Dorsal Retina Research Articles

Monochromatic light effects on refractive error, cone cell density and retinoic acid signaling in dorsal and ventral retina in guinea pigs.

Cone cells have been found to influence refractive states. This study investigated whether cone cells and retinal acid (RA) plays a role in refractive states under monochromatic lights. Guinea pigs were exposed to blue (BL), green (GL), or white light (WL), respectively, for 8 weeks. Refractive error (RE), cone cell density, RA, retinoic acid receptor-β (RAR-β), collagen-I expression, and scleral thickness in dorsal and ventral eyes were assessed. Eyes exposed to BL showed a slower shift from hyperopia to emmetropia, particularly in the ventral retina, where higher S-cone density was linked to greater remaining hyperopia. In contrast, GL exposure led to myopic shifts, notably in the dorsal retina, where increased M-cone density was associated with greater reductions in refractive error. BL exposure resulted in similar decreases in RA and retinoic acid receptor-β (RAR-β) expression in both dorsal and ventral regions, along with elevated scleral collagen-I and thicker sclera. In contrast, GL exposure increased RA and RAR-β levels, while reducing scleral collagen-I and thickness. GL-associated changes in RAR-β expression and scleral thinning were more pronounced in the dorsal retina compared to the ventral retina, despite similar RA levels in both regions. These findings suggested that RA may not contribute to the hyperopic shifts with increased S-cone cell density in BL. However, increased RA and RAR-β may be correlated with ocular growth in guinea pigs exposed to GL, it may underlie myopic shifts with increased M-cone cell density.

Complement propagates visual system pathology following traumatic brain injury

BackgroundTraumatic brain injury (TBI) is associated with the development of visual system disorders. Visual deficits can present with delay and worsen over time, and may be associated with an ongoing neuroinflammatory response that is known to occur after TBI. Complement system activation is strongly associated with the neuroinflammatory response after TBI, but whether it contributes to vision loss after TBI is unexplored.MethodsAcute and chronic neuroinflammatory changes within the dorsal lateral geniculate nucleus (dLGN) and retina were investigated subsequent to a moderate to severe murine unilateral controlled cortical impact. Neuroinflammatory and histopathological outcomes were interpreted in the context of behavioral and visual function data. To investigate the role of complement, cohorts were treated after TBI with the complement inhibitor, CR2-Crry.ResultsAt 3 days after TBI, complement component C3 was deposited on retinogeniculate synapses in the dLGN both ipsilateral and contralateral to the lesion, which was reduced in CR2-Crry treated animals. This was associated with microglia morphological changes in both the ipsilateral and contralateral dLGN, with a less ramified phenotype in vehicle compared to CR2-Crry treated animals. Microglia in vehicle treated animals also had a greater internalized VGlut2 + synaptic volume after TBI compared to CR2-Crry treated animals. Microglia morphological changes seen acutely persisted for at least 49 days after injury. Complement inhibition also reduced microglial synaptic internalization in the contralateral dLGN and increased the association between VGLUT2 and PSD95 puncta, indicating preservation of intact synapses. Unexpectedly, there were no changes in the thickness of the inner retina, retinal nerve fiber layer or retinal ganglion layer. Neuropathological changes in the dLGN were accompanied by reduced visual acuity at subacute and chronic time points after TBI, with improvement seen in CR2-Crry treated animals.ConclusionTBI induces complement activation within the dLGN and promotes microglial activation and synaptic internalization. Complement inhibition after TBI in a clinically relevant paradigm reduces complement activation, maintains a more surveillance-like microglia phenotype, and preserves synaptic density within the dLGN. Together, the data indicate that complement plays a key role in the development of visual deficits after TBI via complement-dependent microglial phagocytosis of synapses within the dLGN.

Transsynaptic Degeneration of Retinal Ganglion Cells Following Lesions to Primary Visual Cortex in Marmosets.

