M4-ipRGCs regulate contrast sensitivity in vision.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice are comprised of at least 6 morphological subtypes, known as M1 to M6. While the M1-ipRGC subtype is well characterized, directly linking cellular manipulation of other subtypes to behavior remains challenging. However, recent transcriptomic studies revealed molecular heterogeneity within ipRGC subtypes that may help bridge this gap. Here, we use intersectional genetics for targeted in-vivo manipulation of a single ipRGC-type, the M4-ipRGC, also known as the ON-sustained alpha ganglion cell. Central projections of M4-ipRGC axons avoid the hypothalamus, including the suprachiasmatic nucleus, but abundantly innervate image-processing regions, particularly the nucleus of the optic tract. Chemogenetic activation of M4-ipRGCs enhances contrast sensitivity in behavioral and physiological tests, whereas chemogenetic inhibition reduces contrast sensitivity. This work presents a robust method for studying behaviors driven by a single ipRGC subtype in-vivo, and highlights the crucial role of M4-ipRGCs in visual tracking and contrast sensitivity.