A Life in Vision

I was drawn into research in George Wald's laboratory at Harvard, where as an undergraduate and graduate student, I studied vitamin A deficiency and dark adaptation. A chance observation while an assistant professor at Harvard led to the major research of my career—to understand the functional organization of vertebrate retinas. I started with a retinal circuit analysis of the primate retina with Brian Boycott and intracellular retinal cell recordings in mudpuppies with Frank Werblin. Subsequent pharmacology studies with Berndt Ehinger primarily with fish focused on dopamine and neuromodulation. Using zebrafish, we studied retinal development, neuronal connectivity, and the effects of genetic mutations on retinal structure and function. Now semi-retired, I have returned to primate retinal circuitry, undertaking a connectomic analysis of the human fovea in Jeffrey Lichtman's laboratory.

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Restoration of the Retinal Structure and Function after Injury

10.21236/ada621299 ◽

2013 ◽

Author(s):

Daniel V. Palanker

Keyword(s):

Structure And Function ◽

Retinal Structure ◽

And Function

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The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

Cellular and Molecular Life Sciences ◽

10.1007/s00018-020-03721-6 ◽

2020 ◽

Author(s):

Enrico Castroflorio ◽

Joery den Hoed ◽

Daria Svistunova ◽

Mattéa J. Finelli ◽

Alberto Cebrian-Serrano ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Regulatory Protein ◽

Molecular Function ◽

Neuronal Connectivity ◽

Nuclear Receptor Coactivator ◽

Lysm Domain ◽

Behavioural Assessment ◽

And Function ◽

The Brain

Abstract Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. Graphic abstract

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Visual Disfunction due to the Selective Effect of Glutamate Agonists on Retinal Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22126245 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6245

Author(s):

Santiago Milla-Navarro ◽

Ariadna Diaz-Tahoces ◽

Isabel Ortuño-Lizarán ◽

Eduardo Fernández ◽

Nicolás Cuenca ◽

...

Keyword(s):

Harmful Effect ◽

Receptor Activation ◽

Structure And Function ◽

Retinal Cell ◽

Retinal Ganglion ◽

Retinal Cells ◽

Great Loss ◽

Intraocular Injection ◽

Glutamate Agonists ◽

And Function

One of the causes of nervous system degeneration is an excess of glutamate released upon several diseases. Glutamate analogs, like N-methyl-DL-aspartate (NMDA) and kainic acid (KA), have been shown to induce experimental retinal neurotoxicity. Previous results have shown that NMDA/KA neurotoxicity induces significant changes in the full field electroretinogram response, a thinning on the inner retinal layers, and retinal ganglion cell death. However, not all types of retinal neurons experience the same degree of injury in response to the excitotoxic stimulus. The goal of the present work is to address the effect of intraocular injection of different doses of NMDA/KA on the structure and function of several types of retinal cells and their functionality. To globally analyze the effect of glutamate receptor activation in the retina after the intraocular injection of excitotoxic agents, a combination of histological, electrophysiological, and functional tools has been employed to assess the changes in the retinal structure and function. Retinal excitotoxicity caused by the intraocular injection of a mixture of NMDA/KA causes a harmful effect characterized by a great loss of bipolar, amacrine, and retinal ganglion cells, as well as the degeneration of the inner retina. This process leads to a loss of retinal cell functionality characterized by an impairment of light sensitivity and visual acuity, with a strong effect on the retinal OFF pathway. The structural and functional injury suffered by the retina suggests the importance of the glutamate receptors expressed by different types of retinal cells. The effect of glutamate agonists on the OFF pathway represents one of the main findings of the study, as the evaluation of the retinal lesions caused by excitotoxicity could be specifically explored using tests that evaluate the OFF pathway.

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Abnormal Retinal Structure and Function of Mother Wistar Rats Supplemented Aspartame, Glutamate and Galactose

Journal of Drug Metabolism & Toxicology ◽

10.4172/2157-7609.1000219 ◽

2016 ◽

Vol 07 (04) ◽

Author(s):

Hassan IH El-Sayyad ◽

Amora M Abou El-Naga ◽

Soad A Khalifa

Keyword(s):

Wistar Rats ◽

Structure And Function ◽

Retinal Structure ◽

And Function

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Retinal Structure and Function in Perinatally HIV-Infected and cART-Treated Children: A Matched Case–Control Study

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.15-16855 ◽

2015 ◽

Vol 56 (6) ◽

pp. 3945 ◽

Cited By ~ 2

Author(s):

Nazli Demirkaya ◽

Sophie Cohen ◽

Ferdinand W. N. M. Wit ◽

Michael D. Abramoff ◽

Reinier O. Schlingemann ◽

...

Keyword(s):

Case Control Study ◽

Case Control ◽

Structure And Function ◽

Matched Case ◽

Retinal Structure ◽

And Function ◽

Matched Case Control Study ◽

Control Study

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Protective effect of LIF-huMSCs on the retina of diabetic model rats

International Journal of Ophthalmology ◽

10.18240/ijo.2021.10.06 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1508-1517

Author(s):

Shan-Na Chen ◽

◽

Ying-Xue Ma ◽

Song Chen ◽

Guang-Hui He ◽

...

