Retinogeniculate Pathway Research Articles

Engineering an in vitro retinothalamic nerve model.

Understanding the retinogeniculate pathway in vitro can offer insights into its development and potential for future therapeutic applications. This study presents a Polydimethylsiloxane-based two-chamber system with axon guidance channels, designed to replicate unidirectional retinogeniculate signal transmission in vitro. Using embryonic rat retinas, we developed a model where retinal spheroids innervate thalamic targets through up to 6 mm long microfluidic channels. Using a combination of electrical stimulation and functional calcium imaging we assessed how channel length and electrical stimulation frequency affects thalamic target response. In the presented model we integrated up to 20 identical functional retinothalamic neural networks aligned on a single transparent microelectrode array, enhancing the robustness and quality of recorded functional data. We found that network integrity depends on channel length, with 0.5-2 mm channels maintaining over 90% morphological and 50% functional integrity. A reduced network integrity was recorded in longer channels. The results indicate a notable reduction in forward spike propagation in channels longer than 4 mm. Additionally, spike conduction fidelity decreased with increasing channel length. Yet, stimulation-induced thalamic target activity remained unaffected by channel length. Finally, the study found that a sustained thalamic calcium response could be elicited with stimulation frequencies up to 31 Hz, with higher frequencies leading to transient responses. In conclusion, this study presents a high-throughput platform that demonstrates how channel length affects retina to brain network formation and signal transmission in vitro.

Electroretinographic responses to periodic stimuli in primates and the relevance for visual perception and for clinical studies.

Currently, electroretinograms (ERGs) are mainly recorded while using flashes as stimuli. In this review, we will argue that strong flashes are not ideal for studying visual information processing. ERG responses to periodic stimuli may be more strongly associated with the activity of post-receptoral neurons (belonging to different retino-geniculate pathways) and, therefore, be more relevant for visual perception. We will also argue that the use of periodic stimuli may be an attractive addition to clinically available retinal electrophysiological methods.

Compartmentalized ciliation changes of oligodendrocytes in aged mouse optic nerve.

Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. Dysfunction of CNS glia is associated with aging-related white matter diseases and neurodegeneration, and ciliopathies are known to affect CNS white matter. To investigate age-related changes in ciliary profile, we examined ciliary length and frequency in the retinogeniculate pathway, a white matter tract commonly affected by diseases of aging but in which expression of cilia has not been characterized. We found expression of Arl13b, a marker of primary cilia, in a small group of Olig2-positive oligodendrocytes in the optic nerve, optic chiasm, and optic tract in young and aged C57BL/6 wild-type mice. While the ciliary length and ciliated oligodendrocyte cells were constant in young mice in the retinogeniculate pathway, there was a significant increase in ciliary length in the anterior optic nerve as compared to the aged animals. Morphometric analysis confirmed a specific increase in the ciliation rate of CC1+ /Olig2+ oligodendrocytes in aged mice compared with young mice. Thus, the prevalence of primary cilia in oligodendrocytes in the visual pathway and the age-related changes in ciliation suggest that they may play important roles in white matter and age-associated optic neuropathies.

Adenosine A2A receptor modulates microglia-mediated synaptic pruning of the retinogeniculate pathway during postnatal development

Synapse pruning is essential not only for the developmental establishment of synaptic connections in the brain but also for the pathogenesis of neurodevelopmental and neurodegenerative disorders. However, there are no effective pharmacological means to regulate synaptic pruning during early development. Using the eye-specific segregation of the dorsal lateral geniculate nucleus (dLGN) as a model of synaptic pruning coupled with adenosine A2A receptor (A2AR) antagonism and knockout, we demonstrated while genetic deletion of the A2AR throughout the development attenuated eye-specific segregation with the attenuated microglial phagocytosis at postnatal day 5 (P5), selective treatment with the A2AR antagonist KW6002 at P2–P4 facilitated synaptic pruning of visual pathway with microglial activation, increased lysosomal activity in microglia and increased microglial engulfment of retinal ganglion cell (RGC) inputs in the dLGN at P5 (but not P10). Furthermore, KW6002-mediated facilitation of synaptic pruning was activity-dependent since tetrodotoxin (TTX) treatment abolished the KW6002 facilitation. Moreover, the A2AR antagonist also modulated postsynaptic proteins and synaptic density at early postnatal stages as revealed by the reduced immunoreactivity of postsynaptic proteins (Homer1 and metabotropic glutamate receptor 5) and colocalization of presynaptic VGlut2 and postsynaptic Homer1 puncta in the dLGN. These findings suggest that A2AR can control pruning by multiple actions involving the retinal wave, microglia engulfment, and postsynaptic stability. Thus, A2AR antagonists may represent a novel pharmacological strategy to modulate microglia-mediated synaptic pruning and treatment of neurodevelopmental disorders associated with dysfunctional pruning.

Limited functional convergence of eye-specific inputs in the retinogeniculate pathway of the mouse

Segregation of retinal ganglion cell (RGC) axons by type and eye of origin is considered a hallmark of dorsal lateral geniculate nucleus (dLGN) structure. However, recent anatomical studies have shown that neurons in mouse dLGN receive input from multiple RGC types of both retinae. Whether convergent input leads to relevant functional interactions is unclear. We studied functional eye-specific retinogeniculate convergence using dual-color optogenetics invitro. dLGN neurons were strongly dominated by input from one eye. Most neurons received detectable input from the non-dominant eye, but this input was weak, with a prominently reduced AMPAR:NMDAR ratio. Consistent with this, only a small fraction of thalamocortical neurons was binocular invivo across visual stimuli and cortical projection layers. Anatomical overlap between RGC axons and dLGN neuron dendrites alone did not explain the strong bias toward monocularity. We conclude thatfunctional eye-specific input selection and refinement limit convergent interactions in dLGN, favoring monocularity.

The influence of temporal frequency and stimulus size on the relative contribution of luminance and L-/M-cone opponent mechanisms in heterochromatic flicker ERGs

PurposeTo study the effect of stimulus size and temporal frequency on the relative contribution of luminance and L-/M-cone opponent signals in the ERG.MethodsIn four healthy, color normal subjects, ERG responses to heterochromatic stimuli with sinusoidal, counter-phase modulation of red and green LEDs were measured. By inverse variation of red and green contrasts, we varied luminance contrast while keeping L-/M-cone opponent chromatic contrast constant. The first harmonic components in the full field ERGs are independent of stimulus contrast at 12 Hz, while responses to 36 Hz stimuli vary, reaching a minimum close to isoluminance. It was assumed that ERG responses reflect L-/M-cone opponency at 12 Hz and luminance at 36 Hz. In this study, we modeled the influence of temporal frequency on the relative contribution of these mechanisms at intermediate frequencies, measured the influence of stimulus size on model parameters, and analyzed the second harmonic component at 12 Hz.ResultsThe responses at all frequencies and stimulus sizes could be described by a linear vector addition of luminance and L-/M-cone opponent reflecting ERGs. The contribution of the luminance mechanism increased with increasing temporal frequency and with increasing stimulus size, whereas the gain of the L-/M-cone opponent mechanism was independent of stimulus size and was larger at lower temporal frequencies. Thus, the luminance mechanism dominated at lower temporal frequencies with large stimuli. At 12 Hz, the second harmonic component reflected the luminance mechanism.ConclusionsThe ERGs to heterochromatic stimuli can be fully described in terms of linear combinations of responses in the (magnocellular) luminance and the (parvocellular) L-/M-opponent retino-geniculate pathways. The non-invasive study of these pathways in human subjects may have implications for basic research and for clinical research.

Microglia Tweak Retinogeniculate Pathways during Visual Circuit Refinement

Cheadle etal. reveal that microglia expressing TWEAK facilitate synapse elimination through a novel, non-phagocytic mechanism in the retinogeniculate pathway during visual circuit development. This mechanism is experience-dependent and occurs through the local binding of TWEAK to postsynaptic Fn14.

Melanopsin hypersensitivity dominates interictal photophobia in migraine.

To define the melanopsin and cone luminance retinogeniculate pathway contributions to photophobia in healthy controls and migraineurs. Healthy controls and migraineurs were categorized according to the International Classification of Headache Disorders criteria. Photophobia was measured under full-field illumination using electromyography in response to narrowband lights spanning the melanopsin and cone luminance action spectra. Migraineurs were tested during their interictal headache-free period. Melanopsin-mediated post-illumination pupil responses quantified intrinsically photosensitive Retinal Ganglion Cell (ipRGC) function. A model combining the melanopsin and cone luminance action spectra best described photophobia thresholds in controls and migraineurs; melanopsin contributions were ∼1.5× greater than cone luminance. In the illumination range causing photophobia, migraineurs had lower photophobia thresholds (∼0.55 log units; p < 0.001) and higher post-illumination pupil response amplitudes (p = 0.03) than controls. Photophobia is driven by melanopsin and cone luminance inputs to the cortex via the retino-thalamocortical pathway. In migraineurs, lower photophobia thresholds reflect hypersensitivity of ipRGC and cone luminance pathways, with the larger and prolonged post-illumination pupil response amplitude indicative of a supranormal melanopsin response. Our findings inform artificial lighting strategies incorporating luminaires with low melanopsin excitation and photopic luminance to limit the lighting conditions leading to photophobia.

Evolution of neural processing for visual perception in vertebrates.

Visual perception requires both visual information and attention. This review compares, across classes of vertebrates, the functional and anatomical characteristics of (a) the neural pathways that process visual information about objects, and (b) stimulus selection pathways that determine the objects to which an animal attends. Early in the evolution of vertebrate species, visual perception was dominated by information transmitted via the midbrain (retinotectal) visual pathway, and attention was probably controlled primarily by a selection network in the midbrain. In contrast, in primates, visual perception is dominated by information transmitted via the forebrain (retinogeniculate) visual pathway, and attention is mediated largely by networks in the forebrain. In birds and nonprimate mammals, both the retinotectal and retinogeniculate pathways contribute critically to visual information processing, and both midbrain and forebrain networks play important roles in controlling attention. The computations and processing strategies in birds and mammals share some strikingly similar characteristics despite over 300 million years of independent evolution and being implemented by distinct brain architectures. The similarity of these functional characteristics suggests that they provide valuable advantages to visual perception in advanced visual systems. A schema is proposed that describes the evolution of the pathways and computations that enable visual perception in vertebrate species.

A Differential Circuit via Retino-Colliculo-Pulvinar Pathway Enhances Feature Selectivity in Visual Cortex through Surround Suppression

In the mammalian visual system, information from the retina streams into parallel bottom-up pathways. It remains unclear how these pathways interact to contribute to contextual modulation of visual cortical processing. By optogenetic inactivation and activation of mouse lateral posterior nucleus (LP) of thalamus, a homolog of pulvinar, or its projection to primary visual cortex (V1), we found that LP contributes to surround suppression of layer (L) 2/3 responses in V1 by driving L1 inhibitory neurons. This results in subtractive suppression of visual responses and an overall enhancement of orientation, direction, spatial, and size selectivity. Neurons in V1-projecting LP regions receive bottom-up input from the superior colliculus (SC) and respond preferably to non-patterned visual noise. The noise-dependent LP activity allows V1 to "cancel" noise effects and maintain its orientation selectivity under varyingnoise background. Thus, the retina-SC-LP-V1 pathway forms a differential circuit with the canonical retino-geniculate pathway to achieve context-dependent sharpening of visual representations.

