Neural circuits underlying multi-feature extraction in the retina

Classic ON-OFF direction-selective ganglion cells (DSGCs) that encode the four cardinal directions were recently shown to also be orientation-selective. To clarify the mechanisms underlying orientation selectivity we employed a variety of electrophysiological, optogenetic, and gene knock-out strategies to test the relative contributions of glutamate, GABA, and acetylcholine (ACh) input that are known to drive DSGCs, in male and female mouse retinas. Extracellular spike recordings revealed that DSGCs respond preferentially to either vertical or horizontal bars, those that are perpendicular to their preferred-null motion axes. By contrast, the glutamate input to all four DSGC types measured using whole-cell patch-clamp techniques was found to be tuned along the vertical axis. Tuned glutamatergic excitation was heavily reliant on type 5A bipolar cells, which appear to be electrically coupled via connexin 36 containing gap junctions to the vertically oriented processes of wide-field amacrine cells. Vertically tuned inputs are transformed by the GABAergic/cholinergic =starburst> amacrine cells (SACs), which are critical components of the direction-selective circuit, into distinct patterns of inhibition and excitation. Feed-forward SAC inhibition appears to ‘veto’ preferred orientation glutamate excitation in dorsal/ventral (but not nasal/temporal) coding DSGCs ‘flipping’ their orientation tuning by 90 degrees, and accounts for the apparent mismatch between glutamate input tuning and the DSGC's spiking response. Together, these results reveal how two distinct synaptic motifs interact to generate complex feature selectivity, shedding light on the intricate circuitry that underlies visual processing in the retina. Significance Statement The classical work of Hubel and Wiesel (1959) demonstrated that neurons in the cat visual cortex are often selective for multiple stimulus features, such as direction and orientation. Here, we show that direction-selective ganglion cells (DSGCs) in the mouse retina are also selective for stimulus orientation, suggesting that multi-feature extraction may begin earlier in the visual system than previously envisioned. Using a combination of patch-clamp, cell-specific genetic KO, and optogenetic strategies, we show that multi-feature coding relies on distinct mechanisms in the nasal/temporal and dorsal/ventral coding DSGC.