Implications of Neural Plasticity in Retinal Prosthesis

Caravaca-Rodriguez, Daniel; Gaytán, Susana P.; Suaning, Gregg J.; Barriga‐Rivera, Alejandro

doi:10.1167/iovs.63.11.11

Cited by 10 publications

(10 citation statements)

References 253 publications

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“…However, as RP progresses a remodeling of the inner retina also occurs including formation of abnormal neural circuits and changes in the electrophysiologic properties of the retinal network [69][70][71]. After photoreceptor cell death, the inner retina changes their synaptic connections affecting the transmission of information [72]. The communication between retinal neurons is mediated electrical but also chemical signals, the former includes the neurotransmitters glutamate, and GABA and their receptors.…”

Section: Discussionmentioning

confidence: 99%

The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery

Esteban-Medina,

Loucera,

Rian

et al. 2024

J Transl Med

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Background Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP. Methods By mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa. Results A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARα1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa. Conclusions The possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.

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Section: Discussionmentioning

confidence: 99%

The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery

Esteban-Medina,

Loucera,

Rian

et al. 2024

J Transl Med

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“…There are also some insights into the functional enhancement of the olfactory bulb. For instance, electrophysiological recordings in the olfactory bulb in form deprived rats revealed stronger local field potentials than in normal ones ( Zhou et al, 2017 ; Caravaca-Rodriguez et al, 2022 ). Therefore, the increased GMV of the olfactory bulb may compensate for the decreased visual cortex, which reflects compensatory or neural plasticity during the sensitive period of visual development in rats.…”

Section: Discussionmentioning

confidence: 99%

Altered whole-brain gray matter volume in form-deprivation myopia rats based on voxel-based morphometry: A pilot study

et al. 2023

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BackgroundMyopia is one of the major public health problems worldwide. However, the exact pathogenesis of myopia remains unclear. This study proposes using voxel-based morphometry (VBM) to investigate potential morphological alterations in gray matter volume (GMV) in form-deprivation myopia (FDM) rats.MethodsA total of 14 rats with FDM (FDM group) and 15 normal controls (NC group) underwent high-resolution magnetic resonance imaging (MRI). Original T2 brain images were analyzed using VBM method to identify group differences in GMV. Following MRI examination, all rats were perfused with formalin, and immunohistochemical analysis of NeuN and c-fos levels was performed on the visual cortex.ResultsIn the FDM group, compared to the NC group, significantly decreased GMVs were found in the left primary visual cortex, left secondary visual cortex, right subiculum, right cornu ammonis, right entorhinal cortex and bilateral molecular layer of the cerebellum. Additionally, significantly increased GMVs were found in the right dentate gyrus, parasubiculum, and olfactory bulb.ConclusionsOur study revealed a positive correlation between mGMV and the expression of c-fos and NeuN in the visual cortex, suggesting a molecular relationship between cortical activity and macroscopic measurement of visual cortex structural plasticity. These findings may help elucidate the potential neural pathogenesis of FDM and its relationship to changes in specific brain regions.

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“…With all of these considerations, it becomes clear that electrical stimulation applied to the granular layer may improve safety and efficacy. However, inherent inter-subject variability in the thickness of the human visual cortex [28], cortical thickness variability induced by differing age of onset blindness [29][30][31][32], and variations in implantation depths can make targeted stimulation difficult. This means a post-hoc method of steering the activation towards layer 4 is needed.…”

Section: Introductionmentioning

confidence: 99%

Cortical layering disrupts multi-electrode current steering

et al. 2023

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Objective:Blindness affects approximately 40 million people worldwide and has inspired the development of cortical visual prostheses for restoring sight. Cortical visual prostheses electrically stimulate neurons of the visual cortex to artificially evoke visual percepts. Of the 6 layers of the visual cortex, layer 4 contains neurons that are likely to evoke a visual percept. Intracortical prostheses therefore aim to target layer 4; however, this can be difficult due to cortical curvature, inter-subject cortical variability, blindness-induced anatomical changes in cortex, and electrode placement variations. We investigated the feasibility of using current steering to stimulate specific cortical layers between electrodes in the laminar column. Approach: We explored whether the multiunit neural activity peak can be manipulated between two simultaneously stimulating electrodes in different layers of the cortical column. A 64-channel, 4-shank electrode array was implanted into the visual cortex of Sprague-Dawley rats (n=7) orthogonal to the cortical surface. A remote return electrode was positioned over the frontal cortex in the same hemisphere. Charge was supplied to two stimulating electrodes along a single shank. Differing ratios of charge (100:0, 75:25, 50:50) and separation distances (300-500 μm) were tested.Results:Current steering across the cortical layers did not result in a consistent shift of the neural activity peak. Both single-electrode and dual-electrode stimulation induced activity throughout the cortical column. This contrasts observations that current steering evoked a controllable peak of neural activity between electrodes implanted at similar cortical depths. However, dual-electrode stimulation across the layers did reduce the stimulation threshold at each site compared to single-electrode stimulation. Significance: Multi-electrode stimulation is not suitable for targeted activation of layers using current steering. However, it can be used to reduce activation thresholds at adjacent electrodes within a given cortical layer. This may be applied to reduce stimulation side effects from neural prostheses, such as seizures.

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Implications of Neural Plasticity in Retinal Prosthesis

Cited by 10 publications

References 253 publications

The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery

The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery

Altered whole-brain gray matter volume in form-deprivation myopia rats based on voxel-based morphometry: A pilot study

Cortical layering disrupts multi-electrode current steering

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