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Cellular and Molecular Neurobiology Feb 2024Retinal vasoactive intestinal peptide amacrine cells (VIP-ACs) play an important role in various retinal light-mediated pathological processes related to different...
Retinal vasoactive intestinal peptide amacrine cells (VIP-ACs) play an important role in various retinal light-mediated pathological processes related to different developmental ocular diseases and even mental disorders. It is important to characterize the developmental changes in VIP-ACs to further elucidate their mechanisms of circuit function. We bred VIP-Cre mice with Ai14 and Ai32 to specifically label retinal VIP-ACs. The VIP-AC soma and spine density generally increased, from postnatal day (P)0 to P35, reaching adult levels at P14 and P28, respectively. The VIP-AC soma density curve was different with the VIP-AC spine density curve. The total retinal VIP content reached a high level plateau at P14 but was decreased in adults. From P14 to P16, the resting membrane potential (RMP) became more negative, and the input resistance decreased. Cell membrane capacitance (MC) showed three peaks at P7, P12 and P16. The RMP and MC reached a stable level similar to the adult level at P18, whereas input resistance reached a stable level at P21. The percentage of sustained voltage-dependent potassium currents peaked at P16 and remained stable thereafter. The spontaneous excitatory postsynaptic current and spontaneous inhibitory postsynaptic current frequencies and amplitudes, as well as charge transfer, peaked at P12 to P16; however, there were also secondary peaks at different time points. In conclusion, we found that the second, third and fourth weeks after birth were important periods of VIP-AC development. Many developmental changes occurred around eye opening. The development of soma, dendrite and electrophysiological properties showed uneven dynamics of progression. Cell differentiation may contribute to soma development whereas the changes of different ion channels may play important role for spine development.
Topics: Animals; Mice; Amacrine Cells; Cell Differentiation; Membrane Potentials; Retina; Vasoactive Intestinal Peptide
PubMed: 38315298
DOI: 10.1007/s10571-024-01452-x -
Stem Cells Translational Medicine Jan 2024Cone cell death is a characteristic shared by various retinal degenerative disorders, such as cone-rod dystrophy, Stargardt disease, achromatopsia, and retinitis...
Cone cell death is a characteristic shared by various retinal degenerative disorders, such as cone-rod dystrophy, Stargardt disease, achromatopsia, and retinitis pigmentosa. This leads to conditions like color blindness and permanently impaired visual acuity. Stem cell therapy focused on photoreceptor replacement holds promise for addressing these conditions. However, identifying surface markers that aid in enriching retinal progenitor cells (RPCs) capable of differentiating into cones remains a complex task. In this study, we employed single-cell RNA sequencing to scrutinize the transcriptome of developing retinas in C57BL/6J mice. This revealed the distinctive expression of somatostatin receptor 2 (Sstr2), a surface protein, in late-stage RPCs exhibiting the potential for photoreceptor differentiation. In vivo lineage tracing experiments verified that Sstr2+ cells within the late embryonic retina gave rise to cones, amacrine and horizontal cells during the developmental process. Furthermore, Sstr2+ cells that were isolated from the late embryonic mouse retina displayed RPC markers and exhibited the capability to differentiate into cones in vitro. Upon subretinal transplantation into both wild-type and retinal degeneration 10 (rd10) mice, Sstr2+ cells survived and expressed cone-specific markers. This study underscores the ability of Sstr2 to enrich late-stage RPCs primed for cone differentiation to a large extent. It proposes the utility of Sstr2 as a biomarker for RPCs capable of generating cones for transplantation purposes.
Topics: Animals; Mice; Mice, Inbred C57BL; Receptors, Somatostatin; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Stem Cells
PubMed: 37935630
DOI: 10.1093/stcltm/szad073 -
BioRxiv : the Preprint Server For... Aug 2023Everything that the brain sees must first be encoded by the retina, which maintains a reliable representation of the visual world in many different, complex natural...
Everything that the brain sees must first be encoded by the retina, which maintains a reliable representation of the visual world in many different, complex natural scenes while also adapting to stimulus changes. Decomposing the population code into independent and cell-cell interactions reveals how broad scene structure is encoded in the adapted retinal output. By recording from the same retina while presenting many different natural movies, we see that the population structure, characterized by strong interactions, is consistent across both natural and synthetic stimuli. We show that these interactions contribute to encoding scene identity. We also demonstrate that this structure likely arises in part from shared bipolar cell input as well as from gap junctions between retinal ganglion cells and amacrine cells.
PubMed: 37609259
DOI: 10.1101/2023.08.08.552526 -
Acta Neuropathologica Communications May 2024Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial...
Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.
Topics: Animals; Retinal Ganglion Cells; Mice, Inbred C57BL; Niacinamide; Neuroprotective Agents; Male; Mice; Administration, Oral; Intravitreal Injections; Disease Models, Animal; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Parkinsonian Disorders; MPTP Poisoning
PubMed: 38773545
DOI: 10.1186/s40478-024-01782-3 -
Experimental Eye Research Sep 2023The purpose was to quantify ocular dopamine in rabbits after stimulation of the optic nerve head with short-wavelength (blue) light to activate melanopsin expressed in...