A lesion to primary visual cortex (V1) in primates can produce retrograde transneuronal degeneration in the dorsal lateral geniculate nucleus (LGN) and retina. We investigated the effect of age at time of lesion on LGN volume and retinal ganglion cell (RGC) density in marmoset monkeys. Retinas and LGNs were obtained about 2years after a unilateral left-sided V1 lesion as infants (n = 7) or young adult (n = 1). Antibodies against RBPMS were used to label all RGCs, and antibodies against CaMKII or GABAA receptors were used to label nonmidget RGCs. Cell densities were compared in the left and right hemiretina of each eye. The LGNs were stained with the nuclear marker NeuN or for Nissl substance. In three animals lesioned within the first 2 postnatal weeks, the proportion of RGCs lost within 5mm of the fovea was ∼twofold higher than after lesions at 4 or 6 weeks. There was negligible loss in the animal lesioned at 2years of age. A positive correlation between RGC loss and LGN volume reduction was evident. No loss of CaMKII-positive or GABAA receptor-positive RGCs was apparent within 2mm of the fovea in any of the retinas investigated. Susceptibility of marmoset RGCs to transneuronal degeneration is high at birth and declines over the first 6 postnatal weeks. High survival rates of CaMKII and GABAA receptor-positive RGCs implies that widefield and parasol cells are less affected by neonatal cortical lesions than are midget-pathway cells.

Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation.

Loss of neurons in the neural retina is a leading cause of vision loss. While humans do not possess the capacity for retinal regeneration, zebrafish can achieve this through activation of resident Müller glia. Remarkably, despite the presence of Müller glia in humans and other mammalian vertebrates, these cells lack an intrinsic ability to contribute to regeneration. Upon activation, zebrafish Müller glia can adopt a stem cell-like state, undergo proliferation and generate new neurons. However, the underlying molecular mechanisms of this activation subsequent retinal regeneration remains unclear. To address this, we performed single-cell RNA sequencing (scRNA-seq) and report remarkable heterogeneity in gene expression within quiescent Müller glia across distinct dorsal, central and ventral retina pools of such cells. Next, we utilized a genetically driven, chemically inducible nitroreductase approach to study Müller glia activation following selective ablation of three distinct photoreceptor subtypes: long wavelength sensitive cones, short wavelength sensitive cones, and rods. There, our data revealed that a region-specific bias in activation of Müller glia exists in the zebrafish retina, and this is independent of the distribution of the ablated cell type across retinal regions. Notably, gene ontology analysis revealed that injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Through scRNA-seq analysis, we identify a shared genetic program underlying initial Müller glia activation and cell cycle entry, followed by differences that drive the fate of regenerating neurons. We observed an initial expression of AP-1 and injury-responsive transcription factors, followed by genes involved in Notch signaling, ribosome biogenesis and gliogenesis, and finally expression of cell cycle, chromatin remodeling and microtubule-associated genes. Taken together, our findings document the regional specificity of gene expression within quiescent Müller glia and demonstrate unique Müller glia activation and regeneration features following neural ablation. These findings will improve our understanding of the molecular pathways relevant to neural regeneration in the retina.

Short-wavelength artificial light affects visual neural pathway development in mice

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.

Two mechanisms of retinal photoreceptor plasticity underlie rapid adaptation to novel light environments.

Fishes experience different light environments over short time periods that may require quick modulation of photoreceptor properties to optimize visual function. Previous research has shown that the relative expression of different visual pigment protein (opsin) transcripts can change within several days following exposure to new light environments, but whether such changes are mirrored by analogous modulation in opsin protein expression is unknown. Here, Atlantic halibut larvae and juveniles raised under white light were exposed to blue light for 1week and their retina compared to that of controls, which remained under white light. Blue light-treated larvae showed increased expression of all cone opsin transcripts, except rh2, over controls. They also had longer outer segments, and higher density of long wavelength sensitive (L) cones in the dorsal retina. In contrast, only the lws transcript was upregulated in juveniles exposed to blue light compared to controls but their L cone density was greater throughout the retina. These results demonstrate two mechanisms of rapid photoreceptor plasticity as a function of developmental stage associated with improved perception of achromatic or chromatic contrasts in line with the animal's ecological needs.

