M1-Type, but Not M4-Type, Melanopsin Ganglion Cells Are Physiologically Tuned to the Central Circadian Clock

Abstract

Proper circadian photoentrainment is crucial for the survival of many organisms. In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) can use the photopigment melanopsin to sense light independently from rod and cone photoreceptors and send this information to many brain nuclei such as the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker. Here, we measure ionic currents and develop mathematical models of the electrical activity of two types of ipRGCs: M1, which projects to the SCN, and M4, which does not. We illustrate how their ionic properties differ, mainly how ionic currents generate lower spike rates and depolarization block in M1 ipRGCs. Both M1 and M4 cells have large geometries and project to higher visual centers of the brain via the optic nerve. Using a partial differential equation model, we show how axons of M1 and M4 cells faithfully convey information from the soma to the synapse even when the signal at the soma is attenuated due to depolarization block. Finally, we consider an ionic model of circadian photoentrainment from ipRGCs synapsing on SCN neurons and show how the properties of M1 ipRGCs are tuned to create accurate transmission of visual signals from the retina to the central pacemaker, whereas M4 ipRGCs would not evoke nearly as efficient a postsynaptic response. This work shows how ipRGCs and SCN neurons' electrical activities are tuned to allow for accurate circadian photoentrainment.

Vision and sensorimotor defects associated with loss of Vps11 function in a zebrafish model of genetic leukoencephalopathy

“…However, detection of light and dark does not equate to visual acuity. In humans, intrinsically photosensitive ganglion cells (pRGCs) function in the light-induced pupillary light reflex, and some studies have suggested that they may also play a role in circadian rhythms and as a rudimentary light detector 26 . In zebrafish, which are semi-transparent during development, neurons in the hindbrain show non-visual sensation 27 , and zebrafish larvae lacking eyes and pineal gland still respond to light and perform light seeking behavior 28 .…”

Current Insights into Optimal Lighting for Promoting Sleep and Circadian Health: Brighter Days and the Importance of Sunlight in the Built Environment

“…[21][22][23][24] The most prominent of the connections is a monosynaptic pathway running along the retinohypothalamic tract to the brain's circadian pacemaker, the suprachiasmatic nucleus (SCN), which enables entrainment to light-dark cycles. [25][26][27][28] NIF processes mediated by pRGCs, including entrainment [29][30][31] but also light suppression of pineal melatonin synthesis [32][33][34][35][36] and light-mediated arousal, [36][37][38] exhibit short-wavelength sensitivity consistent with the action spectrum for melanopsin. Blind humans and animals with mutations causing degeneration of classic photoreceptors retain many NIF functions.…”

Intrinsically photosensitive retinal ganglion cells in glaucoma

“…When ipRGCs projecting to non-SCN and non-IGL (intergeniculate leaflet) brain targets are ablated (Rupp et al, 2019), mice retained circadian photoentrainment, while other functions, such as the pupillary light reflex and contrast sensitivity, showed deficits. Moreover, the M1 electrophysiological profiles are tuned to transmit accurate visual signals to the SCN (Stinchcombe et al, 2021). Therefore, M1 cell loss may lead to deficits in photoentrainment, which has been reported in several studies using rodent glaucoma models (Drouyer et al, 2008;De Zavalía et al, 2011).…”