Asymmetric Activation of ON and OFF Pathways in the Degenerated Retina.

Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns of spiking in retinal ganglion cells (RGCs) in response to electrical stimulation, but less work has examined the underlying retinal circuitry that is activated by electrical stimulation to drive these responses. Surprisingly, little is known about the role of inhibition in generating electrical responses or how inhibition might be altered during degeneration. Using whole-cell voltage-clamp recordings during subretinal electrical stimulation in the rd10 and wild-type (wt) retina, we found electrically evoked synaptic inputs differed between ON and OFF RGC populations, with ON cells receiving mostly excitation and OFF cells receiving mostly inhibition and very little excitation. We found that the inhibition of OFF bipolar cells limits excitation in OFF RGCs, and a majority of both pre- and postsynaptic inhibition in the OFF pathway arises from glycinergic amacrine cells, and the stimulation of the ON pathway contributes to inhibitory inputs to the RGC. We also show that this presynaptic inhibition in the OFF pathway is greater in the rd10 retina, compared with that in the wt retina.

Neuroplasticity of visual brain network induced by hypoxia.

The effects of hypoxia on brain function remain largely unknown. This study aimed to clarify this issue by visual-stimulated functional magnetic resonance imaging design. Twenty-three college students with a 30-d high-altitude exposure were tested before, 1 week and 3 months after returning to sea level. Brain functional magnetic resonance imaging and retinal electroretinogram were acquired. One week after returning to sea level, decreased blood oxygenation level dependent in the right lingual gyrus accompanied with increased blood oxygenation level dependent in the frontal cortex and insular cortex, and decreased amplitude of electroretinogram a-wave in right eye; moreover, the bilateral lingual gyri showed increased functional connectivity within the dorsal visual stream pathway, and the blood oxygenation level dependent signals in the right lingual gyrus showed positive correlation with right retinal electroretinogram a-wave. Three months after returning to sea level, the blood oxygenation level dependent signals recovered to normal level, while intensively increased blood oxygenation level dependent signals in a broad of brain regions and decreased retinal electroretinogram were also existed. In conclusion, hypoxic exposure has long-term effects on visual cortex, and the impaired retinal electroretinogram may contribute to it. The increased functional connectivity of dorsal stream may compensate for the decreased function of retinal photoreceptor cells to maintain normal visual function.

Optical coherence elastography under homolateral parallel acoustic radiation force excitation for ocular elasticity quantification.

Alteration in the elastic properties of biological tissues may indicate changes in the structure and components. Acoustic radiation force optical coherence elastography (ARF-OCE) can assess the elastic properties of the ocular tissues non-invasively. However, coupling the ultrasound beam and the optical beam remains challenging. In this Letter, we proposed an OCE method incorporating homolateral parallel ARF excitation for measuring the elasticity of the ocular tissues. An acoustic-optic coupling unit was established to reflect the ultrasound beam while transmitting the light beam. The ARF excited the ocular tissue in the direction parallel to the light beam from the same side of the light beam. We demonstrated the method on the agar phantoms, the porcine cornea, and the porcine retina. The results show that the ARF-OCE method can measure the elasticity of the cornea and the retina, resulting in higher detection sensitivity and a more extensive scanning range.

In-Depth Retinal Sensitivity Assessment With the MP3 Type S Microperimeter: A Methods Study.

Purpose: Retinal sensitivity is frequently listed as an end point in clinical trials, often with long working practices. The purpose of this methods study was to provide a new workflow and reduced test time for in-depth characterization of retinal sensitivity. Methods: A workflow for the MP3-S microperimeter with detailed functional characterization of the retina under photopic, mesopic, and scotopic conditions was evaluated. Grids of 32 and 28 test positions for photopic/mesopic and scotopic, respectively, were tested in 12 healthy individuals and compared with an established 68-point grid for test time, mean sensitivity (MS), and bivariate contour ellipse area (BCEA). Results: The mean test time (range; ±SD) was 10.5 minutes (8.4-14.9; ±2.0) in the 68-point grid and 4.3 minutes (3.8-5.0; ±0.4) in the 32-point grid, which was significantly different (P < 0.0001). The mean of difference in test time (±SD; 95% confidence interval) was 6.1 minutes (±2.0; 4.6-7.6). MS and BCEA were significantly correlated between grids (r = 0.89 and 0.74; P = 0.0005 and 0.014, respectively). Mean test time of subjects who underwent the full protocol (n = 4) was 2.15 hours. Conclusions: The protocol suggested herein appears highly feasible with in-depth characterization of retinal function under different testing conditions and in a short test time. Translational Relevance: The protocol described herein allows for characterization of the retina under different testing conditions and in a short test time, which is relevant due to its potential for patient prognostication and follow-up in clinical settings and also given its increasing role as a clinical trial end point.