A melanopsin ganglion cell subtype forms a dorsal retinal mosaic projecting to the supraoptic nucleus

Visual input to the hypothalamus from intrinsically photosensitive retinal ganglion cells (ipRGCs) influences several functions including circadian entrainment, body temperature, and sleep. ipRGCs also project to nuclei such as the supraoptic nucleus (SON), which is involved in systemic fluid homeostasis, maternal behavior, social behaviors, and appetite. However, little is known about the SON-projecting ipRGCs or their relationship to well-characterized ipRGC subtypes. Using a GlyT2Cre mouse line, we show a subtype of ipRGCs restricted to the dorsal retina that selectively projects to the SON. These ipRGCs tile a dorsal region of the retina, forming a substrate for encoding ground luminance. Optogenetic activation of their axons demonstrates they release the neurotransmitter glutamate in multiple regions, including the suprachiasmatic nucleus (SCN) and SON. Our results challenge the idea that ipRGC dendrites overlap to optimize photon capture and suggests non-image forming vision operates to sample local regions of the visual field to influence diverse behaviors.

Chromatic organization of retinal photoreceptors during eye migration of Atlantic halibut (Hippoglossus hippoglossus).

The retinas of fishes often have single and double cone photoreceptors that are organized in lattice-like mosaics. In flatfishes experiencing eye migration (i.e., the metamorphic process whereby one eye migrates to the other side of the head), the hexagonal lattice of single cones present in the larva undergoes major restructuring resulting in a dominant square mosaic postmetamorphosis consisting of four double cones surrounding each single cone. The expression of different opsin types during eye migration has not been examined despite its importance in understanding photoreceptor plasticity and whether cell fate (in terms of spectral phenotype) could influence square mosaic formation. Here, we probed the retina of Atlantic halibut undergoing eye migration for opsin expression using two antibodies, AHblue and AB5407, that labeled short wavelength sensitive 2 (SWS2) opsin and longer wavelength (predominantly middle wavelength sensitive, RH2) opsins, respectively. Throughout the retina, double and triple cones labeled with AB5407 exclusively, whereas the vast majority of single cones labeled with AHblue. A minority (<5%) of single cones in the square mosaic of the centroventral retina labeled with AB5407. In regions of mosaic transition and near peripheral growth zones, some single cones co-expressed at least two opsins as they labeled with both antibodies. Short wavelength (SWS2 expressing, or S) cones formed a nonrandom mosaic gradient from central to dorsal retina in a region dominated by the larval single cone mosaic. Our results demonstrate the expression of at least two opsins throughout the postmetamorphic retina and suggest opsin switching as a mechanism to create new cone spectral phenotypes. In addition, the S cone gradient at the onset of eye migration may underlie a plastic, cell induction mechanism by which a cone's phenotype determines that of its neighbors and the formation of the square mosaic.

Light-induced shifts in opsin gene expression in the four-eyed fish Anableps anableps.

The development of the vertebrate eye is a complex process orchestrated by several conserved transcriptional and signaling regulators. Aside from partial or complete loss, examples of exceptional modifications to this intricate organ are scarce. The unique eye of the four-eyed fish Anableps anableps is composed of duplicated corneas and pupils, as well as specialized retina regions associated with simultaneous aerial and aquatic vision. In a previous transcriptomic study of the A. anableps developing eye we identified expression of twenty non-visual and eleven visual opsin genes. Here, we surveyed the expression territories of three non-visual melanopsins genes (opn4×1, opn4×2, opn4m3), one teleost multiple tissue opsin (tmt1b) and two visual opsins (lws and rh2-1) in dorsal and ventral retinas. Our data showed that asymmetry of non-visual opsin expression is only established after birth. During embryonic development, while inside pregnant females, the expression of opn4×1, opn4×2, and tmt1b spans the whole retina. In juvenile fish (post birth), the expression of opn4×1, opn4×2, opn4m3, and tmt1b genes becomes restricted to the ventral retina, which receives aerial light. Raising juvenile fish in clear water instead of the murky waters found in its natural habitat is sufficient to change gene expression territories of opn4×1, opn4×2, opn4m3, tmt1b, and rh2-1, demonstrating that different lighting conditions can shift opsin expression and potentially contribute to changes in spectral sensitivity in the four eyed fish.

