1. Introduction
For the greater part of 150 years it was assumed that the mammalian retina contained only two classes of photoreceptors, rods and cones. However, a flurry of studies in the late 1990s and early 2000s demonstrated the existence of a third class of mammalian photoreceptors that differs greatly from rods and cones. It utilizes a different photopigment, is much less sensitive to light, responds to light far more slowly, and has far lower spatial resolution, characteristics that fit with its primary function of signaling ambient light levels (irradiance) to the brain. Most surprisingly, these photoreceptors are retinal ganglion cells (RGCs), and thus, have the unique ability to communicate directly with higher visual centers of the brain. These intrinsically photosensitive retinal ganglion cells (ipRGCs) are a rare subpopulation of ganglion cells (<5%) whose primary role is to signal light for largely subconscious, non-image-forming visual reflexes, such as pupillary constriction, neuroendocrine regulation, and synchronizing daily (“circadian”) physiological rhythms to the light/dark cycle (“circadian photoentrainment”). Recent research has revealed additional roles for ipRGCs in conscious visual perception, including brightness discrimination and contrast detection. Many visual behaviors under ipRGC control are remarkably tonic, and require prolonged integration of ambient light levels. The unique properties of ipRGCs make them well suited for regulating such behaviors.
2. History and discovery
As a graduate student in 1923, Clyde Keeler made a number of interesting observations from mice that had severe outer retinal degeneration (Keeler et al. 1928; Van Gelder 2008). Though they lacked most of their rod and cone photoreceptors, and were considered functionally blind, these mice were still able to constrict their pupils in response to light (Keeler 1927), leading Keeler to deduce that some other photoreceptive cells must be lurking in the retina. But an alternative, more parsimonious explanation for these pupil reflexes was that they were driven by the small number of surviving cone photoreceptors, and so the existence of non-rod non-cone photoreceptors remained uncertain. Seven decades later, Russell Foster and colleagues engineered mice that lacked all rods and cones, which displayed not only robust pupillary light reflexes, but also maintained the ability to shift their circadian rhythms in accordance with shifting light cycles, and to suppress nocturnal pineal melatonin secretion in response to light pulses (Freedman et al. 1999; Lucas et al. 1999). These processes disappeared, however, when animals had their eyes removed, strongly supporting Keeler’s prediction of a novel ocular photoreceptor (Klein and Weller 1972). But it wasn’t until the discovery of a new light-sensitive molecule (or opsin), from an unlikely source, that Keeler’s prediction would prove true.
Iggy Provencio and colleagues, studying the photosensitive skin cells (“dermal melanophores”) of frogs, cloned a novel opsin-like molecule which they proposed was responsible for the redistribution of skin pigment in response to light (Provencio et al. 1998). Orthologs of this putative opsin, which Provencio et al. called melanopsin, were also found to be expressed in a small subset of RGCs in mouse (Fig. 1A) and human retinas (Provencio et al. 1998; Provencio et al. 2000; Provencio et al. 2002), and additional work found that melanopsin-containing cells send their axons to the suprachiasmatic nucleus (SCN), the site of the mammalian central circadian clock (Gooley et al. 2001; Hannibal et al. 2002).
These findings suggested that these RGCs could be the mysterious third photoreceptor type Keeler had predicted almost 80 years earlier. They express a putative opsin, potentially allowing them to directly respond to light, and they send axon projections to a brain target known to be involved in two of the visual reflexes observable in rodless/coneless mice, i.e. circadian photoentrainment and photic suppression of pineal melatonin release. However, definitive proof that these melanopsin-containing, SCN-projecting RGCs could directly sense light was still lacking. Combining tracer injections into the SCN with electrophysiology, David Berson and colleagues tested the hypothesis that SCN-projecting RGCs are photoreceptive. They made whole-cell recordings from RGCs retrogradely labeled by the tracers (Fig. 1B), and found that these cells were indeed able to respond to light in the presence of a cocktail of drugs that eliminated all rod and cone signaling in the retina (Fig. 1C, top) (Berson et al. 2002). Even after mechanical isolation from the rest of the retina, these cells were still photosensitive (Fig. 1C, bottom), leaving to rest all doubts that the labeled RGCs were true photoreceptors (Berson et al. 2002). Immunohistochemistry performed after whole-cell recording confirmed the presence of melanopsin in these SCN-projecting cells (Hattar et al. 2002). The morphology and distribution of these SCN-projecting ipRGCs are illustrated in Fig. 2.
3. Melanopsin
We now know that the ability of ipRGCs to respond directly to light is indeed due to their expression of melanopsin. The melanopsin gene (opn4) has been found in many mammalian species, e.g. mice, monkeys, and humans (Provencio et al. 2000). Hydrophobicity analysis of melanospin’s amino-acid sequence predicted a 7-transmembrane structure, common to all G protein-coupled receptors (Fig. 3A,B) (Provencio et al. 1998). Interestingly, melanopsin shares higher homology with the rhabdomeric opsins (r-opsins) of invertebrate photoreceptors than with the ciliary opsins (c-opsins) of vertebrate photoreceptors, suggesting that melanopsin could signal light through a different phototransduction mechanism than that used in vertebrate rods and cones (Fig. 3C) (Provencio et al. 1998) (see “Phototransduction” below).
We now know that the ability of ipRGCs to respond directly to light is indeed due to their expression of melanopsin. The melanopsin gene (opn4) has been found in many mammalian species, e.g. mice, monkeys, and humans(Provencio et al. 2000). Hydrophobicity analysis of melanospin’s amino-acid sequence predicted a 7-transmembrane structure, common to all G protein-coupled receptors (Figure 3, A,B)(Provencio et al. 1998). Interestingly, melanopsin shares higher homology with the rhabdomeric opsins (r-opsins) of invertebrate photoreceptors than with the ciliary opsins (c-opsins) of vertebrate photoreceptors, suggesting that melanopsin could signal light through a different phototransduction mechanism than that used in vertebrate rods and cones (Figure 3, C)(Provencio et al. 1998) (see “Phototransduction” below). (For further information on opsins, see the Webvision chapter on Evolution of Phototransduction.)
