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Orienting in space requires the processing of visual spatial cues. The dominant hypothesis about the brain structures mediating the coding of spatial cues stipulates the existence of a hippocampal‐dependent system for the representation of geometry and a striatal‐dependent system for the representation of landmarks. However, this dual‐system hypothesis is based on paradigms that presented spatial cues conveying either conflicting or ambiguous spatial information and that used the term landmark to refer to both discrete three‐dimensional objects and wall features. Here, we test the hypothesis of complex activation patterns in the hippocampus and the striatum during visual coding. We also postulate that object‐based and feature‐based navigation are not equivalent instances of landmark‐based navigation. We examined how the neural networks associated with geometry‐, object‐, and feature‐based spatial navigation compared with a control condition in a two‐choice behavioral paradigm using fMRI. We showed that the hippocampus was involved in all three types of cue‐based navigation, whereas the striatum was more strongly recruited in the presence of geometric cues than object or feature cues. We also found that unique, specific neural signatures were associated with each spatial cue. Object‐based navigation elicited a widespread pattern of activity in temporal and occipital regions relative to feature‐based navigation. These findings extend the current view of a dual, juxtaposed hippocampal–striatal system for visual spatial coding in humans. They also provide novel insights into the neural networks mediating object versus feature spatial coding, suggesting a need to distinguish these two types of landmarks in the context of human navigation. Our article provides novel insights into the neural networks mediating spatial cue processing during navigation including: Complex hippocampal–striatal involvement during visual spatial coding for flexible human navigation behavior. Distinct neural signatures associated with object‐, feature‐, and geometry‐based navigation. Object‐ and feature‐based navigation are not equivalent instances of landmark‐based navigation.

Targeting the photosensitive ion channel channelrhodopsin‐2 (ChR2) to the retinal circuitry downstream of photoreceptors holds promise in treating vision loss caused by retinal degeneration. However, the high intensity of blue light necessary to activate channelrhodopsin‐2 exceeds the safety threshold of retinal illumination because of its strong potential to induce photochemical damage. In contrast, the damage potential of red‐shifted light is vastly lower than that of blue light. Here, we show that a red‐shifted channelrhodopsin (ReaChR), delivered by AAV injections in blind rd1 mice, enables restoration of light responses at the retinal, cortical, and behavioral levels, using orange light at intensities below the safety threshold for the human retina. We further show that postmortem macaque retinae infected with AAV‐ReaChR can respond with spike trains to orange light at safe intensities. Finally, to directly address the question of translatability to human subjects, we demonstrate for the first time, AAV‐ and lentivirus‐mediated optogenetic spike responses in ganglion cells of the postmortem human retina. Synopsis A red‐shifted channelrhodopsin (ReaChR) was targeted to retinal ganglion cells using three models in parallel: mouse, macaque, and human. Safe orange illumination was able to trigger light responses in all three systems. The red‐shifted channelrhodopsin ReaChR restored light responses at the retinal, cortical, and behavioral levels in blind rd1 mice, using light intensities below the safety limit for the human retina. Optogenetic light responses were demonstrated in explanted postmortem macaque and human retina, infected ex vivo with viral vectors encoding ReaChR. The study presents the first electrophysiological recordings of optogenetic light responses in ganglion cells obtained directly from the human fovea as well as the far peripheral human retina. Graphical Abstract A red‐shifted channelrhodopsin (ReaChR) was targeted to retinal ganglion cells using three models in parallel: mouse, macaque, and human. Safe orange illumination was able to trigger light responses in all three systems.

Human induced pluripotent stem cells (hiPSCs) promise a great number of future applications to investigate retinal development, pathophysiology and cell therapies for retinal degenerative diseases. Specific approaches to genetically modulate hiPSC would be valuable for all of these applications. Vectors based on adeno-associated virus (AAV) have shown the ability for gene delivery to retinal organoids derived from hiPSCs. Thus far, little work has been carried out to investigate mechanisms of AAV-mediated gene delivery and the potential advantages of engineered AAVs to genetically modify retinal organoids. In this study, we compared the early transduction efficiency of several recombinant and engineered AAVs in hiPSC-derived RPE cells and retinal organoids in relation to the availability of their cell-surface receptors and as a function of time. The genetic variant AAV2-7m8 had a superior transduction efficiency when applied at day 44 of differentiation on retinal organoids and provided long-lasting expressions for at least 4 weeks after infection without compromising cell viability. All of the capsids we tested transduced the hiPSC-RPE cells, with the AAV2-7m8 variant being the most efficient. Transduction efficiency was correlated with the presence of primary cell-surface receptors on the hiPS-derived organoids. Our study explores some of the mechanisms of cell attachment of AAVs and reports long-term gene expression resulting from gene delivery in retinal organoids.

