Biology subjects

Foik, A. T.

Publications and source records attributed to Foik, A. T..

10 recordsLinked to original sources

bioRxiv2026

A knock-in model of severe GUCA1A cone-rod dystrophy reveals retinal network dysfunction beyond phototransduction

Autosomal dominant cone-rod dystrophy caused by GUCA1A mutations is generally viewed as a disorder of phototransduction, yet the mechanisms linking photoreceptor dysfunction to progressive vision loss remain unclear. Here, using a knock-in mouse carrying the severe GCAP1 p.(E111V) variant, we show that retinal network dysfunction precedes structural degeneration. Mutant mice exhibited delayed rod photoresponses, increased light sensitivity, selective visuospatial deficits, and progressive impairment of visually evoked responses in the superior colliculus and visual cortex, demonstrating propagation of functional deficits beyond photoreceptors. Transcriptomic and ultrastructural analyses revealed early synaptic, mitochondrial and inflammatory alterations despite largely preserved retinal architecture. Acute ex vivo delivery of recombinant wild-type GCAP1 partially restored mutant rod photoresponse kinetics, indicating that these early functional deficits remain biochemically modifiable. These findings redefine severe GUCA1A-associated disease as a progressive disorder of retinal network function, identifying an early therapeutic window before structural degeneration. One-Sentence SummaryVisual function breaks down long before photoreceptors are lost, opening an early window for intervention.

neuroscience↗

bioRxiv2025

Sildenafil-driven cone PDE6 inhibition alters receptive-field properties of retinal ganglion cells ex vivo

Suppressing the phototransduction cascade has a profound impact on visual information processing in the retina. Here, we examined how acute silencing of photoreceptors alters stimulus preference of Retinal Ganglion Cells (RGCs) without affecting retinal anatomy. Using ex vivo recordings from C57BL/6 mouse retinas, we applied the phosphodiesterase 6 (PDE6) inhibitor Sildenafil and compared responses to flash and drifting-grating stimuli before and after treatment. Flash responses revealed six physiological RGC populations under control conditions. After Sildenafil, Off-responses were completely abolished, and most cells adopted On-like profiles with markedly prolonged response latencies. At the population level, orientation selectivity was preserved; however, RGCs lost the ability to detect spatial frequencies above 0.05 cycle/{degrees} and temporal frequencies above 2 cycle/s. A subset of cells increased their firing rates and transformed from orientation-selective into direction-selective cells, indicating reorganization of tuning properties. To assess photoreceptor specificity of Sildenafil, we tested Gnat1 (rod-deficient, cone-only) and Gnat2 (cone-deficient, rod-only) mouse models. Sildenafil completely removed visually evoked responses in Gnat1 retinas, but not in Gnat2, demonstrating preferential inhibition of cone PDE6. These results show that cone-selective suppression of phototransduction is sufficient to abolish Off-pathway signaling, reduce high-frequency visual sensitivity, and alter RGC receptive-field tuning. Beyond providing a mechanistic explanation for the visual side effects of PDE5/6 inhibitors, this establishes a pharmacological model to mimic early cone dysfunction and study inner retinal adaptation. Significance StatementPhotoreceptor degeneration alters visual processing long before anatomical changes are evident, but the early functional consequences for retinal circuits remain poorly defined. Here, we show that pharmacological suppression of phototransduction with the PDE6 inhibitor Sildenafil selectively abolishes cone-driven responses and profoundly alters retinal ganglion cell tuning. Off-pathway signaling is lost, spatiotemporal frequency sensitivity is reduced, and some cells acquire direction selectivity. These findings provide functional evidence that cone pathways are preferentially targeted by Sildenafil, offering a mechanistic explanation for its transient visual side effects in humans. More broadly, this approach establishes a pharmacological model for studying inner retinal adaptation to early cone dysfunction in degenerative disease.

neuroscience↗

bioRxiv2024

Polyunsaturated Fatty Acid - mediated Cellular Rejuvenation for Reversing Age-related Vision Decline

The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), which are primarily localized in cell membranes, where they govern membrane biophysical properties such as diffusion, permeability, domain formation, and curvature generation. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, and this decline is associated with normal age-related visual decline and pathological age-related macular degeneration (AMD). ELOVL2 (Elongation of very-long-chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs, and methylation level of its promoter is currently the best predictor of chronological age. Here, we show that mice lacking ELOVL2-specific enzymatic activity (Elovl2C234W) have impaired contrast sensitivity and slower rod response recovery following bright light exposure. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals significantly improved visual function and reduced accumulation of ApoE, HTRA1 and complement proteins in sub-RPE deposits. At the molecular level, the gene expression pattern observed in retinas supplemented with 24:5n-3 exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature of younger retina. Finally, we present the first human genetic data showing significant association of several variants in the human ELOVL2 locus with the onset of intermediate AMD, underlying the translational significance of our findings. In sum, our study identifies novel therapeutic opportunities and defines ELOVL2 as a promising target for interventions aimed at preventing age-related vision loss.