Keyword(s):

Diabetic Rats ◽

Control Group ◽

Diabetic Model ◽

Group A ◽

Retinal Structure ◽

Hs Crp ◽

Group B ◽

And Function ◽

Group D ◽

Control Group Group

AIM: To investigate the protective effect of human umbilical cord mesenchymal stem cells (hUCMSCs) modified by the LIF gene on the retinal function of diabetic model rats and preliminarily explore the possible mechanism. METHODS: A stably transfected cell line of hUCMSCs overexpressing leukemia inhibitory factor (LIF) was constructed. Overexpression was verified by fluorescent quantitative polymerase chain reaction (qPCR). Forty-eight adult Sprague-Dawley rats were randomly divided into a normal control group (group A), streptozotocin-induced diabetic control group (group B), diabetic rats at 3mo injected with empty vector-transfected hUCMSCs (group C) or injected with LIF-hUCMSCs (group D). Four weeks after the intravitreal injection, analyses in all groups included retinal function using flash electroretinogram (F-ERG), retinal blood vessel examination of retinal flat mounts perfused with fluorescein isothiocyanate-dextran (FITC-dextran), and retinal structure examination of sections using hematoxylin and eosin staining. Expression levels of adiponectin (APN), high-sensitivity C-reactive protein (hs-CRP), and neurotrophin-4 (NT-4) in each group was detected using immunohistochemistry, PCR, Western blotting, and ELISA, respectively. RESULTS: A stable transgenic cell line of LIF-hUCMSCs was constructed. F-ERG and FITC-dextran examinations revealed no abnormalities of retinal structure and function in group A, severe damage of the retinal blood vessels and function in group B, and improved retinal structure and function in group C and especially group D. qPCR, ELISA, and Western blot analyses revealed progressively higher APN and NT-4 expression levels in groups B, C, and D than in group A. hs-CRP expression was significantly higher in group B than in groups A, C, and D, and was significantly higher in group C than in group D (P<0.05). CONCLUSION: LIF-hUCMSCs protect the retina of diabetic rats by upregulating APN and NT-4 expression and downregulating hs-CRP expression in the retina.

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Retinal Structure and Function in Achromatopsia

Ophthalmology ◽

10.1016/j.ophtha.2013.08.017 ◽

2014 ◽

Vol 121 (1) ◽

pp. 234-245 ◽

Cited By ~ 73

Author(s):

Venki Sundaram ◽

Caroline Wilde ◽

Jonathan Aboshiha ◽

Jill Cowing ◽

Colin Han ◽

...

Keyword(s):

Structure And Function ◽

Retinal Structure ◽

And Function

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CRB2 in immature photoreceptors determines the superior-inferior symmetry of the developing retina to maintain retinal structure and function

Human Molecular Genetics ◽

10.1093/hmg/ddy194 ◽

2018 ◽

Vol 27 (18) ◽

pp. 3137-3153 ◽

Cited By ~ 10

Author(s):

Peter M Quinn ◽

C Henrique Alves ◽

Jan Klooster ◽

Jan Wijnholds

Keyword(s):

Structure And Function ◽

Retinal Structure ◽

And Function

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A-102 The Relationship Between Retinal and Cognitive Functioning in Schizophrenia

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acaa068.102 ◽

2020 ◽

Vol 35 (6) ◽

pp. 895-895

Author(s):

Demmin D ◽

Klein S ◽

Silverstein S

Keyword(s):

Cognitive Functioning ◽

Executive Control ◽

Cell Structure ◽

Cell Activity ◽

Amacrine Cells ◽

Structure And Function ◽

Cognitive Test ◽

Retinal Cell ◽

Control Processes ◽

And Function

Abstract Objective The retina may provide a unique window into brain structure and function as an accessible part of the central nervous system. Abnormalities in retinal cell structure and function have been associated with brain pathology (e.g., brain volume loss, cognitive impairment) in several neuropsychiatric disorders (e.g., MS, Alzheimer’s disease, Parkinson’s disease). A number of prior studies using flash electroretinography (fERG) have reported reduced retinal cell activity in schizophrenia (SZ). Impairments in cognitive functioning are a core feature of SZ and deficits in executive control processes involving prefrontal cortex (PFC) activity are strong predictors of functional capacity. This study examined whether retinal cell functioning is related to brain function, as indexed by cognitive function, in SZ, and if these relationships were stronger in particular domains (e.g., PFC dependent functions vs. less PFC dependent functions). Method Twenty-six SZ participants and 24 healthy controls (HC) completed fERG and cognitive testing. fERG measurements included a-wave (photoreceptor cells), b-wave (bipolar-Müller cells), and oscillatory potential (OP; amacrine cells) amplitudes and implicit times. Cognitive tests assessed executive control processes (i.e., attention/processing speed, behavior initiation, response inhibition, working memory), and non-executive control processes (i.e., emotion recognition/discrimination). Results In the HC group, a-wave amplitude was correlated with cognitive test scores and OP amplitude was related to cognitive performance in the SZ group. However, overall, retinal cell activity did not appear to be strongly related to scores on cognitive tasks, regardless of whether or not they involved frontal brain regions. Conclusion Impairments in retinal and cognitive functioning may reflect distinct disease mechanisms in schizophrenia.

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