Ocular and specifically retinal toxicities of systemic medications are prevalent and encompass many disease modalities. For many of these pharmaceuticals, established follow‐up protocols are in place to ensure timely detection and cessation of therapy. However, while for some disorders, cessation of therapy is a viable option due to existing treatment alternatives, for some others cessation of treatment can be life threatening and/or shorten the patient's life expectancy. Such is the case for iron chelating agents used in transfusion‐dependent patients of Thalassemia, of which deferoxamine (DFO) is the most widely used. In their recent article in EMBO Molecular Medicine , Kong et al (2023) addressed the issue of DFO‐induced retinal toxicity used both in vivo and in vitro techniques. Their study suggests a potentially protective role for α‐ketoglutarate (AKG) supplementation against DFO toxicity. Graphical Abstract J.A. Sahel and B. Rosin discuss the study by Kong et al , in this issue of EMBO Mol. Med. , that shows that inhibiting HIF2α and protecting mitochondrial function via α‐ketoglutarate supplementation may effectively delay the progression of retinal degeneration in the clinic.

Counteracting splice defects in the CEP290 gene using RNA antisense oligonucleotides or Cas9-mediated gene editing is a therapeutic strategy for Leber congenital amaurosis type 10—a severe untreatable retinal dystrophy leading to childhood blindness.

Deep regions of the brain are not easily accessible to investigation at the mesoscale level in awake animals or humans. We have recently developed a functional ultrasound (fUS) technique that enables imaging hemodynamic responses to visual tasks. Using fUS imaging on two awake nonhuman primates performing a passive fixation task, we constructed retinotopic maps at depth in the visual cortex (V1, V2, and V3) in the calcarine and lunate sulci. The maps could be acquired in a single-hour session with relatively few presentations of the stimuli. The spatial resolution of the technology is illustrated by mapping patterns similar to ocular dominance (OD) columns within superficial and deep layers of the primary visual cortex. These acquisitions using fUS suggested that OD selectivity is mostly present in layer IV but with extensions into layers II/III and V. This imaging technology provides a new mesoscale approach to the mapping of brain activity at high spatiotemporal resolution in awake subjects within the whole depth of the cortex.

Physiologically, the retinal pigment epithelium (RPE) expresses immunosuppressive signals such as FAS ligand (FASL), which prevents the accumulation of leukocytes in the subretinal space. Age‐related macular degeneration (AMD) is associated with a breakdown of the subretinal immunosuppressive environment and chronic accumulation of mononuclear phagocytes (MPs). We show that subretinal MPs in AMD patients accumulate on the RPE and express high levels of APOE. MPs of Cx3cr1 −/− mice that develop MP accumulation on the RPE, photoreceptor degeneration, and increased choroidal neovascularization similarly express high levels of APOE. ApoE deletion in Cx3cr1 −/− mice prevents pathogenic age‐ and stress‐induced subretinal MP accumulation. We demonstrate that increased APOE levels induce IL‐6 in MPs via the activation of the TLR2‐CD14‐dependent innate immunity receptor cluster. IL‐6 in turn represses RPE FasL expression and prolongs subretinal MP survival. This mechanism may account, in part, for the MP accumulation observed in Cx3cr1 −/− mice. Our results underline the inflammatory role of APOE in sterile inflammation in the immunosuppressive subretinal space. They provide rationale for the implication of IL‐6 in AMD and open avenues toward therapies inhibiting pathogenic chronic inflammation in late AMD. Synopsis In age‐related macular degeneration, subretinal mononuclear phagocytes (MP) express high APOE levels, which prolongs their survival and accumulation by inducing IL‐6, which in turn promotes chronic subretinal inflammation. Pathogenic subretinal mononuclear phagocytes, observed in age‐related macular degeneration in human donor tissue and in the Cx3cr1 −/− mouse model of subretinal inflammation, express high levels of APOE. High levels of APOE activate the TLR2‐CD14‐dependent innate immunity receptor cluster and induce IL‐6 in mononuclear phagocytes. IL‐6 inhibits FASL expression in the retinal pigment epithelium and increases subretinal mononuclear phagocyte survival. ApoE deletion and pharmacological IL‐6 inhibition prevents pathogenic age‐ and stress‐induced subretinal MP accumulation in Cx3cr1 −/− mice. Graphical Abstract In age‐related macular degeneration, subretinal mononuclear phagocytes (MP) express high APOE levels, which prolongs their survival and accumulation by inducing IL‐6, which in turn promotes chronic subretinal inflammation.