Visuomotor adaptation in the absence of input from early visual cortex

Prism adaptation is a time-honored tool for studying how the motor system adapts to sensory perturbations. Past research on the neural substrates of prism adaptation has implicated the posterior parietal cortex (PPC) and the cerebellum, under the assumption that these structures gain their visual input from the dominant retinogeniculate pathway to V1. Here we question whether this pathway is even required for visuomotor adaptation to occur. To investigate this, we examined prism adaptation in ‘MC’, someone who is blind to static stimuli following bilateral lesions that encompass much of her occipital cortex and the caudal-most areas of ventrotemporal cortex. Remarkably, MC shows evidence of prism adaptation that is similar to healthy control participants. First, when pointing with either the left or the right hand, MC shows spatial realignment; the classical after-effect exhibited by most people when adapting to displacing prisms. Second, MC demonstrates strategic recalibration – a reduction in her pointing error over time – that is similar in magnitude to healthy controls. These findings suggest that the geniculostriate pathway is not necessary for visuomotor adaptation to take place. Alternatively, we suggest that an extrageniculostriate pathway which provides visual inputs to the cerebellum from area MT and the PPC via the dorsolateral pons plays a significant and appreciable role in the guidance of unconscious automatic visuomotor adaptation.

Fourier Analysis of Cerebral Metabolism of Glucose: Gender Differences in Mechanisms of Color Processing in the Ventral and Dorsal Streams in Mice

Conventional imaging methods could not distinguish processes within the ventral and dorsal streams. The application of Fourier time series analysis was helpful to segregate changes in the ventral and dorsal streams of the visual system in male and female mice. The present study measured the accumulation of [18F]fluorodeoxyglucose ([18F]FDG) in the mouse brain using small animal positron emission tomography and magnetic resonance imaging (PET/MRI) during light stimulation with blue and yellow filters, compared to during conditions of darkness. Fourier analysis was performed using mean standardized uptake values (SUV) of [18F]FDG for each stimulus condition to derive spectral density estimates for each condition. In male mice, luminance opponency occurred by S-peak changes in the sub-cortical retino-geniculate pathways in the dorsal stream supplied by ganglionic arteries in the left visual cortex, while chromatic opponency involved C-peak changes in the cortico-subcortical pathways in the ventral stream perfused by cortical arteries in the left visual cortex. In female mice, there was resonance phenomenon at C-peak in the ventral stream perfused by the cortical arteries in the right visual cortex during luminance processing. Conversely, chromatic opponency caused by S-peak changes in the subcortical retino-geniculate pathways in the dorsal stream supplied by the ganglionic arteries in the right visual cortex. In conclusion, Fourier time series analysis uncovered distinct mechanisms of color processing in the ventral stream in males, while in female mice color processing was in the dorsal stream. It demonstrated that computation of colour processing as a conscious experience could have a wide range of applications in neuroscience, artificial intelligence and quantum mechanics.

Spatiotemporal distribution of glia in and around the developing mouse optic tract.

In the developing mouse optic tract, retinal ganglion cell (RGC) axon position is organized by topography and laterality (i.e., eye-specific or ipsi- and contralateral segregation). Our lab previously showed that ipsilaterally projecting RGCs are segregated to the lateral aspect of the developing optic tract and found that ipsilateral axons self-fasciculate to a greater extent than contralaterally projecting RGC axons in vitro. However, the full complement of axon-intrinsic and -extrinsic factors mediating eye-specific segregation in the tract remain poorly understood. Glia, which are known to express several guidance cues in the visual system and regulate the navigation of ipsilateral and contralateral RGC axons at the optic chiasm, are natural candidates for contributing to eye-specific pre-target axon organization. Here, we investigate the spatiotemporal expression patterns of both putative astrocytes (Aldh1l1+ cells) and microglia (Iba1+ cells) in the embryonic and neonatal optic tract. We quantified the localization of ipsilateral RGC axons to the lateral two-thirds of the optic tract and analyzed glia position and distribution relative to eye-specific axon organization. While our results indicate that glial segregation patterns do not strictly align with eye-specific RGC axon segregation in the tract, we identify distinct spatiotemporal organization of both Aldh1l1+ cells and microglia in and around the developing optic tract. These findings inform future research into molecular mechanisms of glial involvement in RGC axon growth and organization in the developing retinogeniculate pathway.

Eye-specific segregation and differential fasciculation of developing retinal ganglion cell axons in the mouse visual pathway.

