FLRT3 Marks Direction-Selective Retinal Ganglion Cells That Project to the Medial Terminal Nucleus

The mammalian retina extracts a multitude of diverse features from the visual scene such as color, contrast, and direction of motion. These features are transmitted separately to the brain by more than 40 different retinal ganglion cell (RGC) subtypes. However, so far only a few genetic markers exist to fully characterize the different RGC subtypes. Here, we present a novel genetic Flrt3-CreERT2 knock-in mouse that labels a small subpopulation of RGCs. Using single-cell injection of fluorescent dyes in Flrt3 positive RGCs, we distinguished four morphological RGC subtypes. Anterograde tracings using a fluorescent Cre-dependent Adeno-associated virus (AAV) revealed that a subgroup of Flrt3 positive RGCs specifically project to the medial terminal nucleus (MTN), which is part of the accessory optic system (AOS) and is essential in driving reflex eye movements for retinal image stabilization. Functional characterization using ex vivo patch-clamp recordings showed that the MTN-projecting Flrt3 RGCs preferentially respond to downward motion in an ON-fashion. These neurons distribute in a regular pattern and most of them are bistratified at the level of the ON and OFF bands of cholinergic starburst amacrine cells where they express the known ON-OFF direction-selective RGC marker CART. Together, our results indicate that MTN-projecting Flrt3 RGCs represent a new functionally homogeneous AOS projecting direction-selective RGC subpopulation.

Response Properties of Optic Flow Neurons in the Accessory Optic System of Hummingbirds vs. Zebra Finches and Pigeons

Optokinetic responses function to maintain retinal image stabilization by minimizing optic flow that occurs during self-motion. The hovering ability of hummingbirds is an extreme example of this behaviour. Optokinetic responses are mediated by direction-selective neurons with large receptive fields in the accessory optic system (AOS) and pretectum. Recent studies in hummingbirds showed that, compared to other bird species, (i) the pretectal nucleus lentiformis mesencephali (LM) is hypertrophied, (ii) LM has a unique distribution of direction preferences, and (iii) LM neurons are more tightly tuned to stimulus velocity. In this study, we sought to determine if there are concomitant changes in the nucleus of the basal optic root (nBOR) of the AOS. We recorded the visual response properties of nBOR neurons to largefield drifting random dot patterns and sine wave gratings in Anna's hummingbirds and zebra finches and compared these with archival data from pigeons. We found no differences with respect to the distribution of direction preferences: Neurons responsive to upwards, downwards and nasal-to-temporal motion were equally represented in all three species, and neurons responsive to temporal-to-nasal motion were rare or absent (<5%). Compared to zebra finches and pigeons, however, hummingbird nBOR neurons were more tightly tuned to stimulus velocity of random dot stimuli. Moreover, in response to drifting gratings, hummingbird nBOR neurons are more tightly tuned in the spatio-temporal domain. These results, in combination with specialization in LM, supports a hypothesis that hummingbirds have evolved to be "optic flow specialist" to cope with the optomotor demands of sustained hovering flight.

Conserved Circuits for Direction Selectivity in the Primate Retina

The detection of motion direction is a fundamental visual function and a classic model for neural computation. In the non-primate mammalian retina, direction selectivity arises in starburst amacrine cell (SAC) dendrites, which provide selective inhibition to ON and ON-OFF direction selective retinal ganglion cells (dsRGCs). While SACs are present in primates, their connectivity is unknown and the existence of primate dsRGCs remains an open question. Here we present a connectomic reconstruction of the primate ON SAC circuit from a serial electron microscopy volume of macaque central retina. We show that the structural basis for the SAC's ability to compute and confer directional selectivity on post-synaptic RGCs is conserved in primates and that SACs selectively target a single ganglion cell type, a candidate homolog to the mammalian ON-sustained dsRGCs that project to the accessory optic system and contribute to gaze-stabilizing reflexes. These results indicate that the capacity to compute motion direction is present in the retina, far earlier in the primate visual system than classically thought, and they shed light on the distinguishing features of primate motion processing by revealing the extent to which ancestral motion circuits are conserved.

Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing direction-selective retinal ganglion cells

Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here we investigated whether nystagmus associated with congenital stationary nightblindness (CSNB) can result from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lack functional nyctalopin protein (NYX, nyx) in ON bipolar cells (ON-BC) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4-7Hz. nob ON direction selective ganglion cells (ON-DSGC), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GC) oscillated asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light. Retinal pharmacological manipulations that blocked nob ON-DSGC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced oscillation frequency of nob ON-DSGCs also reduced oscillation frequency of their eye movements. We conclude that, in nob mice, oscillations of retinal ON-DSGCs cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus paving the way for development of therapeutic strategies.