Subcellular pathways through VGluT3-expressing mouse amacrine cells provide locally tuned object-motion-selective signals in the retina.

VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing input distributions to VG3 dendrite responses, we show that VG3 dendrites have a short functional length constant that likely depends on inhibitory shunting. This model predicts that RGCs that extend dendrites into the middle layers of the inner plexiform encounter VG3 dendrites whose responses vary according to the local bipolar cell response type.

Statistical Evaluation of ERG Responses: A New Method to Validate Cycle-by-Cycle Recordings in Advanced Retinal Degenerations.

Purpose: To describe and evaluate a novel method to determine the validity of measurements made using cycle-by-cycle (CxC) recording techniques in patients with advanced retinal degenerations (RD) having low-amplitude flicker electroretinogram (ERG) responses. Methods: The method extends the original CxC recording algorithm introduced by Sieving et al., retaining the original recording setup and the preliminary analysis of raw data. Novel features include extended use of spectrum analysis, reduction of errors due to known sources, and a comprehensive statistical assessment using three different tests. The method was applied to ERG recordings from seven patients with RD and two patients with CNGB3 achromatopsia. Results: The method was implemented as a Windows application to processes raw data obtained from a commercial ERG system, and it features a computational toolkit for statistical assessment of ERG recordings with amplitudes as low as 1 µV, commonly found in advanced RD patients. When recorded using conditions specific for eliciting cone responses, none of the CNGB3 patients had a CxC validated response, indicating that no signal artifacts were present with our recording conditions. A comparison of the presented method with conventional 30 Hz ERG was performed. Bland-Altman plots indicated good agreement (mean difference, -0.045 µV; limits of agreement, 0.193 to -0.282 µV) between the resulting amplitudes. Within-session test-retest variability was 15%, comparing favorably to the variability of standard ERG amplitudes. Conclusions: This novel method extracts highly reliable clinical recordings of low-amplitude flicker ERGs and effectively detects artifactual responses. It has potential value both as a cone outcome variable and planning tool in clinical trials on natural history and treatment of advanced RDs.

Photoreceptor Integrity in MEWDS: Longitudinal Structure-Function Correlations.

Purpose: The purpose of this study was to investigate structure-function correlations in multiple evanescent white dot syndrome (MEWDS) using microperimetry (MP) and spectral-domain optical coherence tomography (SD-OCT). Methods: Single-center prospective observational study including 14 eyes from 13 patients with MEWDS monitored over a median of 49.5 days (interquartile range = 29-92 days). Investigations focused on best-corrected visual acuity (BCVA), foveal granularity, and the Photoreceptor Reflectivity Ratio (PRR) as a measure of photoreceptor integrity. MP assessed average retinal threshold sensitivity (RTS) and bivariate contour ellipse area (BCEA) for fixation stability. A linear mixed model was used to test associations and interactions among RTS, time, and clinical variables. A hierarchical linear mixed model was used to analyze structure-function relationships, addressing both individual and location-specific variations. Results: Overall, 2340 MP locations were tested. PRR revealed a transient decrease within 30 days post-presentation, indicative of early photoreceptor disruption, followed by a progressive increase, signaling recovery. Significantly lower foveal sensitivity (RTS = 14.8 ± 7.4 vs. 22.5 ± 4.4 decibel [dB], P = 0.04) and increased fixation spread (63% BCEA = 1.26 ± 0.97 vs. 0.48 ± 0.35 deg2, P = 0.06) were noted in eyes with foveal granularity compared to those without. A significant increase in RTS was demonstrated over time (0.066 dB/day, P < 0.001), with a central-to-peripheral gradient of improvement. The interaction between follow-up time and baseline BCVA (P < 0.001) indicated more rapid improvement in eyes with worse initial vision. There was a robust, nonlinear association between PRR and RTS across all tested locations (P < 0.001), becoming asymptotic for sensitivity losses exceeding 20 dB. Conclusions: Photoreceptor reflectivity accurately aligned with visual function in MEWDS on longitudinal examinations. The central-to-peripheral gradient of improvement may suggest specific vulnerabilities underlying the area around the disc.