The purpose was to quantify ocular dopamine in rabbits after stimulation of the optic nerve head with short-wavelength (blue) light to activate melanopsin expressed in the axons of intrinsically photosensitive retinal ganglion cells (ipRGCs). Dopamine levels in tears, aqueous humor, vitreous body, and retina (including choroid) were quantified after blue light stimulation of the optic nerve head of 15 rabbits with an optical fiber for 1 min, 10 min, or no stimulation (n = 5, each group). The left eye of all rabbits was operated on to introduce the optical fiber and stimulate the optic nerve, while the contralateral eye served as internal control. One minute of blue light stimulation significantly increased dopamine concentration in the vitreous body of the treated eyes compared to the contralateral ones (P = 0.015). Stimulation for 10 min significantly increased dopamine concentration in the vitreous body, as well as the aqueous humor (P < 0.05). Therefore, using an optical fiber approach to stimulate the optic nerve head with blue light significantly increased dopamine concentration in the aqueous humor and the vitreous body. This likely reflects an upregulation of retinal dopamine synthesis that could be attributed to ipRGC activation. However, the data provided in this study fell short of establishing a definitive link between dopamine release and ipRGC activation, mainly due to the lack of evidence supporting the expression of the melanopsin photopigment in the optic nerve.
Topics: Animals; Rabbits; Optic Disk; Dopamine; Retina; Retinal Ganglion Cells; Light; Rod Opsins; Photic Stimulation
PubMed: 37499737
DOI: 10.1016/j.exer.2023.109604 -
PLoS Biology Feb 2024In mammals, retinal direction selectivity originates from GABAergic/cholinergic amacrine cells (ACs) specifically expressing the sox2 gene. However, the cellular...
In mammals, retinal direction selectivity originates from GABAergic/cholinergic amacrine cells (ACs) specifically expressing the sox2 gene. However, the cellular diversity of GABAergic/cholinergic ACs of other vertebrate species remains largely unexplored. Here, we identified 2 morphologically and genetically distinct GABAergic/cholinergic AC types in zebrafish, a previously undescribed bhlhe22+ type and a mammalian counterpart sox2+ type. Notably, while sole sox2 disruption removed sox2+ type, the codisruption of bhlhe22 and bhlhe23 was required to remove bhlhe22+ type. Also, both types significantly differed in dendritic arbors, lamination, and soma position. Furthermore, in vivo two-photon calcium imaging and the behavior assay suggested the direction selectivity of both AC types. Nevertheless, the 2 types showed preferential responses to moving bars of different sizes. Thus, our findings provide new cellular diversity and functional characteristics of GABAergic/cholinergic ACs in the vertebrate retina.
Topics: Animals; Amacrine Cells; Zebrafish; Retina; Cholinergic Agents; Transcription Factors; Mammals
PubMed: 38363811
DOI: 10.1371/journal.pbio.3002506 -
Ecotoxicology and Environmental Safety Sep 2023Nearly all modern life depends on artificial light; however, it does cause health problems. With certain restrictions of artificial light emitting technology, the...
Nearly all modern life depends on artificial light; however, it does cause health problems. With certain restrictions of artificial light emitting technology, the influence of the light spectrum is inevitable. The most remarkable problem is its overload in the short wavelength component. Short wavelength artificial light has a wide range of influences from ocular development to mental problems. The visual neuronal pathway, as the primary light-sensing structure, may contain the fundamental mechanism of all light-induced abnormalities. However, how the artificial light spectrum shapes the visual neuronal pathway during development in mammals is poorly understood. We placed C57BL/6 mice in three different spectrum environments (full-spectrum white light: 400-750 nm; violet light: 400 ± 20 nm; green light: 510 ± 20 nm) beginning at eye opening, with a fixed light time of 7:00-19:00. During development, we assessed the ocular axial dimension, visual function and retinal neurons. After two weeks under short wavelength conditions, the ocular axial length (AL), anterior chamber depth (ACD) and length of lens thickness, real vitreous chamber depth and retinal thickness (LLVR) were shorter, visual acuity (VA) decreased, and retinal electrical activity was impaired. The density of S-cones in the dorsal and ventral retinas both decreased after one week under short wavelength conditions. In the ventral retina, it increased after three weeks. Retinal ganglion cell (RGC) density and axon thickness were not influenced; however, the axonal terminals in the lateral geniculate nucleus (LGN) were less clustered and sparse. Amacrine cells (ACs) were significantly more activated. Green light has few effects. The KEGG and GO enrichment analyses showed that many genes related to neural circuitry, synaptic formation and neurotransmitter function were differentially expressed in the short wavelength light group. In conclusion, exposure to short wavelength artificial light in the early stage of vision-dependent development in mice delayed the development of the visual pathway. The axon terminus structure and neurotransmitter function may be the major suffering.
Topics: Animals; Mice; Mice, Inbred C57BL; Retina; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Neural Pathways; Mammals
PubMed: 37494734
DOI: 10.1016/j.ecoenv.2023.115282 -
Cells, Tissues, Organs Feb 2024Ocular diseases pose a significant health concern for donkeys. However, studies examining the microanatomy and cell populations of the donkey retina are scarce. The...