Sensitivity of the Dorsal-Central Retinal Pigment Epithelium to Sodium Iodate-Induced Damage Is Associated With Overlying M-Cone Photoreceptors in Mice.

PurposeRetinal pigment epithelium (RPE) degeneration is a leading cause of blindness in retinal degenerative diseases, but the mechanism of RPE regional degeneration remains largely unknown. This study aims to investigate the sensitivity of RPE to sodium iodate (SI) injury in the dorsal and ventral visual fields in mice and analyze whether overlaying cone photoreceptors regulate the sensitivity of RPE to SI-induced damage.MethodsSI was used to induce RPE degeneration in mice. Hematoxylin-eosin staining, immunostaining, and TUNEL assay were used to evaluate retinal degeneration along the dorsal-ventral axis. Flat-mounted and sectional retinal immunostaining were used to analyze the distribution of cones along the dorsoventral axis in C57BL/6, albino, and 129 mice. Electroretinography was used to examine the retinal function.ResultsDorsal-central RPE was more sensitive to SI-mediated injury along the dorsal-ventral axis in C57BL/6 mice. Compared with the ventral RPE, the dorsal-central RPE was dominantly covered by M cone photoreceptors in these mice. Interestingly, M cone photoreceptor degeneration was followed by dorsal RPE degeneration under a low dose of SI. Furthermore, the sensitivity of dorsal RPE to a low dose of SI was reduced in both albino and 129 mouse strains with dominant mixed cones instead of M cones in the dorsal visual field.ConclusionsThese findings suggest that dorsal-central RPE is more sensitive to SI injury and that SI-induced RPE degeneration could be controlled by modifying the dominant overlying cone population in the mouse dorsal retina, thereby highlighting a potential role of M cones in RPE regional degeneration.

Visual Stimulation Induces Distinct Forms of Sensitization of On-Off Direction-Selective Ganglion Cell Responses in the Dorsal and Ventral Retina.

Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction [i.e. posterior DSGCs (pDSGCs)] in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show the sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support dendritic integration between On and Off dendritic layers bypassing the soma. By contrast, ventral pDSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral pDSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.SIGNIFICANCE STATEMENT Visual neuronal responses are dynamically influenced by the prior visual experience. This form of plasticity reflects the efficient coding of the naturalistic environment by the visual system. We found that a class of retinal output neurons, On-Off direction-selective ganglion cells, transiently increase their responsiveness after visual stimulation. Cells located in dorsal and ventral retinas exhibit distinct sensitization patterns because of different adaptive properties of Off bipolar cell signaling. A previously overlooked dendritic morphologic feature of the On-Off direction-selective ganglion cell is implicated in the cross talk between On and Off pathways during sensitization. Together, these findings uncover a topographic difference in the adaptive encoding of upper and lower visual fields and the underlying neural mechanism in the dorsal and ventral retinas.

Morphological Plasticity of the Retina of Viperidae Snakes Is Associated With Ontogenetic Changes in Ecology and Behavior.

