Encoding of environmental illumination by primate melanopsin neurons.

Light regulates physiology, mood, and behavior through signals sent to the brain by intrinsically photosensitive retinal ganglion cells (ipRGCs). How primate ipRGCs sense light is unclear, as they are rare and challenging to target for electrophysiological recording. We developed a method of acute identification within the live, ex vivo retina. Using it, we found that ipRGCs of the macaque monkey are highly specialized to encode irradiance (the overall intensity of illumination) by blurring spatial, temporal, and chromatic features of the visual scene. We describe mechanisms at the molecular, cellular, and population scales that support irradiance encoding across orders-of-magnitude changes in light intensity. These mechanisms are conserved quantitatively across the ~70 million years of evolution that separate macaques from mice.

Optimized Signal Flow through Photoreceptors Supports the High-Acuity Vision of Primates.

The fovea is a neural specialization that endows humans and other primates with the sharpest vision among mammals. This performance originates in the foveal cones, which are extremely narrow and long to form a high-resolution pixel array. Puzzlingly, this form is predicted to impede electrical conduction to an extent that appears incompatible with vision. We observe the opposite: signal flow through even the longest cones (0.4-mm axons) is essentially lossless. Unlike in most neurons, amplification and impulse generation by voltage-gated channels are dispensable. Rather, sparse channel activity preserves intracellular current, which flows as if unobstructed by organelles. Despite these optimizations, signaling would degrade if cones were lengthier. Because cellular packing requires that cone elongation accompanies foveal expansion, this degradation helps explain why the fovea is a constant, miniscule size despite multiplicative changes in eye size through evolution. These observations reveal how biophysical mechanisms tailor form-function relationships for primate behavioral performance.

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina.

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity.

The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4(+)SNS-Cre/TdTomato(+), 2) IB4(-)SNS-Cre/TdTomato(+), and 3) Parv-Cre/TdTomato(+) cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation.