tratamiento con láser en Hospital de Niños Benjamín Bloom de Enero 2012 a Diciembre 2013

Las retinas inmaduras de los recién nacidos prematuros son susceptibles a insultos que interrumpen el crecimiento neurovascular, que conduce a la retinopatía de la prematuridad. Por eso es de gran importancia conocer los factores de riesgo que se ven involucrados en la génesis de dicha enfermedad. Objetivos: conocer los factores de riesgos asociados a retinopatía del prematuro menor o igual a 1750 gramos al nacer que requirió tratamiento con láser en el Hospital de Niños Benjamín Bloom de Enero de 2012 a Diciembre 2013. Material y método: se realizó un estudio de tipo descriptivo, de corte retrospectivo en el cual se hará revisión sistemática de los expedientes de los pacientes sin dar a conocer la identidad de los mismos, seleccionando a pacientes menor o igual a 1750 gramos independientemente del sexo, evaluado en Hospital Nacional de Niños Benjamín Bloom y al que se le ha realizado intervención con láser; de los cuales se verificará los factores de riesgo asociados al desarrollo de retinopatía del prematuro en estadios severos, se realizó una hoja de datos en Excel y se utilizó el programa SPSS para la agrupación de los datos, posterior se realizó el análisis de los datos. Resultado: se encontraron 56 casos de prematuros con grado severo de retinopatía que utilizó laser, de los cuales fueron 30 masculinos y 26 femeninos; se excluyeron veinte casos por no cumplir criterios de inclusión. Los dos factores de riesgo principalmente involucrados en la ROP son edad gestacional igual o inferior a 30 semanas de gestación y peso al nacimiento igual o inferior a 1300 gr. Otros factores de riesgo encontrados son: la no ganancia de peso para la edad gestacional con un 92.7%, anemia y transfusión sanguínea con un 76.9%, sepsis temprana y nososcomial, en menor proporción apneas, aplicación de surfactante, administración de esteroides prenatales, el estadio con mayor frecuencia encontrado es el III, el déficit visual y ceguera son las secuelas encontradas en los pacientes con retinopatía severa. Conclusiones: la retinopatía de la prematuridad es una entidad multifactorial en la que cada uno de los factores juega un papel importante en la evolución de dicha patología.

The Impact of the Eye in Dementia: The Eye and its Role in Diagnosis and Follow‐up

Over the last few decades, the importance of ophthalmic examination in neurodegenerative diseases of the CNS has reportedly increased. The retina is an extension of the CNS and thus should not be surprising to find abnormal results in both the test exploring visual processing and those examining the retina of patients with CNS degeneration. Current in vivo imaging techniques are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of Alzheimer’s disease (AD) patients and may help to reveal unsuspected retinal and optic‐nerve repercussions of other CNS diseases. In this chapter, we perform an analysis of the physiological changes in ocular and cerebral ageing. We analyse the ocular manifestations in CNS disorders such as stroke, AD and Parkinson’s disease. In addition, the pathophysiology of both the eye and the visual pathway in AD are described. The value of the visual psychophysical tests in AD diagnosis is reviewed as well as the main findings of the optical coherence tomography as a contribution to the diagnosis and monitoring of the disease. Finally, we examine the association of two neurodegenerative diseases, AD and glaucoma, as mere coincidence or possible role in the progression of the neurodegeneration.

Inherited Photoreceptor Degeneration Causes the Death of Melanopsin-Positive Retinal Ganglion Cells and Increases Their Coexpression of Brn3a

