Molecular classification of zebrafish retinal ganglion cells links genes to cell types to behavior

Abstract

Retinal ganglion cells (RGCs) form an array of feature detectors, which convey visual information to central brain regions. Characterizing RGC diversity is required to understand the logic of the underlying functional segregation. Using single-cell transcriptomics, we systematically classified RGCs in adult and larval zebrafish, thereby identifying marker genes for at least 33 stable and transient cell types. We used this dataset to engineer transgenic driver lines, enabling experimental access to specific RGC types. Strikingly, expression of one or few transcription factors often predicts dendrite morphologies and axonal projections to specific tectal layers and extratectal targets. In vivo calcium imaging revealed that molecularly defined RGCs exhibit highly specific functional tuning. Finally, chemogenetic ablation of eomesa + RGCs, which comprise melanopsin-expressing types with projections to a small subset of central targets, selectively impaired phototaxis. Together, our study establishes a framework for systematically studying the functional architecture of the visual system.

The tectum/superior colliculus as the vertebrate solution for spatial sensory integration and action

“…Tectal processing in zebrafish In larval zebrafish, retinal ganglion cells dominate the inputs to the superficial layers, with at least 20 discrete categories of retinal ganglion cells delivering information on visual stimuli's motion, orientation, and (through the retinotectal map) position 75,89 . These retinal ganglion cells have distinct molecular profiles and morphologies, and they target specific laminae and are sensitive to particular visual features 30 . Deeper retinorecipient layers in the central regions of the neuropil receive luminance information from retinal ganglion cells.…”

“…Based on the soma size, dendritic stratification pattern, and visual response patterns, 20-30 morphologically and physiologically distinct retinal ganglion cell types are estimated to exist in the mouse and primates [23][24][25] . Retinal ganglion cells can also be categorized based on molecular markers, and while some categories of retinal ganglion cells have characteristic sets of markers, there is as yet no clear understanding of whether these markers identify specific structural and functional subtypes of retinal ganglion cells [26][27][28][29] (but see Kö lsch et al 30 ). In rodents, more than 90% of retinal ganglion cells project to the SC 31,32 , and different retinal Review ganglion cell subtypes target distinct laminar depths in the superficial SC (sSC) 33 .…”

Circuit mechanisms for colour vision in zebrafish

“…While the adult crystalline cone-mosaic arrangement prevents numerical regional biases in the distribution of cones, adults nonetheless feature a pronounced ventro-temporal acute zone at the level of downstream circuits 57 which is structurally highly reminiscent of the larval one 35 . In fact, many (but not all) of the downstream retinal neurons in larvae, such as diverse genetically defined retinal ganglion cell types, have a direct counterpart in adults 58 . However, to what extent the adult retina exhibits larval-like anisotropies, including in spectral processing, remains largely unknown.…”

“…Beyond setting up this 'spectral layering' 33 , as a population bipolar cells further build on existing eye-wide cone asymmetries (for example, Figure 2B,C) to set up a profoundly asymmetrical inner retina 33,35,49,58,82 (Figure 3N; compare Figure 1H-J). To explore the many possible links between cell types, retinal structures, and their functions, it will be instrumental to further develop our genetic handle on bipolar cell types in zebrafish while in parallel pursuing detailed ultrastructural analysis of their synaptic connections, as is available for mice 76,83,84 .…”

“…If and how these putative circuits are combined at the level of the brain, presumably involving the 'prey-capture' centre AF7 106 , will be important to address in the future. This should be readily enabled by the recent availability of a transcriptomic atlas for zebrafish retinal ganglion cells 58 , which already identified one marker that specifically targets an acute-zone-biased and diffusely On-stratifying population of retinal ganglion cells. Investigating the spectral tuning of the 'AF7-adjacent KalTA4u508' neurons 111 , whose activity suffices to trigger prey-capture-like behaviour, should provide another important puzzle piece.…”