Fig. 3: The light entrainment of OPN4 on circadian rhythms may involve multiple neural projection pathways, including neurotransmitters or neuropeptides.

ipRGCs are a class of retinal ganglion cells that express OPN4 (red) and can transmit OPN4-mediated photosensitive signals to the SCN via RHT projections. a Vglut2, but not Vglut1, packages glutamate (solid blue circles) into synaptic vesicles in these axons. These ipRGCs axons mainly make synaptic contacts with VIP neurons (green), AVP (pink), and other light-responsive neurons (gray) in the SCN^169,170. The VIP neurons form part of the SCN core region and may communicate with AVP neurons via VIP receptor type 2. b Some ipRGC axons can also release PACAP (solid brown circles) to regulate VIP neurons via VPAC₂ and PAC₁ receptors¹⁷¹. In addition, some OPN4-expressing ipRGCs also expressed VP (solid pink circles). c The axons of these ipRGCs are glutamatergic and VP-positive, and light stimulation can affect their secretion of VP. VP⁺ ipRGCs showed synaptic co-localization with GRP (yellow) and VIP neurons, but VP⁺ ipRGCs were not directly connected to AVP neurons¹³⁵. d Some ipRGCs expressed GAD2 and could transmit GABA (solid purple circles) to the SCN regions. These GABAergic signals can excite or inhibit some SCN neurons, including VIP neurons, and maintain the homeostasis of the central rhythms¹⁴⁴. AVP arginine vasopressin, GAD2 glutamic acid decarboxylase 2, GABA γ-aminobutyric acid, GRP gastrin releasing peptide, ipRGC intrinsically photosensitive retinal ganglion cell, RHT retinal hypothalamic tract, SCN supra-chiasmatic nucleus, VIP vasoactive intestinal peptide, VP vasopressin, PACAP pituitary adenylate cyclase-activating peptide.