Direct comparison reveals algorithmic similarities in fly and mouse visual motion detection.

Evolution has equipped vertebrates and invertebrates with neural circuits that selectively encode visual motion. While similarities in the computations performed by these circuits in mouse and fruit fly have been noted, direct experimental comparisons have been lacking. Because molecular mechanisms and neuronal morphology in the two species are distinct, we directly compared motion encoding in these two species at the algorithmic level, using matched stimuli and focusing on a pair of analogous neurons, the mouse ON starburst amacrine cell (ON SAC) and Drosophila T4 neurons. We find that the cells share similar spatiotemporal receptive field structures, sensitivity to spatiotemporal correlations, and tuning to sinusoidal drifting gratings, but differ in their responses to apparent motion stimuli. Both neuron types showed a response to summed sinusoids that deviates from models for motion processing in these cells, underscoring the similarities in their processing and identifying response features that remain to be explained.

Thy1 transgenic mice expressing the red fluorescent calcium indicator jRGECO1a for neuronal population imaging in vivo.

Calcium imaging is commonly used to measure the neural activity of large groups of neurons in mice. Genetically encoded calcium indicators (GECIs) can be delivered for this purpose using non-invasive genetic methods. Compared to viral gene transfer, transgenic targeting of GECIs provides stable long-term expression and obviates the need for invasive viral injections. Transgenic mice expressing the green GECI GCaMP6 are already widely used. Here we present the generation and characterization of transgenic mice expressing the sensitive red GECI jRGECO1a, driven by the Thy1 promoter. Four transgenic lines with different expression patterns showed sufficiently high expression for cellular in vivo imaging. We used two-photon microscopy to characterize visual responses of individual neurons in the visual cortex in vivo. The signal-to-noise ratio in transgenic mice was comparable to, or better than, mice transduced with adeno-associated virus. In addition, we show that Thy1-jRGECO1a transgenic mice are useful for transcranial population imaging and functional mapping using widefield fluorescence microscopy. We also demonstrate imaging of visual responses in retinal ganglion cells in vitro. Thy1-jRGECO1a transgenic mice are therefore a useful addition to the toolbox for imaging activity in intact neural networks.

Temporally Diverse Excitation Generates Direction-Selective Responses in ON- and OFF-Type Retinal Starburst Amacrine Cells.

The complexity of sensory receptive fields increases from one synaptic stage to the next. In many cases, increased complexity is achieved through spatiotemporal interactions between convergent excitatory and inhibitory inputs. Here, we present evidence that direction selectivity (DS), a complex emergent receptive field property of retinal starburst amacrine cells (SACs), is generated by spatiotemporal interactions between functionally diverse excitatory inputs. Electrophysiological whole-cell recordings from ON and OFF SACs show distinct temporal differences in excitation following proximal compared with distal stimulation of their receptive fields. Distal excitation is both faster and more transient, ruling out passive filtering by the dendrites and indicating a task-specific specialization. Model simulations demonstrate that this specific organization of excitation generates robust DS responses in SACs, consistent with elementary motion detector models. These results indicate that selective integration of spatiotemporally patterned excitation is a computational mechanism for motion detection in the mammalian retina.

Functional changes in Tg P23H-1 rat retinal responses: differences between ON and OFF pathway transmission to the superior colliculus.

The morphological consequences of retinal photoreceptor degeneration are well documented. Much less is known about changes in visual function during degeneration and whether central visual structures directly reflect changes in retinal ganglion cell (RGC) function. To address this, we compared changes in visual function of RGCs and cells in the superior colliculus (SC) in transgenic (Tg) P23H-1 rats, a model of retinitis pigmentosa (RP), and wild-type (WT) rats at postnatal days 35-50 (P35-50) and P300. RGCs were classified on the basis of their responses to light: onset (ON), offset (OFF), or both (ON-OFF). The distribution of ON, OFF, and ON-OFF RGCs is similar between WT and P35 Tg P23H-1 rats. By P300, many Tg P23H-1 RGCs are nonresponsive (NR). At this age, there is a sharp decline in ON and ON-OFF RGCs, and the majority that remain are OFF RGCs. Spontaneous rhythmic activity was observed in many RGCs at P300, but only in OFF or NR RGCs. In the SC, WT and P50 Tg P23H-1 responses are similar. At P300, Tg P23H-1 ON SC responses declined but OFF responses increased. We examined postsynaptic glutamate receptor expression located on the bipolar cells (BC), where the ON and OFF pathways arise. At P150, metabotropic glutamate receptor 6 (mGluR6) expression is lower than in WT, consistent with a decrease in ON RGC responses. GluR4 expression, an ionotropic glutamate receptor associated with OFF BCs, appears similar to that in WT. The loss of ON responses in Tg P23H-1 RGCs and in the SC is conserved and related to reduced mGluR6 signaling.

Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays.

Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission.

Local signaling from a retinal prosthetic in a rodent retinitis pigmentosa model in vivo.

OBJECTIVE: In clinical trials, retinitis pigmentosa patients implanted with a retinal prosthetic device show enhanced spatial vision, including the ability to read large text and navigate. New prosthetics aim to increase spatial resolution by decreasing pixel/electrode size and limiting current spread. To examine spatial resolution of a new prosthetic design, we characterized and compared two photovoltaic array (PVA) designs and their interaction with the retina after subretinal implantation in transgenic S334ter line 3 rats (Tg S334ter-3). APPROACH: PVAs were implanted subretinally at two stages of degeneration and assessed in vivo using extracellular recordings in the superior colliculus (SC). Several aspects of this interaction were evaluated by varying duration, irradiance and position of a near infrared laser focused on the PVA. These characteristics included: activation threshold, response linearity, SC signal topography and spatial localization. The major design difference between the two PVA designs is the inclusion of local current returns in the newer design. MAIN RESULTS: When tested in vivo, PVA-evoked response thresholds were independent of pixel/electrode size, but differ between the new and old PVA designs. Response thresholds were independent of implantation age and duration (⩽7.5 months). For both prosthesis designs, threshold intensities were within established safety limits. PVA-evoked responses require inner retina synaptic transmission and do not directly activate retinal ganglion cells. The new PVA design evokes local retinal activation, which is not found with the older PVA design that lacks local current returns. SIGNIFICANCE: Our study provides in vivo evidence that prosthetics make functional contacts with the inner nuclear layer at several stages of degeneration. The new PVA design enhances local activation within the retina and SC. Together these results predict that the new design can potentially harness the inherent processing within the retina and is likely to produce higher spatial resolution in patients.

Cone photoreceptors develop normally in the absence of functional rod photoreceptors in a transgenic swine model of retinitis pigmentosa.

PURPOSE: Human and swine retinas have morphological and functional similarities. In the absence of primate models, the swine is an attractive model to study retinal function and disease, with its cone-rich visual streak, our ability to manipulate their genome, and the differences in susceptibility of rod and cone photoreceptors to disease. We characterized the normal development of cone function and its subsequent decline in a P23H rhodopsin transgenic (TgP23H) miniswine model of autosomal dominant RP. METHODS: Semen from TgP23H miniswine 53-1 inseminated domestic swine and produced TgP23H and Wt hybrid littermates. Retinal function was evaluated using ERGs between postnatal days (P) 14 and 120. Retinal ganglion cell (RGC) responses were recorded to full-field stimuli at several intensities. Retinal morphology was assessed using light and electron microscopy. RESULTS: Scotopic retinal function matures in Wt pigs up to P60, but never develops in TgP23H pigs. Wt and TgP23H photopic vision matures similarly up to P30 and diverges at P60 where TgP23H cone vision declines. There are fewer TgP23H RGCs with visually evoked responses at all ages and their response to light is compromised. Photoreceptor morphological changes mirror these functional changes. CONCLUSIONS: Lack of early scotopic function in TgP23H swine suggests it as a model of an aggressive form of RP. In this mammalian model of RP, normal cone function develops independent of rod function. Therefore, its retina represents a system in which therapies to rescue cones can be developed to prolong photopic visual function in RP patients.

Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity.

Detailed characterization of neural circuitries furthers our understanding of how nervous systems perform specific functions and allows the use of those systems to test hypotheses. We have characterized the sensory input to the cutaneous trunk muscle (CTM; also cutaneus trunci [rat] or cutaneus maximus [mouse]) reflex (CTMR), which manifests as a puckering of the dorsal thoracolumbar skin and is selectively driven by noxious stimuli. CTM electromyography and neurogram recordings in naïve rats revealed that CTMR responses were elicited by natural stimuli and electrical stimulation of all segments from C4 to L6, a much greater extent of segmental drive to the CTMR than previously described. Stimulation of some subcutaneous paraspinal tissue can also elicit this reflex. Using a selective neurotoxin, we also demonstrate differential drive of the CTMR by trkA-expressing and nonexpressing small-diameter afferents. These observations highlight aspects of the organization of the CTMR system that make it attractive for studies of nociception and anesthesiology and plasticity of primary afferents, motoneurons, and the propriospinal system. We use the CTMR system to demonstrate qualitatively and quantitatively that experimental pharmacological treatments can be compared with controls applied either to the contralateral side or to another segment, with the remaining segments providing controls for systemic or other treatment effects. These data indicate the potential for using the CTMR system as both an invasive and a noninvasive quantitative assessment tool providing improved statistical power and reduced animal use.