molecular biology↗

bioRxiv2022

Visual system hyperexcitability and compromised V1 receptive field properties in early-stage retinitis pigmentosa in mice

Inherited retinal degenerative diseases are a prominent cause of blindness. Even though mutations causing death of photoreceptors are mostly known, the pathophysiology downstream in the inner retina and along the visual pathway is incompletely characterized in the earliest disease stages. Here we investigated retinal, midbrain and cortical visual function using electroretinography (ERG), the optomotor response (OMR), visual evoked potentials (VEPs), respectively, and single unit electrophysiology at the primary visual cortex (V1) in light-adapted juvenile ([~] 1-month-old) and young adult (3-month-old) RhoP23H/WT mice, representative of early-stage retinitis pigmentosa (RP). Photopic ERG revealed up to [~] 30 % hypersensitivity to light in RhoP23H/WT mice, as measured by the light intensity required to generate half-maximal b-wave (I50 parameter). RhoP23H/WT mice also showed increased optomotor responses towards low spatial frequency drifting gratings, indicative of visual overexcitation at the midbrain level. At the V1 level, VEPs and single-cell recordings revealed prominent hyperexcitability in the juvenile RhoP23H/WT mice. Mean VEP amplitudes for light ON stimuli were nearly doubled in 1-month-old RhoP23H/WT mice compared to controls, and more than doubled for light OFF. Single-cell recordings showed a significantly increased spontaneous V1 neuron firing in the RhoP23H/WT mice, and persistent contrast and temporal sensitivities. In contrast, direction selectivity was severely compromised. Our data suggest that during early RP, the visual pathway becomes hyperexcited. This could have both compensatory and deleterious consequences for visual behavior. Further studies on the mechanisms of hyperexcitability are warranted as this could lead to therapeutic interventions for RP. Significance statementLost retinal function in many blinding retinal degenerative disorders could soon be alleviated by advanced therapies that restore photoreception. However, it is unknown whether a visual system rewired downstream of the photoreceptors can process signals adequately. We studied the functional consequences of early rod death along the visual pathway in young retinitis pigmentosa (RP) mice. Photopic inner retina responses were moderately hypersensitized in the electroretinograms of RP mice. Reflex-based visual behavior and visual cortex electrophysiology showed hyperexcitability. Some aspects of complex visual processing were remarkably resistant to degeneration, whereas others were severely impacted. We conclude that the visual system adapts to lost photoreception by increasing sensitivity, but simultaneously becomes detrimentally hyperexcited. Mechanistic understanding could lead to therapeutic preservation and restoration of vision.

physiology↗

bioRxiv2020

Primary visual cortex injury produces loss of inhibitory neurons and long-term visual circuit dysfunction

Primary sensory areas of the mammalian neocortex have a remarkable degree of plasticity, allowing neural circuits to adapt to dynamic environments. However, little is known about the effect of traumatic brain injury on visual system function. Here we applied a mild focal contusion injury to primary visual cortex (V1) in adult mice. We found that, although V1 was largely intact in brain-injured mice, there was a reduction in the number of inhibitory interneurons that extended into deep cortical layers. In general, we found a preferential reduction of interneurons located in superficial layers, near the impact site, while interneurons positioned in deeper layers were better preserved. Three months after injury, V1 neurons showed dramatically reduced responses to visual stimuli and weaker orientation selectivity and tuning, consistent with the loss of cortical inhibition. Our results demonstrate that V1 neurons no longer robustly and stably encode visual input following a mild traumatic injury. HighlightsO_LIInhibitory neurons are lost throughout brain injured visual cortex C_LIO_LIVisually-evoked potentials are severely degraded after injury C_LIO_LIInjured V1 neurons show weaker selectivity and tuning consistent with reduced interneurons C_LI

neuroscience↗

bioRxiv2020

Novel rabies virus variant for bi-directional optical control reveals modulatory influence of the pulvinar on visual cortex in rat

Optogenetic tools have become of great utility in the causal analysis of systems in the brain. However, current optogenetic techniques do not reliably support both excitation and suppression of the same cells in vivo, limiting analysis and slowing research. Here we developed a novel glycoprotein-deleted rabies virus expressing two channelrhodopsin proteins, GtACR2 and Chrimson, in order to independently manipulate excitatory and inhibitory transmembrane potentials, respectively. Using this approach, we demonstrated that rodent pulvinar neurons modulate cortical size tuning and suppress flash responses, but do not drive activity in visual cortex. While our goal was primarily to develop this novel method to study the structure-function organization of thalamocortical circuits, this technique is readily applicable to study any brain region.

neuroscience↗

bioRxiv2020

Cortical inactivation does not block response enhancement in the superior colliculus