Retinal pigmented epithelial (RPE) cells are essential for maintaining normal visual function, especially in their role in the visual cycle, and are thought to be one of the first cell classes affected by age-related macular degeneration (AMD). Clinical imaging systems routinely evaluate the structure of the RPE at the tissue level, but cellular level information may provide valuable RPE biomarkers of health, aging and disease. In this exploratory study, participants were imaged with 795 nm excitation in adaptive optics scanning laser ophthalmoscopy (AOSLO) to observe the microstructure of the near-infrared autofluorescence (AO-IRAF) from the RPE layer in healthy retinas and patients with AMD. The expected hexagonal mosaic of RPE cells was only sometimes seen in normal eyes, while AMD patients exhibited highly variable patterns of altered AO-IRAF. In some participants, AO-IRAF structure corresponding to cones was observed, as we have demonstrated previously. In some AMD patients, marked alterations in the pattern of AO-IRAF could be seen even in areas where the RPE appeared relatively normal in clinical imaging modalities, such as spectral domain optical coherence tomography (SD-OCT). AO-IRAF imaging using AOSLO offers promise for better detection and understanding of early RPE changes in the course of AMD, potentially before clinical signs appear.

The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Although the role of mTORC1 in retinal pigmented epithelium (RPE) homeostasis and age–related macular degeneration (AMD) pathogenesis is established, the function of mTORC2 remains unclear. We investigated both complexes in RPE health and disease. Therefore, in this study, we have attempted to demonstrate that the specific overexpression of mammalian lethal with Sec13 protein 8 (mLST8) in the mouse RPE activates both mTORC1 and mTORC2, inducing epithelial–mesenchymal transition (EMT)‐like changes and subretinal/RPE deposits resembling early AMD‐like pathogenesis. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in vitro or βA3/A1‐crystallin in vivo normalized mTORC1/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease. Our study reveals that overactivation of both mTOR complexes through mLST8 in RPE cells triggers AMD‐like pathology and cellular dysfunction. This finding highlights the critical role of balanced mTOR signaling in retinal health and suggests that targeting both complexes could be therapeutic for AMD treatment.

Alternative splicing of nucleoredoxin-like 1 (Nxnl1) results in 2 isoforms of the rod-derived cone viability factor. The truncated form (RdCVF) is a thioredoxin-like protein secreted by rods that promotes cone survival, while the full-length isoform (RdCVFL), which contains a thioredoxin fold, is involved in oxidative signaling and protection against hyperoxia. Here, we evaluated the effects of these different isoforms in 2 murine models of rod-cone dystrophy. We used adeno-associated virus (AAV) to express these isoforms in mice and found that both systemic and intravitreal injection of engineered AAV vectors resulted in RdCVF and RdCVFL expression in the eye. Systemic delivery of AAV92YF vectors in neonates resulted in earlier onset of RdCVF and RdCVFL expression compared with that observed with intraocular injection using the same vectors at P14. We also evaluated the efficacy of intravitreal injection using a recently developed photoreceptor-transducing AAV variant (7m8) at P14. Systemic administration of AAV92YF-RdCVF improved cone function and delayed cone loss, while AAV92YF-RdCVFL increased rhodopsin mRNA and reduced oxidative stress by-products. Intravitreal 7m8-RdCVF slowed the rate of cone cell death and increased the amplitude of the photopic electroretinogram. Together, these results indicate different functions for Nxnl1 isoforms in the retina and suggest that RdCVF gene therapy has potential for treating retinal degenerative disease.