Prior to forming and refining synaptic connections, axons of projection neurons navigate long distances to their targets. While much is known about guidance cues for axon navigation through intermediate choice points, whether and how axons are organized within tracts is less clear. Here we analyze the organization of retinal ganglion cell (RGC) axons in the developing mouse retinogeniculate pathway. RGC axons are organized by both eye-specificity and topography in the optic nerve and tract: ipsilateral RGC axons are segregated from contralateral axons and are offset laterally in the tract relative to contralateral axon topographic position. To identify potential cell-autonomous factors contributing to the segregation of ipsilateral and contralateral RGC axons in the visual pathway, we assessed their fasciculation behavior in a retinal explant assay. Ipsilateral RGC neurites self-fasciculate more than contralateral neurites in vitro and maintain this difference in the presence of extrinsic chiasm cues. To further probe the role of axon self-association in circuit formation in vivo, we examined RGC axon organization and fasciculation in an EphB1-/- mutant, in which a subset of ipsilateral RGC axons aberrantly crosses the midline but targets the ipsilateral zone in the dorsal lateral geniculate nucleus on the opposite side. Aberrantly crossing axons retain their association with ipsilateral axons in the contralateral tract, indicating that cohort-specific axon affinity is maintained independently of guidance signals present at the midline. Our results provide a comprehensive assessment of RGC axon organization in the retinogeniculate pathway and suggest that axon self-association contributes to pre-target axon organization.

Organization of the dorsal lateral geniculate nucleus in the mouse.

The dorsal lateral geniculate nucleus (dLGN) of the thalamus is the principal conduit for visual information from retina to visual cortex. Viewed initially as a simple relay, recent studies in the mouse reveal far greater complexity in the way input from the retina is combined, transmitted, and processed in dLGN. Here we consider the structural and functional organization of the mouse retinogeniculate pathway by examining the patterns of retinal projections to dLGN and how they converge onto thalamocortical neurons to shape the flow of visual information to visual cortex.

Perifoveal L- and M-cone-driven temporal contrast sensitivities at different retinal illuminances.

We established a protocol using a well-established LED stimulator to measure temporal contrast sensitivities driven by sine-wave modulation of L- and M-cones in the perifovea using triple silent substitution. The stimulus was presented in an annular field (2° inner diameter, 13° outer diameter). We validated this technique by studying the contrast sensitivity of three color normal observers at 10 different temporal frequencies (between 1 and 28 Hz) over a large range of retinal illuminances (between 0.07 and 587 phot Td), spanning the complete mesopic range. In one subject, sensitivities to counterphase modulation of L- and M-cones and in-phase modulation of L, M, and S-cones were additionally measured, which putatively reflected the parvo- and magnocellular retinogeniculate pathways, respectively. Furthermore, we performed measurements of temporal contrast sensitivities as a function of frequency at 294 phot Td in two protanopes, in two deuteranopes, and in one subject with S-cone monochromacy. Quality of isolation was satisfactory and we were able to reproduce known physiological patterns of temporal vision, such as the typical temporal contrast sensitivity functions of the L- and M-cone, the parvo- and magnocellular retinogeniculate pathways, as well as the light adaptation curves. These results will help determine optimal stimulus conditions in future studies. Results from the dichromats and the S-cone monochromat also support the quality of isolation of our protocol and underpin its potential clinical value.

Dynamic Modulation of Myelination in Response to Visual Stimuli Alters Optic Nerve Conduction Velocity.

