Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs

Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and regulate a wide array of light-dependent physiological processes1–11. Genetic ablation of ipRGCs eliminates circadian photoentrainment and severely disrupts the pupillary light reflex (PLR)12,13. Here we show that ipRGCs consist of distinct subpopulations that differentially express the Brn3b transcription factor, and can be functionally distinguished. Brn3b-negative M1 ipRGCs innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, whereas Brn3b-positive ipRGCs innervate all other known brain targets, including the olivary pretectal nucleus. Consistent with these innervation patterns, selective ablation of Brn3b-positive ipRGCs severely disrupts the PLR, but does not impair circadian photoentrainment. Thus, we find that molecularly distinct subpopulations of M1 ipRGCs, which are morphologically and electrophysiologically similar, innervate different brain regions to execute specific light-induced functions.

Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells

“…Brn3b-negative M1 pRGCs that project to the SCN are capable of driving circadian entrainment following the genetic ablation of all other pRGCs (Brn3b-positive and including M1-M5 pRGCs). 38 The ablation of all Brn3b-positive M1-M5 pRGCs was also shown to disrupt the PLR, yet, given the widespread loss of pRGC subtypes using this approach, it is not possible to conclude from this study which class of pRGC mediates the PLR or other behaviours. However, the timeline with which M1 cells innervate the shell of the OPN coincides with the development of the PLR, 37 and the selective ablation of M1-type pRGCs has been shown to severely impair the PLR.…”

“…To date at least five distinct subtypes of pRGC have been identified, termed M1-M5-type pRGCs. 1,2,[32][33][34][35] These cells show differences in morphology and retinal connections, and exhibit light responses with markedly different kinetics and sensitivities ( Figure 1b) [32][33][34][37][38][39] (Figure 1c), and would therefore seem to be tasked with performing different physiological roles (for review see Schmidt et al 36,40 ). However, the innervations of each class of pRGC are only partially resolved, and the specific roles performed by each class of pRGC are yet to be fully determined.…”

“…To date only one study has shown a direct link between distinct populations of pRGCs and behavioural responses. 38 Chen et al 38 show that M1-type pRGCs that innervate the SCN and OPN are two molecularly distinct subtypes of M1-type pRGCs, distinguished by their differential expression of the transcription factor Brn3b. Brn3b-negative M1 pRGCs that project to the SCN are capable of driving circadian entrainment following the genetic ablation of all other pRGCs (Brn3b-positive and including M1-M5 pRGCs).…”

Pupillary light reflex and circadian synchronization in the elderly

“…Thus, the SCN, our inner master clock that controls the day-night cycle, fails to receive adequate information from ipRGCs for synchronization. Initial attempts to monitor the function of ipRGCs using chromatic pupillometry showed that specific light stimuli can help distinguish between cone functions with and without ipRGC input by looking at the post-illumination pupillary light reflex (PIPLR), since ipRGCs are related to the PIPLR (Chen, Badea, & Hattar, 2011;Park et al, 2011).…”

“…Thus, the SCN, our inner master clock that controls the day-night cycle, fails to receive adequate information from ipRGCs for synchronization. Initial attempts to monitor the function of ipRGCs using chromatic pupillometry showed that specific light stimuli can help distinguish between cone functions with and without ipRGC input by looking at the post-illumination pupillary light reflex (PIPLR), since ipRGCs are related to the PIPLR (Chen, Badea, & Hattar, 2011;Park et al, 2011).To evaluate whether one cause of bad sleep behavior in obviously demented elderly might be a dysfunction in ipRGCs, preclinical testing was performed at two homes for the elderly near Vienna, Austria, first to test its acceptance and feasibility with this population, and then to evaluate individual PIPLRs and optimize the screening method. A total of 31 participants aged 60-99 years (M = 84.2, SD = 8.8) were tested, consisting of 23 females (60-99 years, M = 85.0, SD = 8.4) and eight males (65-95 years, M = 81.9, SD = 9.4).…”