Snakes of the Viperidae family have retinas adapted to low light conditions, with high packaging of rod-photoreceptors containing the rhodopsin photopigment (RH1), and three types of cone-photoreceptors, large single and double cones with long-wavelength sensitive opsins (LWS), and small single cones with short-wavelength sensitive opsins (SWS1). In this study, we compared the density and distribution of photoreceptors and ganglion cell layer (GCL) cells in whole-mounted retinas of two viperid snakes, the lancehead Bothrops jararaca and the rattlesnake Crotalus durissus, and we estimated the upper limits of spatial resolving power based on anatomical data. The ground-dwelling C. durissus inhabits savannah-like habitats and actively searches for places to hide before using the sit-and-wait hunting strategy to ambush rodents. B. jararaca inhabits forested areas and has ontogenetic changes in ecology and behavior. Adults are terrestrial and use similar hunting strategies to those used by rattlesnakes to prey on rodents. Juveniles are semi-arboreal and use the sit-and-wait strategy and caudal luring to attract ectothermic prey. Our analyses showed that neuronal densities were similar for the two species, but their patterns of distribution were different between and within species. In adults and juveniles of C. durissus, cones were distributed in poorly defined visual streaks and rods were concentrated in the dorsal retina, indicating higher sensitivity in the lower visual field. In adults of B. jararaca, both cones and rods were distributed in poorly defined visual streaks, while in juveniles, rods were concentrated in the dorsal retina and cones in the ventral retina, enhancing sensitivity in the lower visual field and visual acuity in the upper field. The GCL cells had peak densities in the temporal retina of C. durissus and adults of B. jararaca, indicating higher acuity in the frontal field. In juveniles of B. jararaca, the peak density of GCL cells in the ventral retina indicates better acuity in the upper field. The estimated visual acuity varied from 2.3 to 2.8 cycles per degree. Our results showed interspecific differences and suggest ontogenetic plasticity of the retinal architecture associated with changes in the niche occupied by viperid snakes, and highlight the importance of the retinal topography for visual ecology and behavior of snakes.

Natural image statistics for mouse vision.

The mouse has dichromatic color vision based on two different types of opsins: short (S)- and middle (M)-wavelength-sensitive opsins with peak sensitivity to ultraviolet (UV; 360 nm) and green light (508 nm), respectively. In the mouse retina, cone photoreceptors that predominantly express the S-opsin are more sensitive to contrasts and denser towards the ventral retina, preferentially sampling the upper part of the visual field. In contrast, the expression of the M-opsin gradually increases towards the dorsal retina that encodes the lower visual field. Such a distinctive retinal organization is assumed to arise from a selective pressure in evolution to efficiently encode the natural scenes. However, natural image statistics of UV light remain largely unexplored. Here we developed a multi-spectral camera to acquire high-quality UV and green images of the same natural scenes, and examined the optimality of the mouse retina to the image statistics. We found that the local contrast and the spatial correlation were both higher in UV than in green for images above the horizon, but lower in UV than in green for those below the horizon. This suggests that the dorsoventral functional division of the mouse retina is not optimal for maximizing the bandwidth of information transmission. Factors besides the coding efficiency, such as visual behavioral requirements, will thus need to be considered to fully explain the characteristic organization of the mouse retina.

Asymmetric Distributions of Achromatic Bipolar Cells in the Mouse Retina.

In the retina, evolutionary changes can be traced in the topography of photoreceptors. The shape of the visual streak depends on the height of the animal and its habitat, namely, woods, prairies, or mountains. Also, the distribution of distinct wavelength-sensitive cones is unique to each animal. For example, UV and green cones reside in the ventral and dorsal regions in the mouse retina, respectively, whereas in the rat retina these cones are homogeneously distributed. In contrast with the abundant investigation on the distribution of photoreceptors and the third-order neurons, the distribution of bipolar cells has not been well understood. We utilized two enhanced green fluorescent protein (EGFP) mouse lines, Lhx4-EGFP (Lhx4) and 6030405A18Rik-EGFP (Rik), to examine the topographic distributions of bipolar cells in the retina. First, we characterized their GFP-expressing cells using type-specific markers. We found that GFP was expressed by type 2, type 3a, and type 6 bipolar cells in the Rik mice and by type 3b, type 4, and type 5 bipolar cells in the Lhx4 mice. All these types are achromatic. Then, we examined the distributions of bipolar cells in the four cardinal directions and three different eccentricities of the retinal tissue. In the Rik mice, GFP-expressing bipolar cells were more highly observed in the nasal region than those in the temporal retina. The number of GFP cells was not different along with the ventral-dorsal axis. In contrast, in the Lhx4 mice, GFP-expressing cells occurred at a higher density in the ventral region than in the dorsal retina. However, no difference was observed along the nasal-temporal axis. Furthermore, we examined which type of bipolar cells contributed to the asymmetric distributions in the Rik mice. We found that type 3a bipolar cells occurred at a higher density in the temporal region, whereas type 6 bipolar cells were denser in the nasal region. The asymmetricity of these bipolar cells shaped the uneven distribution of the GFP cells in the Rik mice. In conclusion, we found that a subset of achromatic bipolar cells is asymmetrically distributed in the mouse retina, suggesting their unique roles in achromatic visual processing.

