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The tetrapod double cone is a pair of tightly associated cones called the "principal" and the "accessory" member. It is found in amphibians, reptiles, and birds, as well as monotreme and marsupial mammals but is absent in fish and eutherian mammals. To explore the potential evolutionary origins of the double cone, we analyzed single-cell and -nucleus transcriptomic atlases of photoreceptors from six vertebrate species: zebrafish, chicken, lizard, opossum, ground squirrel, and human. Computational analyses separated the principal and accessory members in chicken and lizard, identifying molecular signatures distinguishing either member from single cones and rods in the same species. Comparative transcriptomic analyses suggest that both the principal and accessory originated from ancestral red cones. Furthermore, the gene expression variation among cone subtypes mirrors their spectral order (red → green → blue → UV), suggesting a constraint in their order of emergence during evolution. Finally, we find that rods are equally dissimilar to all cone types, suggesting that they emerged before the spectral diversification of cones.

How early sensory experience during "critical periods" of postnatal life affects the organization of the mammalian neocortex at the resolution of neuronal cell types is poorly understood. We previously reported that the functional and molecular profiles of layer 2/3 (L2/3) cell types in the primary visual cortex (V1) are vision-dependent (Tan et al., Neuron, 108 (4), 2020; Cheng et al., Cell, 185 (2), 2022). Here, we characterize the spatial organization of L2/3 cell types with and without visual experience. Spatial transcriptomic profiling based on 500 genes recapitulates the zonation of L2/3 cell types along the pial-ventricular axis in V1. By applying multi-tasking theory (Adler et al., Cell Systems, 8, 2019), we suggest that the spatial zonation of L2/3 cell types is linked to the continuous nature of their gene expression profiles, which can be represented as a 2D manifold bounded by three archetypal cell types ("A", "B", and "C"). By comparing normally reared and dark reared L2/3 cells, we show that visual deprivation-induced transcriptomic changes comprise two independent gene programs. The first, induced specifically in the visual cortex, includes immediate-early genes and genes associated with metabolic processes. It manifests as a change in cell state that is orthogonal to cell type-specific gene expression programs. By contrast, the second program impacts L2/3 cell type identity, regulating a subset of cell type-specific genes and shifting the distribution of cells within the L2/3 manifold, with a depression of the B-type and C-type and a gain of the A-type. Through an integrated analysis of spatial transcriptomic measurements with single-nucleus RNA-seq data from our previous study, we describe how vision patterns L2/3 cortical cell types during the postnatal critical period., Significance Statement: Layer 2/3 (L2/3) glutamatergic neurons are important sites of experience-dependent plasticity and learning in the mammalian cortex. Their properties vary continuously with cortical depth and depend upon experience. Here, by applying spatial transcriptomics and different computational approaches in the mouse primary visual cortex, we show that vision regulates orthogonal gene expression programs underlying cell states and cell types. Visual deprivation not only induces an activity-dependent cell state, but also alters the composition of L2/3 cell types, which are appropriately described as a transcriptomic continuum. Our results provide insights into how experience shapes transcriptomes that may, in turn, sculpt brain wiring, function, and behavior., Competing Interests: Declaration of interests The authors declare no competing interests.

Mouse whisker somatosensory cortex (wS1) is a major model system to study the experience-dependent plasticity of cortical neuron physiology, morphology, and sensory coding. However, the role of sensory experience in regulating neuronal cell type development and gene expression in wS1 remains poorly understood. We assembled and annotated a transcriptomic atlas of wS1 during postnatal development comprising 45 molecularly distinct neuronal types that can be grouped into eight excitatory and four inhibitory neuron subclasses. Using this atlas, we examined the influence of whisker experience from postnatal day (P) 12, the onset of active whisking, to P22, on the maturation of molecularly distinct cell types. During this developmental period, when whisker experience was normal, ~250 genes were regulated in a neuronal subclass-specific fashion. At the resolution of neuronal types, we found that only the composition of layer (L) 2/3 glutamatergic neuronal types, but not other neuronal types, changed substantially between P12 and P22. These compositional changes resemble those observed previously in the primary visual cortex (V1), and the temporal gene expression changes were also highly conserved between the two regions. In contrast to V1, however, cell type maturation in wS1 is not substantially dependent on sensory experience, as 10-day full-face whisker deprivation did not influence the transcriptomic identity and composition of L2/3 neuronal types. A one-day competitive whisker deprivation protocol also did not affect cell type identity but induced moderate changes in plasticity-related gene expression. Thus, developmental maturation of cell types is similar in V1 and wS1, but sensory deprivation minimally affects cell type development in wS1.

How does evolution act on neuronal populations to match computational characteristics to functional demands? We address this problem by comparing visual code and retinal cell composition in closely related murid species with different behaviours. Rhabdomys pumilio are diurnal and have substantially thicker inner retina and larger visual thalamus than nocturnal Mus musculus. High-density electrophysiological recordings of visual response features in the dorsal lateral geniculate nucleus (dLGN) reveals that Rhabdomys attains higher spatiotemporal acuity both by denser coverage of the visual scene and a selective expansion of elements of the code characterised by non-linear spatiotemporal summation. Comparative analysis of single cell transcriptomic cell atlases reveals that realignment of the visual code is associated with increased relative abundance of bipolar and ganglion cell types supporting OFF and ON-OFF responses. These findings demonstrate how changes in retinal cell complement can reconfigure the coding of visual information to match changes in visual needs., Competing Interests: Declaration of interests The authors declare no competing interests