Repetitive visual stimulation is successfully used in a study on the visual evoked potential (VEP) plasticity in the visual system in mammals. Practicing visual tasks or repeated exposure to sensory stimuli can induce neuronal network changes in the cortical circuits and improve the perception of these stimuli. However little is known about the effect of visual training at the subcortical level. In the present study, we extend the knowledge showing positive results of this training in the rats superior colliculus (SC). In electrophysiological experiments, we showed that a single training session lasting several hours induces a response enhancement both in the primary visual cortex (V1) and in the SC. Further, we tested if collicular responses will be enhanced without V1 input. For this reason, we inactivated the V1 by applying xylocaine solution onto the cortical surface during visual training. Our results revealed that SCs response enhancement was present even without V1 inputs and showed no difference in amplitude comparing to VEPs enhancement while the V1 was active. These data suggest that the visual system plasticity and facilitation can develop independently but simultaneously in different parts of the visual system.

neuroscience↗

bioRxiv2020

Projections between visual cortex and pulvinar nucleus in the rat

The extrageniculate visual pathway, which carries visual information from the retina through the superficial layers of the superior colliculus and the pulvinar nucleus, is poorly understood. The pulvinar is thought to modulate information flow between cortical areas, and has been implicated in cognitive tasks like directing visually guided actions. In order to better understand the underlying circuitry, we performed retrograde injections of modified rabies virus in the visual cortex and pulvinar of the Long-Evans rat. We found a relatively small population of cells projecting to primary visual cortex (V1), compared to a much larger population projecting to higher visual cortex. Reciprocal corticothalamic projections showed a similar result, implying that pulvinar does not play as big a role in directly modulating V1 activity as previously thought.

neuroscience↗

bioRxiv2020

Visual response characteristics in lateral and medial subdivisions of the rat pulvinar

The pulvinar is a higher-order thalamic relay and a central component of the extrageniculate visual pathway, with input from the superior colliculus and visual cortex and output to all of visual cortex. Rodent pulvinar, more commonly called the lateral posterior nucleus (LP), consists of three highly-conserved subdivisions, and offers the advantage of simplicity in its study compared to more subdivided primate pulvinar. Little is known about receptive field properties of LP, let alone whether functional differences exist between different LP subdivisions, making it difficult to understand what visual information is relayed and what kinds of computations the pulvinar might support. Here, we characterized single-cell response properties in two V1 recipient subdivisions of rat pulvinar, the rostromedial (LPrm) and lateral (LPl), and found that a fourth of the cells were selective for orientation, compared to half in V1, and that LP tuning widths were significantly broader. Response latencies were also significantly longer and preferred size more than three times larger on average than in V1; the latter suggesting pulvinar as a source of spatial context to V1. Between subdivisons, LPl cells preferred higher temporal frequencies, whereas LPrm showed a greater degree of direction selectivity and pattern motion detection. Taken together with known differences in connectivity patterns, these results suggest two separate visual feature processing channels in the pulvinar, one in LPl related to higher speed processing which likely derives from superior colliculus input, and the other in LPrm for motion processing derived through input from visual cortex. Significance StatementThe pulvinar has a perplexing role in visual cognition as no clear link has been found between the functional properties of its neurons and behavioral deficits that arise when it is damaged. The pulvinar, called the lateral posterior nucleus (LP) in rats, is a higher order thalamic relay with input from the superior colliculus and visual cortex and output to all of visual cortex. By characterizing single-cell response properties in anatomically distinct subdivisions we found two separate visual feature processing channels in the pulvinar, one in lateral LP related to higher speed processing which likely derives from superior colliculus input, and the other in rostromedial LP for motion processing derived through input from visual cortex.

neuroscience↗

bioRxiv2018

Oscillations in spontaneous and visually evoked neuronal activity in the superficial layers of the cat’s superior colliculus

Oscillations are ubiquitous features of neuronal activity in sensory systems and are considered as a substrate for the integration of sensory information. Several studies have described oscillatory activity in the geniculate visual pathway, but little is known about this phenomenon in the extrageniculate visual pathway. We describe oscillations in evoked and background activity in the cats superficial layers of the superior colliculus, a retinorecipient structure in the extrageniculate visual pathway. Extracellular singleunit activity was recorded during periods with and without visual stimulation under isoflurane anesthesia in the mixture of N2O/O2. Autocorrelation, FFT and renewal density analyses were used to detect and characterize oscillations in the neuronal activity. Oscillations were common in the background and stimulus-evoked activity. Frequency range of background oscillations spanned between 5 - 90 Hz. Oscillations in evoked activity were observed in about half of the cells and could appear in two forms - stimulus-phase-locked (10 - 100 Hz), and stimulus-phase-independent (8 - 100 Hz) oscillations. Stimulus-phase-independent and background oscillatory frequencies were very similar within activity of particular neurons suggesting that stimulus-phase-independent oscillations may be a form of enhanced \"spontaneous\" oscillations. Stimulus-phase-locked oscillations were present in responses to moving and flashing stimuli. In contrast to stimulus-phase-independent oscillations, the strength of stimulus-phase-locked oscillations was positively correlated with stimulus velocity and neuronal firing rate. Our results suggest that in the superficial layers of the superior colliculus stimulus-phase-independent oscillations may be generated by the same mechanism(s) that lie in the base of \"spontaneous\" oscillations, while stimulus-phase-locked oscillations may result from interactions within the intra-collicular network and/or from a phase reset of oscillations present in the background activity.

neuroscience↗