How Does the Inner Retinal Network Shape the Ganglion Cells Receptive Field? A Computational Study.

We consider a model of basic inner retinal connectivity where bipolar and amacrine cells interconnect and both cell types project onto ganglion cells, modulating their response output to the brain visual areas. We derive an analytical formula for the spatiotemporal response of retinal ganglion cells to stimuli, taking into account the effects of amacrine cells inhibition. This analysis reveals two important functional parameters of the network: (1) the intensity of the interactions between bipolar and amacrine cells and (2) the characteristic timescale of these responses. Both parameters have a profound combined impact on the spatiotemporal features of retinal ganglion cells' responses to light. The validity of the model is confirmed by faithfully reproducing pharmacogenetic experimental results obtained by stimulating excitatory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expressed on ganglion cells and amacrine cells' subclasses, thereby modifying the inner retinal network activity to visual stimuli in a complex, entangled manner. Our mathematical model allows us to explore and decipher these complex effects in a manner that would not be feasible experimentally and provides novel insights in retinal dynamics.

Visual omitted stimulus potentials are not retinotopic.

Omitted stimulus potentials (OSPs) are elicited in response to the omission of expected stimuli and are thought to reflect prediction errors. If prediction errors are signaled in the sensory cortex, OSPs are expected to be generated in the sensory cortex. The present study investigated the involvement of the early visual cortex in the generation of OSPs by testing whether omitted visual stimuli elicit brain responses in a spatially specific manner. Checkerboard pattern stimuli were presented alternately in the upper and lower visual fields, and the stimuli were omitted in 10 % of the trials. Event-related potentials were recorded from 33 participants. While a retinotopic C1 component was evoked by real visual stimuli, omitted stimuli did not produce any response reflecting retinotopy but did elicit a visual mismatch negativity, which was larger for omitted stimuli expected in the lower visual field than for those in the upper visual field. These results suggest that omitted visual stimuli are processed in a different pathway than actual stimuli.

Morphological and electrophysiological characterization of a novel displaced astrocyte in the mouse retina.

Astrocytes throughout the central nervous system are heterogeneous in both structure and function. This diversity leads to tissue-specific specialization where morphology is adapted to the surrounding neuronal circuitry, as seen in Bergman glia of the cerebellum and Müller glia of the retina. Because morphology can be a differentiating factor for cellular classification, we recently developed a mouse where glial-fibrillary acidic protein (GFAP)-expressing cells stochastically label for full membranous morphology. Here we utilize this tool to investigate whether morphological and electrophysiological features separate types of mouse retinal astrocytes. In this work, we report on a novel glial population found in the inner plexiform layer and ganglion cell layer which expresses the canonical astrocyte markers GFAP, S100ß, connexin-43, Sox2 and Sox9. Apart from their retinal layer localization, these cells are unique in their radial distribution. They are notably absent from the mid-retina but are heavily concentrated near the optic nerve head, and to a lesser degree the peripheral retina. Additionally, their morphology is distinct from both nerve fiber layer astrocytes and Müller glia, appearing more similar to amacrine cells. Despite this structural similarity, these cells lack protein expression of common neuronal markers. Additionally, they do not exhibit action potentials, but rather resemble astrocytes and Müller glia in their small amplitude, graded depolarization to both light onset and offset. Their structure, protein expression, physiology, and intercellular connections suggest that these cells are astrocytic, displaced from their counterparts in the nerve fiber layer. As such, we refer to these cells as displaced retinal astrocytes.

Transformation of Motion Pattern Selectivity from Retina to Superior Colliculus.

The superior colliculus (SC) is a prominent and conserved visual center in all vertebrates. In mice, the most superficial lamina of the SC is enriched with neurons that are selective for the moving direction of visual stimuli. Here, we study how these direction selective neurons respond to complex motion patterns known as plaids, using two-photon calcium imaging in awake male and female mice. The plaid pattern consists of two superimposed sinusoidal gratings moving in different directions, giving an apparent pattern direction that lies between the directions of the two component gratings. Most direction selective neurons in the mouse SC respond robustly to the plaids and show a high selectivity for the moving direction of the plaid pattern but not of its components. Pattern motion selectivity is seen in both excitatory and inhibitory SC neurons and is especially prevalent in response to plaids with large cross angles between the two component gratings. However, retinal inputs to the SC are ambiguous in their selectivity to pattern versus component motion. Modeling suggests that pattern motion selectivity in the SC can arise from a nonlinear transformation of converging retinal inputs. In contrast, the prevalence of pattern motion selective neurons is not seen in the primary visual cortex (V1). These results demonstrate an interesting difference between the SC and V1 in motion processing and reveal the SC as an important site for encoding pattern motion.