INTRODUCTION
Ocular diseases pose a significant health concern for donkeys. However, studies examining the microanatomy and cell populations of the donkey retina are scarce. The current study aims to describe the vascular pattern of the donkey retina and document its cellular components.
METHODS
The donkey retina specimens were obtained from different retinal regions and prepared for semithin sectioning and immunohistochemistry.
RESULTS
The donkey has a paurangiotic retina in which retinal vessels are confined to a narrow area around the optic disc. Glial cells coexist with the blood vessels being very numerous in the vascular region and become scanty in the avascular ones. S-100 positive astrocytes could be observed in these avascular areas. Ganglion cells are organized in a single layer with the least population existing in the peripheral retina. Acidic fibroblast growth factor (AFGF) is immunoreactive in amacrine and ganglion cells. A subpopulation of amacrine cells reacted strongly to tyrosine hydroxylase (TH), and others reacted positively to S-100 protein. Ganglion cell nuclei exhibited a strong immunoreactivity to S-100 protein as well. Furthermore, glial fibrillary acidic protein (GFAP) is used to identify Müller cells which extend their processes across the retina from the inner to the outer limiting membrane.
CONCLUSIONS
In conclusion, our findings provide novel insights into the normal retinal organization. The donkey retina shows the characteristic expression of immunohistochemical markers for the major cell types. In addition, the distribution of glial cells is comparable between the vascular and avascular regions.
PubMed: 38320535
DOI: 10.1159/000537688 -
Experimental Eye Research Oct 2023CRX is a transcription factor essential for normal photoreceptor development and survival. The CRX cat has a naturally occurring truncating mutation in CRX and is a...
CRX is a transcription factor essential for normal photoreceptor development and survival. The CRX cat has a naturally occurring truncating mutation in CRX and is a large animal model for dominant Leber congenital amaurosis. This study investigated retinal remodeling that occurs as photoreceptors degenerate. CRX cats from 6 weeks to 10 years of age were investigated. In vivo structural changes of retinas were analyzed by fundus examination, confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. Histologic analyses included immunohistochemistry for computational molecular phenotyping with macromolecules and small molecules. Affected cats had a cone-led photoreceptor degeneration starting in the area centralis. Initially there was preservation of inner retinal cells such as bipolar, amacrine and horizontal cells but with time migration of the deafferented neurons occurred. Early in the process of degeneration glial activation occurs ultimately resulting in formation of a glial seal. With progression the macula-equivalent area centralis developed severe atrophy including loss of retinal pigmentary epithelium. Microneuroma formation occured in advanced stages as more marked retinal remodeling occurred. This study indicates that retinal degeneration in the Crx cat retina follows the progressive, phased revision of retina that have been previously described for retinal remodeling. These findings suggest that therapy dependent on targeting inner retinal cells may be useful in young adults with preserved inner retinas prior to advanced stages of retinal remodeling and neuronal cell loss.
Topics: Animals; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Leber Congenital Amaurosis; Homeodomain Proteins
PubMed: 37625575
DOI: 10.1016/j.exer.2023.109630 -
Experimental Animals Feb 2024Nonhuman primates are important research models for basic vision research, preclinical pathogenesis, and treatment studies due to strong similarities in retinal...
Nonhuman primates are important research models for basic vision research, preclinical pathogenesis, and treatment studies due to strong similarities in retinal structure and function with humans. We compared retinal parameters between 10 healthy normal rhesus macaques (Macaca mulatta) and 10 cynomolgus macaques (Macaca fascicularis) by optical coherence tomography and electroretinography. The Heidelberg Spectralis® HRA+OCT and Roland multifocal electrophysiometer were used to analyze retinal morphology, multifocal electroretinograms (mfERGs), and full-field electroretinograms (ff-ERGs). Mean retinal thickness was lowest in the central fovea of macaques and did not differ significantly between species, but the retinal thicknesses of the nerve fiber ganglion cell layer and the inner plexiform layer were significantly different. The amplitude density of the N1 wave was lower in rhesus macaques than in cynomolgus macaques in ring and quadrant areas. Dark-adapted 3.0 oscillatory potentials (reflection of amacrine cell activity) and light-adapted 30-hz flicker ERG (a sensitive cone-pathway-driven response) waveforms of the ff-ERG were similar in both species, while the times to peaks in dark-adapted 0.01 ERG (the rod-driven response of bipolar cells) and dark-adapted 3.0 ERG (combined rod and cone system responses) as well as the implicit times of the a- and b-waves in light-adapted 3.0 ERG (the single-flash cone response) were substantially different. This study provides normative retinal parameters for nonhuman primate research on basic and clinical ophthalmology, as well as a reference for researchers in the appropriate selection of rhesus or cynomolgus macaques as models for ophthalmology studies.
Topics: Humans; Animals; Macaca mulatta; Macaca fascicularis; Retina; Electroretinography; Neurons
PubMed: 37460311
DOI: 10.1538/expanim.22-0022