In vivo analysis of onset and progression of retinal degeneration in the Nr2e3rd7/rd7 mouse model of enhanced S-cone sensitivity syndrome

The photoreceptor-specific nuclear receptor Nr2e3 is not expressed in Nr2e3rd7/rd7 mice, a mouse model of the recessively inherited retinal degeneration enhanced S-cone sensitivity syndrome (ESCS). We characterized in detail C57BL/6J Nr2e3rd7/rd7 mice in vivo by fundus photography, optical coherence tomography and fluorescein angiography and, post mortem, by histology and immunohistochemistry. White retinal spots and so-called ‘rosettes’ first appear at postnatal day (P) 12 in the dorsal retina and reach maximal expansion at P21. The highest density in ‘rosettes’ is observed within a region located between 100 and 350 µM from the optic nerve head. ‘Rosettes’ disappear between 9 to 12 months. Non-apoptotic cell death markers are detected during the slow photoreceptor degeneration, at a rate of an approximately 3% reduction of outer nuclear layer thickness per month, as observed from 7 to 31 months of age. In vivo analysis of Nr2e3rd7/rd7 Cx3cr1gfp/+ retinas identified microglial cells within ‘rosettes’ from P21 on. Subretinal macrophages were observed in vivo and by confocal microscopy earliest in 12-months-old Nr2e3rd7/rd7 retinas. At P21, S-opsin expression and the number of S-opsin expressing dorsal cones was increased. The dorso-ventral M-cone gradient was present in Nr2e3rd7/rd7 retinas, but M-opsin expression and M-opsin expressing cones were decreased. Retinal vasculature was normal.

The Timecourses of Functional, Morphological, and Molecular Changes Triggered by Light Exposure in Sprague-Dawley Rat Retinas.

Retinal neurodegeneration can impair visual perception at different levels, involving not only photoreceptors, which are the most metabolically active cells, but also the inner retina. Compensatory mechanisms may hide the first signs of these impairments and reduce the likelihood of receiving timely treatments. Therefore, it is essential to characterize the early critical steps in the neurodegenerative progression to design adequate therapies. This paper describes and correlates early morphological and biochemical changes in the degenerating retina with in vivo functional analysis of retinal activity and investigates the progression of neurodegenerative stages for up to 7 months. For these purposes, Sprague–Dawley rats were exposed to 1000 lux light either for different durations (12 h to 24 h) and examined seven days afterward (7d) or for a fixed duration (24 h) and monitored at various time points following the exposure (up to 210d). Flash electroretinogram (fERG) recordings were correlated with morphological and histological analyses to evaluate outer and inner retinal disruptions, gliosis, trophic factor release, and microglial activation. Twelve hours or fifteen hours of exposure to constant light led to a severe retinal dysfunction with only minor morphological changes. Therefore, early pathological signs might be hidden by compensatory mechanisms that silence retinal dysfunction, accounting for the discrepancy between photoreceptor loss and retinal functional output. The long-term analysis showed a transient functional recovery, maximum at 45 days, despite a progressive loss of photoreceptors and coincident increases in glial fibrillary acidic protein (GFAP) and basic fibroblast growth factor-2 (bFGF-2) expression. Interestingly, the progression of the disease presented different patterns in the dorsal and ventral retina. The information acquired gives us the potential to develop a specific diagnostic tool to monitor the disease’s progression and treatment efficacy.