Functional OCT reveals anisotropic changes of retinal flicker-evoked vasodilation.

The purpose of this study is to verify the effect of anisotropic property of retinal biomechanics on vasodilation measurement. A custom-built optical coherence tomography (OCT) was used for time-lapse imaging of flicker stimulation-evoked vessel lumen changes in mouse retinas. A comparative analysis revealed significantly larger (18.21%) lumen dilation in the axial direction compared to the lateral (10.77%) direction. The axial lumen dilation predominantly resulted from the top vessel wall movement toward the vitreous direction, whereas the bottom vessel wall remained stable. This observation indicates that the traditional vasodilation measurement in the lateral direction may result in an underestimated value.

Distributed feature representations of natural stimuli across parallel retinal pathways.

How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population two-photon calcium imaging in mice, we discover that retinal ON bipolar cells (second-order neurons of the visual system) are divided into two blocks of four types. The two blocks distribute temporal and spatial information encoding, respectively. ON bipolar cell axons co-stratify within each block, but separate laminarly between them (upper block: diverse temporal, uniform spatial tuning; lower block: diverse spatial, uniform temporal tuning). ON bipolar cells extract temporal and spatial features similarly from artificial and naturalistic stimuli. In addition, they differ in sensitivity to coherent motion in naturalistic movies. Motion information is distributed across ON bipolar cells in the upper and the lower blocks, multiplexed with temporal and spatial contrast, independent features of natural scenes. Comparing the responses of different boutons within the same arbor, we find that axons of all ON bipolar cell types function as computational units. Thus, our results provide insights into the visual feature extraction from naturalistic stimuli and reveal how structural and functional organization cooperate to generate parallel ON pathways for temporal and spatial information in the mammalian retina.

Fractal Phototherapy in Maximizing Retina and Brain Plasticity.

The neuroplasticity potential is reduced with aging and impairs during neurodegenerative diseases and brain and visual system injuries. This limits the brain's capacity to repair the structure and dynamics of its activity after lesions. Maximization of neuroplasticity is necessary to provide the maximal CNS response to therapeutic intervention and adaptive reorganization of neuronal networks in patients with degenerative pathology and traumatic injury to restore the functional activity of the brain and retina.Considering the fractal geometry and dynamics of the healthy brain and the loss of fractality in neurodegenerative pathology, we suggest that the application of self-similar visual signals with a fractal temporal structure in the stimulation therapy can reactivate the adaptive neuroplasticity and enhance the effectiveness of neurorehabilitation. This proposition was tested in the recent studies. Patients with glaucoma had a statistically significant positive effect of fractal photic therapy on light sensitivity and the perimetric MD index, which shows that methods of fractal stimulation can be a novel nonpharmacological approach to neuroprotective therapy and neurorehabilitation. In healthy rabbits, it was demonstrated that a long-term course of photostimulation with fractal signals does not harm the electroretinogram (ERG) and retina structure. Rabbits with modeled retinal atrophy showed better dynamics of the ERG restoration during daily stimulation therapy for a week in comparison with the controls. Positive changes in the retinal function can indirectly suggest the activation of its adaptive plasticity and the high potential of stimulation therapy with fractal visual stimuli in a nonpharmacological neurorehabilitation, which requires further study.

Axonal stimulation affects the linear summation of single-point perception in three Argus II users.