Purpose: To study the population of intrinsically photosensitive retinal ganglion cells (melanopsin-expressing RGCs, m+RGCs) in P23H-1 rats, a rat model of inherited photoreceptor degeneration. Methods: At postnatal (P) times P30, P365, and P540, retinas from P23H dystrophic rats (line 1, rapid degeneration; and line 3, slow degeneration) and Sprague Dawley (SD) rats (control) were dissected as whole-mounts and immunodetected for melanopsin and/or Brn3a. The dendritic arborization of m+RGCs and the numbers of Brn3a+RGCs and m+RGCs were quantified and their retinal distribution and coexpression analyzed. Results: In SD rats, aging did not affect the population of Brn3a+RGCs or m+RGCs or the percentage that showed coexpression (0.27%). Young P23H-1 rats had a significantly lower number of Brn3a+RGCs and showed a further decline with age. The population of m+RGCs in young P23H-1 rats was similar to that found in SD rats and decreased by 22.6% and 28.2% at P365 and P540, respectively, similarly to the decrease of the Brn3a+RGCs. At these ages the m+RGCs showed a decrease of their dendritic arborization parameters, which was similar in both the P23H-1 and P23H-3 lines. The percentage of coexpression of Brn3a was, however, already significantly higher at P30 (3.31%) and increased significantly with age (10.65% at P540). Conclusions: Inherited photoreceptor degeneration was followed by secondary loss of Brn3a+RGCs and m+RGCs. Surviving m+RGCs showed decreased dendritic arborization parameters and increased coexpression of Brn3a and melanopsin, phenotypic and molecular changes that may represent an effort to resist degeneration and/or preferential survival of m+RGCs capable of synthesizing Brn3a.

Steroid induced neuroprotection of damaged photoreceptor cells

Retinitis Pigmentosa (RP) is the name given to a group of hereditary diseases causing progressive and degenerative blindness. RP affects over 1 in 4000 individuals, making it the most prevalent inherited retinal disease worldwide, yet currently there is no cure. In 2011, our group released a paper detailing the protective effects of the synthetic progestin ‘Norgestrel’. A common component of the female oral contraceptive pill, Norgestrel was shown to protect against retinal cell death in two distinct mouse models of retinal degeneration: in the Balb/c light damage model and the Pde6brd10 (rd10) model. Little was known of the molecular workings of this compound however and thus this study aimed to elucidate the protective manner in which Norgestrel worked. To this aim, the 661W cone photoreceptor-like cell line and ex vivo retinal explanting was utilised. We found that Norgestrel induces a increase in neuroprotective basic fibroblast growth factor (bFGF) with subsequent downstream actions on the inhibition of glycogen synthase kinase 3β. Progesterone receptor expression was subsequently characterised in the C57 and rd10 retinas and in the 661W cell line. Norgestrel caused nuclear trafficking of progesterone receptor membrane complex one (PGRMC1) in 661W cells and thus Norgestrel was hypothesised to work primarily through the actions of PGRMC1. This trafficking was shown to be responsible for the critical upregulation of bFGF and PGRMC1- Norgestrel binding was proven to cause a neuroprotective bFGF-mediated increase in intracellular calcium. The protective properties of Norgestrel were further studied in the rd10 mouse model of retinitis pigmentosa. Using non-invasive diet supplementation (80mg/kg), we showed that Norgestrel gave significant retinal protection out to postnatal day 40 (P40). Overactive microglia have previously been shown to potentiate photoreceptor cell loss in the degenerating rd10 retina and thus we focussed on Norgestrel-mediated changes in photoreceptor-microglial crosstalk. Norgestrel acted to dampen pro-inflammatory microglial cell reactivity, decreasing chemokine (MCP1, MCP3, MIP-1α, MIP-1β) and subsequent damaging cytokine (TNFα, Il-1β) production. Critically, Norgestrel up-regulated photoreceptor-microglial, fractalkine-CX3CR1 signalling 1000-fold in the P20 rd10 mouse. Known to prevent microglial activation, we hypothesise that Norgestrel acts as a vital anti-inflammatory in the diseased retina, driving fractalkine-CX3CR1 signalling to delay retinal degeneration. This study stands to highlight some of the neuroprotective mechanisms utilised by Norgestrel in the prevention of photoreceptor cell death. We identify for the first time, not only a pro-survival pathway activated directly in photoreceptor cells, but also a Norgestreldriven mediation of an otherwise damaging microglial cell response. All taken, these results form the beginning of a case to bring Norgestrel to clinical trials, as a potential therapeutic for the treatment of RP.