Myelin controls the time required for an action potential to travel from the neuronal soma to the axon terminal, defining the temporal manner in which information is processed within the CNS. The presence of myelin, the internodal length, and the thickness of the myelin sheath are powerful structural factors that control the velocity and fidelity of action potential transmission. Emerging evidence indicates that myelination is sensitive to environmental experience and neuronal activity. Activity-dependent modulation of myelination can dynamically alter action potential conduction properties but direct functional in vivo evidence and characterization of the underlying myelin changes is lacking. We demonstrate that in mice long-term monocular deprivation increases oligodendrogenesis in the retinogeniculate pathway but shortens myelin internode lengths without affecting other structural properties of myelinated fibers. We also demonstrate that genetically attenuating synaptic glutamate neurotransmission from retinal ganglion cells phenocopies the changes observed after monocular deprivation, suggesting that glutamate may constitute a signal for myelin length regulation. Importantly, we demonstrate that visual deprivation and shortened internodes are associated with a significant reduction in nerve conduction velocity in the optic nerve. Our results reveal the importance of sensory input in the building of myelinated fibers and suggest that this activity-dependent alteration of myelination is important for modifying the conductive properties of brain circuits in response to environmental experience. Oligodendrocyte precursor cells differentiate into mature oligodendrocytes and are capable of ensheathing axons with myelin without molecular cues from neurons. However, this default myelination process can be modulated by changes in neuronal activity. Here, we show, for the first time, that experience-dependent activity modifies the length of myelin internodes along axons altering action potential conduction velocity. Such a mechanism would allow for variations in conduction velocities that provide a degree of plasticity in accordance to environmental needs. It will be important in future work to investigate how these changes in myelination and conduction velocity contribute to signal integration in postsynaptic neurons and circuit function.

Endogenous spontaneous ultraweak photon emission in the formation of eye-specific retinogeniculate projections before birth.

In 1963, it was suggested [Sperry, R.W. (1963). Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc. Natl. Acad. Sci. USA 50, 703-710.] that molecular cues can direct the development of orderly connections between the eye and the brain (the "chemoaffinity hypothesis"). In the same year, the amazing degree of functional accuracy of the visual pathway in the absence of any external light/photon perception prior to birth [Wiesel, T.N and Hubel, D.H. (1963). Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003-1017.] was discovered. These recognitions revealed that the wiring of the visual system relies on innate cues. However, how the eye-specific retinogeniculate pathway can be developed before birth without any visual experience is still an unresolved issue. In the present paper, we suggest that Müller cells (functioning as optical fibers), Müller cell cone (i.e. the inner half of the foveola that is created of an inverted cone-shaped zone of Müller cells), discrete retinal noise of rods, and intrinsically photosensitive retinal ganglion cells might have key functions by means of retinal spontaneous ultraweak photon emission in the development of eye-specific retinogeniculate pathways prior to birth.

Correlated and Uncorrelated Invisible Temporal White Noise Alters Mesopic Rod Signaling

We determined how rod signaling at mesopic light levels is altered by extrinsic temporal white noise that is correlated or uncorrelated with the activity of one (magnocellular, parvocellular, or koniocellular) postreceptoral pathway. Rod and cone photoreceptor excitations were independently controlled using a four-primary photostimulator. Psychometric (Weibull) functions were measured for incremental rod pulses (50 to 250 ms) in the presence (or absence; control) of perceptually invisible subthreshold extrinsic noise. Uncorrelated (rod) noise facilitates rod detection. Correlated postreceptoral pathway noise produces differential changes in rod detection thresholds and decreases the slope of the psychometric functions. We demonstrate that invisible extrinsic noise changes rod-signaling characteristics within the three retinogeniculate pathways at mesopic illumination depending on the temporal profile of the rod stimulus and the extrinsic noise type.

Correlated and uncorrelated invisible temporal white noise alters mesopic rod signaling.

We determined how rod signaling at mesopic light levels is altered by extrinsic temporal white noise that is correlated or uncorrelated with the activity of one (magnocellular, parvocellular, or koniocellular) postreceptoral pathway. Rod and cone photoreceptor excitations were independently controlled using a four-primary photostimulator. Psychometric (Weibull) functions were measured for incremental rod pulses (50 to 250ms) in the presence (or absence; control) of perceptually invisible subthreshold extrinsic noise. Uncorrelated (rod) noise facilitates rod detection. Correlated postreceptoral pathway noise produces differential changes in rod detection thresholds and decreases the slope of the psychometric functions. We demonstrate that invisible extrinsic noise changes rod-signaling characteristics within the three retinogeniculate pathways at mesopic illumination depending on the temporal profile of the rod stimulus and the extrinsic noise type.