Objective.Retinal implants use electrical stimulation to elicit perceived flashes of light ('phosphenes'). Single-electrode phosphene shape has been shown to vary systematically with stimulus parameters and the retinal location of the stimulating electrode, due to incidental activation of passing nerve fiber bundles. However, this knowledge has yet to be extended to paired-electrode stimulation.Approach.We retrospectively analyzed 3548 phosphene drawings made by three blind participants implanted with an Argus II Retinal Prosthesis. Phosphene shape (characterized by area, perimeter, major and minor axis length) and number of perceived phosphenes were averaged across trials and correlated with the corresponding single-electrode parameters. In addition, the number of phosphenes was correlated with stimulus amplitude and neuroanatomical parameters: electrode-retina and electrode-fovea distance as well as the electrode-electrode distance to ('between-axon') and along axon bundles ('along-axon'). Statistical analyses were conducted using linear regression and partial correlation analysis.Main results.Simple regression revealed that each paired-electrode shape descriptor could be predicted by the sum of the two corresponding single-electrode shape descriptors (p < .001). Multiple regression revealed that paired-electrode phosphene shape was primarily predicted by stimulus amplitude and electrode-fovea distance (p < .05). Interestingly, the number of elicited phosphenes tended to increase with between-axon distance (p < .05), but not with along-axon distance, in two out of three participants.Significance.The shape of phosphenes elicited by paired-electrode stimulation was well predicted by the shape of their corresponding single-electrode phosphenes, suggesting that two-point perception can be expressed as the linear summation of single-point perception. The impact of the between-axon distance on the perceived number of phosphenes provides further evidence in support of the axon map model for epiretinal stimulation. These findings contribute to the growing literature on phosphene perception and have important implications for the design of future retinal prostheses.

Avoidance of axonal stimulation with sinusoidal epiretinal stimulation.

Objective.Neuromodulation, particularly electrical stimulation, necessitates high spatial resolution to achieve artificial vision with high acuity. In epiretinal implants, this is hindered by the undesired activation of distal axons. Here, we investigate focal and axonal activation of retinal ganglion cells (RGCs) in epiretinal configuration for different sinusoidal stimulation frequencies.Approach.RGC responses to epiretinal sinusoidal stimulation at frequencies between 40 and 100 Hz were tested inex-vivophotoreceptor degenerated (rd10) isolated retinae. Experiments were conducted using a high-density CMOS-based microelectrode array, which allows to localize RGC cell bodies and axons at high spatial resolution.Main results.We report current and charge density thresholds for focal and distal axon activation at stimulation frequencies of 40, 60, 80, and 100 Hz for an electrode size with an effective area of 0.01 mm2. Activation of distal axons is avoided up to a stimulation amplitude of 0.23µA (corresponding to 17.3µC cm-2) at 40 Hz and up to a stimulation amplitude of 0.28µA (14.8µC cm-2) at 60 Hz. The threshold ratio between focal and axonal activation increases from 1.1 for 100 Hz up to 1.6 for 60 Hz, while at 40 Hz stimulation frequency, almost no axonal responses were detected in the tested intensity range. With the use of synaptic blockers, we demonstrate the underlying direct activation mechanism of the ganglion cells. Finally, using high-resolution electrical imaging and label-free electrophysiological axon tracking, we demonstrate the extent of activation in axon bundles.Significance.Our results can be exploited to define a spatially selective stimulation strategy avoiding axonal activation in future retinal implants, thereby solving one of the major limitations of artificial vision. The results may be extended to other fields of neuroprosthetics to achieve selective focal electrical stimulation.

Explainable machine learning predictions of perceptual sensitivity for retinal prostheses.

Objective.Retinal prostheses evoke visual precepts by electrically stimulating functioning cells in the retina. Despite high variance in perceptual thresholds across subjects, among electrodes within a subject, and over time, retinal prosthesis users must undergo 'system fitting', a process performed to calibrate stimulation parameters according to the subject's perceptual thresholds. Although previous work has identified electrode-retina distance and impedance as key factors affecting thresholds, an accurate predictive model is still lacking.Approach.To address these challenges, we (1) fitted machine learning models to a large longitudinal dataset with the goal of predicting individual electrode thresholds and deactivation as a function of stimulus, electrode, and clinical parameters ('predictors') and (2) leveraged explainable artificial intelligence (XAI) to reveal which of these predictors were most important.Main results.Our models accounted for up to 76% of the perceptual threshold response variance and enabled predictions of whether an electrode was deactivated in a given trial with F1 and area under the ROC curve scores of up to 0.732 and 0.911, respectively. Our models identified novel predictors of perceptual sensitivity, including subject age, time since blindness onset, and electrode-fovea distance.Significance.Our results demonstrate that routinely collected clinical measures and a single session of system fitting might be sufficient to inform an XAI-based threshold prediction strategy, which has the potential to transform clinical practice in predicting visual outcomes.

