Architecture of retinal projections to the central circadian pacemaker

Abstract

The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/ gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCNprojecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.melanopsin | circadian | suprachiasmatic nucleus | non-image-forming functions | ipRGCs T he suprachiasmatic nucleus (SCN) houses a central pacemaker that orchestrates circadian (circa: "about" and diem: "day") behaviors that cycle with a period close to 24 h. This endogenous clock is self-sustained even in the complete absence of external stimuli, but can be entrained to the light/dark cycle of the solar day in a process defined as circadian photoentrainment (1). In mammals, phototransduction solely occurs in the retina (2). Retinal ganglion cells (RGCs) are projection neurons of the retina that send light information to brain targets (3). Although the majority of RGCs project to brain areas involved in object tracking and image formation, some RGCs also innervate non-image-forming brain regions to influence circadian activity, sleep, the pupillary light response, mood, and learning functions (4).Recent studies showed that a small subpopulation of RGCs expresses a photopigment called melanopsin (Opn4), making these cells intrinsically photosensitive (ip)RGCs (5-7). It is now known that there are at least five different ipRGC subtypes (M1-M5) (8, 9). Using genetic tracing techniques, it was shown that ipRGCs send projections to non-image-forming centers in the brain, including the SCN, which receives retinal input predominantly from M1 ipRGCs (10-12) and to a lesser extent from M2 ipRGCs (12). The SCN is a smal...

The flexible clock: predictive and reactive homeostasis, energy balance and the circadian regulation of sleep–wake timing

“…First, direct and indirect projections from light-capturing retinal ganglion cells reach neurons of the SCN, modulating their activity (Abrahamson and Moore, 2001;Edelstein and Amir, 1999;Fernandez et al, 2016;Michel et al, 2006;Nakamura et al, 2004). Depending on the phase of the receiving SCN neuron, light input can stimulate active firing of the neuron and modulate clock gene expression (Brown and Piggins, 2007;Hamada et al, 2001; but also see Drouyer et al, 2007, highlighting SCN heterogenetity in this response).…”

Clinical Significance and Pathogenesis of Visual Impairment in Parkinson’s Disease

“…The retinothalamic system transmits critical information about circadian rhythms, thanks to which biological rhythms, the wake-sleep cycle are regulated, locomotive activity and food consumption change during a day, etc. Most fibers comprised in this system are axons of RGC [10,11]. There also is the centrifugal hypothalamoretinal pathway starting from the hypothalamic neurosecreting fibers and finishing in the RGC, etc.…”

“…There also is the centrifugal hypothalamoretinal pathway starting from the hypothalamic neurosecreting fibers and finishing in the RGC, etc. Nowadays it is well known that this pathway is used in regulating retinal vascular pressure, changing retinal electric potential, regulates light sensitivity and adaptation of the eyes to darkness [10,11]. This aspect is crucial in understanding some disorders in the visual system in PD, e.g., association of visual hallucinations with evening and/or night time, etc.…”

Image and Non-Image Forming Melanopsin Function in Age-Related Macular Degeneration

“…At least five different ipRGC subtypes (M 1 -M 5 ) (Ecker et al 2010;Schmidt et al 2011a) have been identified that project to non-image forming centres in the rodent brain, with the M 1 and M 2 subtypes likely to be homologous to the outer and inner stratifying melanopsin cells found in humans and non-human primates (Dacey et al 2005;Jusuf et al 2007;Liao et al 2016). A recent mouse study using single M 1 ipRGC axonal tracing and confocal microscopic analysis identified up to five different brain targets that received input from a single M 1 subtype ipRGC, indicating that a single ipRGC can affect brain areas involved in numerous lightmediated behaviours (Fernandez, Chang, Hattar & Chen 2016). Therefore, the correlation between poorer sleep efficiency and reduced PIPR may be attributed to individual M 1 ipRGCs projecting to both the SCN and OPN.…”

“…A more recent mouse study using single M 1 ipRGC axonal tracing and confocal microscopic analysis identified up to five different brain targets that received input from a single M 1 subtype ipRGC, indicating that a single retinal cell can affect brain areas involved in numerous light-mediated behaviours (Fernandez et al 2016).…”