GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC Necroptosis After Ischemia/Reperfusion

Investigative Ophthalmology & Visual Science, Год журнала: 2023, Номер 64(14), С. 42 - 42

Опубликована: Ноя. 28, 2023

Purpose: This study aimed to explore the impact of GSK840 on retinal neuronal injury after ischemia/reperfusion (IR) and its associated mechanism. Methods: We established an in vivo mouse model IR vitro oxygen glucose deprivation/reoxygenation (OGDR) primary ganglion cells (RGCs). GSK840, a small-molecule compound, was used specifically inhibit RIPK3/MLKL-dependent necroptosis. Retinal structure function evaluation performed by using hematoxylin eosin staining, optical coherence tomography, electroretinography. Propidium Iodide (PI) staining for detection necroptotic cell death, whereas Western blot analysis immunofluorescence were assess necroptosis-related proteins inner neurons. Results: necroptosis rapidly activated RGCs following or OGDR. helped maintain relatively normal thickness preserving neurons, particularly RGCs. Meanwhile, ameliorated IR-induced visual dysfunction, as evidenced improved amplitudes photopic negative response, a-wave, b-wave, oscillatory potentials. And treatment significantly reduced population PI+ injury. Mechanistically, RGC inhibiting RIPK3/MLKL pathway. Conclusions: exerts protective effects against RIPK3/MLKL-mediated may represent strategy degeneration ischemic retinopathy.

Язык: Английский

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Diverse GABA signaling in the inner retina enables spatiotemporal coding

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 11, 2024

Summary paragraph GABA ( ψ -aminobutyric acid) is the primary inhibitory neurotransmitter in mammalian central nervous system (CNS) 1,2 . There a wide range of GABAergic neuronal types, each which plays an important role neural processing and etiology neurological disorders 3–5 However, there no comprehensive understanding this functional diversity, due to lack genetic tools target study multitude cell types. Here we perform two-photon imaging release inner plexiform layer (IPL) mouse retina using newly developed sensor iGABASnFR2. By applying varied light stimuli isolated retinae, reveal over 40 different GABA-releasing neurons, including some not previously described. Individual types show unique distributions synaptic sites sublayers comprising IPL, allowing layer-specific visual encoding. Synaptic input output are aligned along specific retinal orientations for multiple Furthermore, computational modeling reveals that combination type-specific spatial structure kinetics enables neurons suppress sculpt excitatory signals response behaviorally relevant motion structures. Our high-throughput approach provides first physiological characterization signaling vertebrate CNS. Future applications method will enable interrogation function dysfunction diverse circuits health disease.

Язык: Английский

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A circuit motif for color in the human foveal retina

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(36)

Опубликована: Авг. 27, 2024

The neural pathways that start human color vision begin in the complex synaptic network of foveal retina where signals originating long (L), middle (M), and short (S) wavelength-sensitive cone photoreceptor types are compared through antagonistic interactions, referred to as opponency. In nonhuman primates, two opponent well established: an L vs. M circuit linked midget ganglion cell type, often called red-green pathway, S + small bistratified blue-yellow pathway. These have been taken correspond cardinal directions a trichromatic space, providing parallel inputs higher-level processing. Yet linking opponency primate mechanisms has proven particularly difficult. Here, we apply connectomic reconstruction trace excitatory outputs from S-ON (or “blue-cone”) bipolar additional types: large subpopulation ON-midget cells, whose connections suggest significant unique role vision. postsynaptic both cells thus define merge circuits, with potential for at first stage

Язык: Английский

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Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 16, 2025

Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, aging. Because remyelination is often incomplete, better understanding endogenous developing therapies that restore function are clinical imperatives. Here, we use in vivo two-photon microscopy electrophysiology study dynamics therapeutic-induced cortical functional recovery after cuprizone-mediated demyelination mice. We focus on visual pathway, which uniquely positioned provide insights into structure-function relationships during de/remyelination. show driven by recent oligodendrocyte highly efficacious following mild demyelination, but fails population when high rates occur quickly. Testing a thyromimetic (LL-341070) compared clemastine, find it enhances gain hastens neuronal function. The therapeutic benefit temporally restricted, acts exclusively moderate severe eliminating deficit. However, regeneration oligodendrocytes myelin healthy levels not necessary for These findings advance our its impact inform future strategies.

