Origins of direction selectivity in the primate retina

From mouse to primate, there is a striking discontinuity in our current understanding of the neural coding of motion direction. In non-primate mammals, directionally selective cell types and circuits are a signature feature of the retina, situated at the earliest stage of the visual process1,2. In primates, by contrast, direction selectivity is a hallmark of motion processing areas in visual cortex3,4, but has not been found in the retina, despite significant effort5,6. Here we combined functional recordings of light-evoked responses and connectomic reconstruction to identify diverse direction-selective cell types in the macaque monkey retina with distinctive physiological properties and synaptic motifs. This circuitry includes an ON-OFF ganglion cell type, a spiking, ON-OFF poly-axonal amacrine cell and the starburst amacrine cell, all of which show direction selectivity. Moreover, we found unexpectedly that macaque starburst cells possess a strong, non-GABAergic, antagonistic surround mediated by input from excitatory bipolar cells that is critical for the generation of radial motion sensitivity in these cells. Our findings open a new door to investigation of a novel circuitry that computes motion direction in the primate visual system.

Computational and Molecular Properties of Starburst Amacrine Cell Synapses Differ With Postsynaptic Cell Type

A presynaptic neuron can increase its computational capacity by transmitting functionally distinct signals to each of its postsynaptic cell types. To determine whether such computational specialization occurs over fine spatial scales within a neurite arbor, we investigated computation at output synapses of the starburst amacrine cell (SAC), a critical component of the classical direction-selective (DS) circuit in the retina. The SAC is a non-spiking interneuron that co-releases GABA and acetylcholine and forms closely spaced (<5 μm) inhibitory synapses onto two postsynaptic cell types: DS ganglion cells (DSGCs) and neighboring SACs. During dynamic optogenetic stimulation of SACs in mouse retina, whole-cell recordings of inhibitory postsynaptic currents revealed that GABAergic synapses onto DSGCs exhibit stronger low-pass filtering than those onto neighboring SACs. Computational analyses suggest that this filtering difference can be explained primarily by presynaptic properties, rather than those of the postsynaptic cells per se. Consistent with functionally diverse SAC presynapses, blockade of N-type voltage-gated calcium channels abolished GABAergic currents in SACs but only moderately reduced GABAergic and cholinergic currents in DSGCs. These results jointly demonstrate how specialization of synaptic outputs could enhance parallel processing in a compact interneuron over fine spatial scales. Moreover, the distinct transmission kinetics of GABAergic SAC synapses are poised to support the functional diversity of inhibition within DS circuitry.

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.

Retinal direction selectivity in the absence of asymmetric starburst amacrine cell responses

In the mammalian retina, direction-selectivity is thought to originate in the dendrites of GABAergic/cholinergic starburst amacrine cells, where it is first observed. However, here we demonstrate that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst dendrites are rendered non-directional, using a novel strategy combining a conditional GABAA α2 receptor knockout mouse with optogenetics. We show that temporal asymmetries between excitation/inhibition, arising from the differential connectivity patterns of starburst cholinergic and GABAergic synapses to ganglion cells, form the basis for a parallel mechanism generating direction selectivity. We further demonstrate that these distinct mechanisms work in a coordinated way to refine direction selectivity as the stimulus crosses the ganglion cell’s receptive field. Thus, precise spatiotemporal patterns of inhibition and excitation that determine directional responses in ganglion cells are shaped by two ‘core’ mechanisms, both arising from distinct specializations of the starburst network.

Retinal direction selectivity in the absence of asymmetric starburst amacrine cell responses

SummaryIn the mammalian retina, asymmetric inhibitory signals arising from the direction-selective dendrites of GABAergic/cholinergic starburst amacrine cells are thought to be crucial for originating direction selectivity. Contrary to this notion, however, we found that direction selectivity in downstream ganglion cells remains remarkably unaffected when starburst output is rendered non-directional (using a novel strategy combining a conditional GABAA α2 receptor knockout mouse with optogenetics). We show that temporal asymmetries between excitation/inhibition, arising from the differential connectivity patterns of starburst cholinergic and GABAergic synapses to ganglion cells, form the basis for a parallel mechanism generating direction selectivity. We further demonstrate that these distinct mechanisms work in a coordinated way to refine direction selectivity as the stimulus crosses the ganglion cell’s receptive field. Thus, precise spatiotemporal patterns of inhibition and excitation that shape directional responses in ganglion cells are shaped by two ‘core’ mechanisms, both arising from distinct specializations of the starburst network.