Differential Expression Analysis Identifies Candidate Synaptogenic Molecules for Wiring Direction-Selective Circuits in the Retina.

An organizational feature of neural circuits is the specificity of synaptic connections. A striking example is the direction-selective (DS) circuit of the retina. There are multiple subtypes of DS retinal ganglion cells (DSGCs) that prefer motion along one of four preferred directions. This computation is mediated by selective wiring of a single inhibitory interneuron, the starburst amacrine cell (SAC), with each DSGC subtype preferentially receiving input from a subset of SAC processes. We hypothesize that the molecular basis of this wiring is mediated in part by unique expression profiles of DSGC subtypes. To test this, we first performed paired recordings from isolated mouse retinas of both sexes to determine that postnatal day 10 (P10) represents the age at which asymmetric synapses form. Second, we performed RNA sequencing and differential expression analysis on isolated P10 ON-OFF DSGCs tuned for either nasal or ventral motion and identified candidates which may promote direction-specific wiring. We then used a conditional knock-out strategy to test the role of one candidate, the secreted synaptic organizer cerebellin-4 (Cbln4), in the development of DS tuning. Using two-photon calcium imaging, we observed a small deficit in directional tuning among ventral-preferring DSGCs lacking Cbln4, though whole-cell voltage-clamp recordings did not identify a significant change in inhibitory inputs. This suggests that Cbln4 does not function primarily via a cell-autonomous mechanism to instruct wiring of DS circuits. Nevertheless, our transcriptomic analysis identified unique candidate factors for gaining insights into the molecular mechanisms that instruct wiring specificity in the DS circuit.

A Retina-Inspired Optoelectronic Synapse Using Quantum Dots for Neuromorphic Photostimulation of Neurons.

Neuromorphic electronics, inspired by the functions of neurons, have the potential to enable biomimetic communication with cells. Such systems require operation in aqueous environments, generation of sufficient levels of ionic currents for neurostimulation, and plasticity. However, their implementation requires a combination of separate devices, such as sensors, organic synaptic transistors, and stimulation electrodes. Here, a compact neuromorphic synapse that combines photodetection, memory, and neurostimulation functionalities all-in-one is presented. The artificial photoreception is facilitated by a photovoltaic device based on cell-interfacing InP/ZnS quantum dots, which induces photo-faradaic charge-transfer mediated plasticity. The device sends excitatory post-synaptic currents exhibiting paired-pulse facilitation and post-tetanic potentiation to the hippocampal neurons via the biohybrid synapse. The electrophysiological recordings indicate modulation of the probability of action potential firing due to biomimetic temporal summation of excitatory post-synaptic currents. The results pave the way for the development of novel bioinspired neuroprosthetics and soft robotics and highlight the potential of quantum dots for achieving versatile neuromorphic functionality in aqueous environments.

An early enriched experience drives targeted microglial engulfment of miswired neural circuitry during a restricted postnatal period.

Brain function is critically dependent on correct circuit assembly. Microglia are well-known for their important roles in immunological defense and neural plasticity, but whether they can also mediate experience-induced correction of miswired circuitry is unclear. Ten-m3 knockout (KO) mice display a pronounced and stereotyped visuotopic mismapping of ipsilateral retinal inputs in their visual thalamus, providing a useful model to probe circuit correction mechanisms. Environmental enrichment (EE) commenced around birth, but not later in life, can drive a partial correction of the most mismapped retinal inputs in Ten-m3 KO mice. Here, we assess whether enrichment unlocks the capacity for microglia to selectively engulf and remove miswired circuitry, and the timing of this effect. Expression of the microglial-associated lysosomal protein CD68 showed a clear enrichment-driven, spatially restricted change which had not commenced at postnatal day (P)18, was evident at P21, more robust at P25, and had ceased by P30. This was observed specifically at the corrective pruning site and was absent at a control site. An engulfment assay at the corrective pruning site in P25 mice showed EE-driven microglial-uptake of the mismapped axon terminals. This was temporally and spatially specific, as no enrichment-driven microglial engulfment was seen in P18 KO mice, nor the control locus. The timecourse of the EE-driven corrective pruning as determined anatomically, aligned with this pattern of microglia reactivity and engulfment. Collectively, these findings show experience can drive targeted microglial engulfment of miswired neural circuitry during a restricted postnatal window. This may have important therapeutic implications for neurodevelopmental conditions involving aberrant neural connectivity.