Язык: Английский

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A spherical code of retinal orientation selectivity enables decoding in ensembled and retinotopic operation

Cell Reports, Год журнала: 2025, Номер 44(3), С. 115373 - 115373

Опубликована: Март 1, 2025

Язык: Английский

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Distinct inhibitory pathways control velocity and directional tuning in the mouse retina

Current Biology, Год журнала: 2022, Номер 32(10), С. 2130 - 2143.e3

Опубликована: Апрель 7, 2022

The sensory periphery is responsible for detecting ethologically relevant features of the external world, using compact, predominantly feedforward circuits. Visual motion a particularly prevalent feature, presence which can be signal to enact diverse behaviors ranging from gaze stabilization reflexes predator avoidance or prey capture. To understand how retina constructs distinct neural representations required these behaviors, we investigated two circuits encoding different aspects image motion: ON and ON-OFF direction-selective ganglion cells (DSGCs). Using combination two-photon targeted whole-cell electrophysiology, pharmacology, conditional knockout mice, show that inhibitory pathways independently control tuning velocity direction in cell types. We further employ dynamic clamp numerical modeling techniques asymmetric inhibition provides velocity-invariant mechanism directional tuning, despite strong dependence classical models selectivity. therefore demonstrate invariant by interneurons act as computational building blocks construct distinct, behaviorally signals at earliest stages visual system.

Язык: Английский

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Neural Circuits Underlying Multifeature Extraction in the Retina

Journal of Neuroscience, Год журнала: 2023, Номер 44(10), С. e0910232023 - e0910232023

Опубликована: Ноя. 13, 2023

Classic ON-OFF direction-selective ganglion cells (DSGCs) that encode the four cardinal directions were recently shown to also be orientation-selective. To clarify mechanisms underlying orientation selectivity, we employed a variety of electrophysiological, optogenetic, and gene knock-out strategies test relative contributions glutamate, GABA, acetylcholine (ACh) input are known drive DSGCs, in male female mouse retinas. Extracellular spike recordings revealed DSGCs respond preferentially either vertical or horizontal bars, those perpendicular their preferred-null motion axes. By contrast, glutamate all DSGC types measured using whole-cell patch-clamp techniques was found tuned along axis. Tuned glutamatergic excitation heavily reliant on type 5A bipolar cells, which appear electrically coupled via connexin 36 containing gap junctions vertically oriented processes wide-field amacrine cells. Vertically inputs transformed by GABAergic/cholinergic "starburst" (SACs), critical components circuit, into distinct patterns inhibition excitation. Feed-forward SAC appears "veto" preferred dorsal/ventral (but not nasal/temporal) coding "flipping" tuning 90° accounts for apparent mismatch between DSGC's spiking response. Together, these results reveal how two synaptic motifs interact generate complex feature shedding light intricate circuitry underlies visual processing retina.

Язык: Английский

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Molecular identification of wide-field amacrine cells in mouse retina that encode stimulus orientation

Опубликована: Фев. 26, 2024

Visual information processing is sculpted by a diverse group of inhibitory interneurons in the retina called amacrine cells. Yet, for most >60 cell types, molecular identities and specialized functional attributes remain elusive. Here, we developed an intersectional genetic strategy to target wide-field cells (WACs) mouse that co-express transcription factor Bhlhe22 Kappa Opioid Receptor (KOR; B/K WACs). WACs feature straight, unbranched dendrites spanning over 0.5 mm (∼15° visual angle) produce non-spiking responses either light increments or decrements. Two-photon dendritic population imaging reveals Ca 2+ signals tuned physical orientations WAC dendrites, signifying robust structure-function alignment. establish divergent connections with multiple retinal neurons, including unexpected non-orientation-tuned ganglion bipolar Our work sets stage future comprehensive investigations enigmatic neurons: WACs.

Язык: Английский

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Roles of visually evoked and spontaneous activity in the development of retinal direction selectivity maps

Trends in Neurosciences, Год журнала: 2022, Номер 45(7), С. 529 - 538

Опубликована: Апрель 29, 2022

Язык: Английский

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Realistic retinal modeling unravels the differential role of excitation and inhibition to starburst amacrine cells in direction selectivity

PLoS Computational Biology, Год журнала: 2021, Номер 17(12), С. e1009754 - e1009754

Опубликована: Дек. 30, 2021

Retinal direction-selectivity originates in starburst amacrine cells (SACs), which display a centrifugal preference, responding with greater depolarization to stimulus expanding from soma dendrites than collapsing stimulus. Various mechanisms were hypothesized underlie SAC but dissociating them is experimentally challenging and the remain debatable. To address this issue, we developed Stimulation Modeling Environment (RSME), multifaceted data-driven retinal model that encompasses detailed neuronal morphology biophysical properties, retina-tailored connectivity scheme visual input. Using genetic algorithm, demonstrated spatiotemporally diverse excitatory inputs-sustained proximal transient distal processes-are sufficient generate validated preference single SAC. Reversing these input kinetics did not produce any centrifugal-preferring We then explored contribution of SAC-SAC inhibitory connections establishing preference. network enhanced failed it its absence. Embedding direction selective ganglion cell (DSGC) showed known SAC-DSGC asymmetric by itself produces selectivity. Still, selectivity sharpened network. Finally, use RSME demonstrate mediating recapitulate recent experimental findings. Thus, using RSME, obtained mechanistic understanding SACs'

Язык: Английский

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