Natural environment statistics in the upper and lower visual field are reflected in mouse retinal specializations

Pressures for survival make sensory circuits adapted to a species' natural habitat and its behavioral challenges. Thus, to advance our understanding of the visual system, it is essential to consider an animal's specific visual environment by capturing natural scenes, characterizing their statistical regularities, and using them to probe visual computations. Mice, a prominent visual system model, have salient visual specializations, being dichromatic with enhanced sensitivity to green and UV in the dorsal and ventral retina, respectively. However, the characteristics of their visual environment that likely have driven these adaptations are rarely considered. Here, we built a UV-green-sensitive camera to record footage from mouse habitats. This footage is publicly available as a resource for mouse vision research. We found chromatic contrast to greatly diverge in the upper, but not the lower, visual field. Moreover, training a convolutional autoencoder on upper, but not lower, visual field scenes was sufficient for the emergence of color-opponent filters, suggesting that this environmental difference might have driven superior chromatic opponency in the ventral mouse retina, supporting color discrimination in the upper visual field. Furthermore, the upper visual field was biased toward dark UV contrasts, paralleled by more light-offset-sensitive ganglion cells in the ventral retina. Finally, footage recorded at twilight suggests that UV promotes aerial predator detection. Our findings support that natural scene statistics shaped early visual processing in evolution.

Eya2 expression during mouse embryonic development revealed by Eya2lacZ knockin reporter and homozygous mice show mild hearing loss.

Eya2 expression during mouse development has been studied by in situ hybridization and it has been shown to be involved skeletal muscle development and limb formation. Here, we generated Eya2 knockout (Eya2- ) and a lacZ knockin reporter (Eya2lacZ ) mice and performed a detailed expression analysis for Eya2lacZ at different developmental stages to trace Eya2lacZ -positive cells in Eya2-null mice. We describe that Eya2 is not only expressed in cranial sensory and dorsal root ganglia, retina and olfactory epithelium, and somites as previously reported, but also Eya2 is specifically detected in other organs during mouse development. We found that Eya2 is expressed in ocular and trochlear motor neurons. In the inner ear, Eya2lacZ is specifically expressed in differentiating hair cells in both vestibular and cochlear sensory epithelia of the inner ear and Eya2-/- or Eya2lacZ/lacZ mice displayed mild hearing loss. Furthermore, we detected Eya2 expression during both salivary gland and thymus development and Eya2-null mice had a smaller thymus. As Eya2 is coexpressed with other members of the Eya family genes, these results together highlight that Eya2 as a potential regulator may act synergistically with other Eya genes to regulate the differentiation of the inner ear sensory hair cells and the formation of the salivary gland and thymus.

Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2

The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.

Dorsal-Ventral Differences in Retinal Structure in the Pigmented Royal College of Surgeons Model of Retinal Degeneration.

Retinitis pigmentosa is a family of inherited retinal degenerations associated with gradual loss of photoreceptors, that ultimately leads to irreversible vision loss. The Royal College of Surgeon's (RCS) rat carries a recessive mutation affecting mer proto-oncogene tyrosine kinase (merTK), that models autosomal recessive disease. The aim of this study was to understand the glial, microglial, and photoreceptor changes that occur in different retinal locations with advancing disease. Pigmented RCS rats (RCS-p+/LAV) and age-matched isogenic control rdy (RCS-rdy +p+/LAV) rats aged postnatal day 18 to 6 months were evaluated for in vivo retinal structure and function using optical coherence tomography and electroretinography. Retinal tissues were assessed using high resolution immunohistochemistry to evaluate changes in photoreceptors, glia and microglia in the dorsal, and ventral retina. Photoreceptor dysfunction and death occurred from 1 month of age. There was a striking difference in loss of photoreceptors between the dorsal and ventral retina, with a greater number of photoreceptors surviving in the dorsal retina, despite being adjacent a layer of photoreceptor debris within the subretinal space. Loss of photoreceptors in the ventral retina was associated with fragmentation of the outer limiting membrane, extension of glial processes into the subretinal space that was accompanied by possible adhesion and migration of mononuclear phagocytes in the subretinal space. Overall, these findings highlight that breakdown of the outer limiting membrane could play an important role in exacerbating photoreceptor loss in the ventral retina. Our results also highlight the value of using the RCS rat to model sectorial retinitis pigmentosa, a disease known to predominantly effect the inferior retina.