Although the first studies of ipRGCs implicated melanopsin as the photopigment in these cells, a role for a group of blue-light-absorbing flavoproteins known as cryptochromes could not be initially ruled out (Berson 2007). Cryptochromes function as photopigments in plants and invertebrate animals, and early studies favored their functioning as retinal photopigments in the mammalian circadian system (Kavakli and Sancar 2002; Van Gelder et al. 2002). However, subsequent work provided overwhelming evidence that melanopsin is the photopigment in ipRGCs. When the melanopsin gene was deleted via transgenic techniques in mice (“melanopsin-knockout mice”), RGCs retrogradely labeled from the SCN no longer could respond directly to light (Lucas et al. 2003). In addition, animals missing the melanopsin gene showed deficiencies in multiple visual reflexes such as pupillary constriction and photoentrainment (Hattar et al. 2003; Lucas et al. 2003; Panda et al. 2003; Panda et al. 2002; Ruby et al. 2002). Despite this evidence, there were still controversies regarding melanopsin’s ability to function as a photopigment. For example, it remained possible that melanopsin is not the ipRGC photopigment, but is instead an isomerase essential for the proper functioning of the ipRGC photopigment. These doubts were firmly extinguished with a series of experiments whereby the melanopsin gene was heterologously expressed in multiple cell types that are normally insensitive to light. When made to express melanopsin, these cells were able to robustly respond to light, indicating melanopsin’s ability to function as a bona fide photopigment (Melyan et al. 2005; Panda et al. 2005; Qiu et al. 2005).
4. Phototransduction
As seen in Fig. 4, the intrinsic light response of ipRGCs differs dramatically from those of rods and cones. Most notable, is the difference in response polarity: the direct photoresponse of ipRGCs is depolarizing, whereas rods and cones hyperpolarize to light. In addition, ipRGCs are much less sensitive to light than the classical photoreceptors, and signal with far slower kinetics (Fig. 4A) (Berson et al. 2002; Do et al. 2009). IpRGCs are also capable of very long-lasting light responses, faithfully encoding stimulus energy over relatively long periods of time (Fig. 4C). This feature sets ipRGCs apart from all other mammalian RGCs, which cannot stably represent ambient light levels in this fashion (Barlow and Levick 1969; Wong 2012; Wong et al. 2007). Another remarkable feature of ipRGC physiology is the ability of their dendrites (which contain melanopsin) to respond directly to light (Berson et al. 2002). Combined with their large overlapping dendritic fields, the entire ipRGC population creates what Provencio and colleagues called a “photoreceptive net” (Provencio et al. 2002). These characteristics of ipRGCs are no doubt tailored to their role in signaling diffuse ambient light levels over many hours for tonic, non-image-forming visual behaviors such as photoentrainment and pupillary reflex. A further distinction of ipRGCs is their action spectrum (i.e. wavelength-sensitivity function), due to the utilization of melanopsin as their photopigment. IpRGC photoreception is most sensitive to light at around 480 nm (Berson et al. 2002; Dacey et al. 2005; Tu et al. 2005), significantly different (≥20 nm) from the best wavelengths for stimulating rods and cones (Fig. 4B).
As noted earlier, animal photoreceptors come in two basic flavors: rhabdomeric (found mainly in invertebrates), and ciliary (vertebrate rods and cones being most notable). A defining feature of rhabdomeric and ciliary photoreceptors is the distinct biochemical cascades both cell classes use to transduce light energy into an electrical signal the brain can interpret. Rods and cones use a cascade involving cyclic guanosine monophosphate (cGMP) as a second messenger (Fig. 5B) (Arendt 2003; Fu and Yau 2007). The response to light is a decrease in cGMP levels which closes cGMP-gated cation channels, causing the plasma membrane to hyperpolarize. This is in stark contrast to rhabdomeric photoreceptors which use a phosphoinositide signaling cascade involving the enzyme phospholipase C (PLC) and breakdown of the membrane lipid phosphatidylinositol bisphosphate (PIP2) (Fig. 5A), leading to the opening of cation channels and membrane depolarization (Hardie 2001; Hardie and Raghu 2001). In addition, although both phototransduction cascades are G protein-mediated, the specific G proteins required are different. Ciliary photoreceptors require transducin, a member of the Gi/o family of G proteins, whereas rhabdomeric photoreceptors use a G protein of the Gq/11 family (Fig. 5).
Just like rod and cone photopigments, melanopsin uses 11-cis-retinal as their light-absorbing chromophore, and light-induced isomerization of 11-cis-retinal to all-trans-retinal is the first step in the phototransduction process (Hubbard and Kropf, 1958; Fu et al. 2005; Walker et al. 2008). However, melanopsin’s relatively high homology with invertebrate opsins and the depolarizing intrinsic light response of ipRGCs suggest these neurons may use a rhabdomeric phototransduction cascade distinct from rods’ and cones’ ciliary cascade. Early pharmacological studies of ipRGCs could not confirm this hypothesis, most likely due to the whole-mount retina preparation employed. The combination of photosensitive ipRGC dendrites buried deep within the inner plexiform layer (IPL, where synapses are formed among bipolar, amacrine and ganglion cells) and a glial membrane sheath covering the retinal surface, created a significant diffusion barrier for pharmacological agents, especially hydrophobic drugs commonly used to study transduction mechanisms. To overcome this hurdle, David Berson and colleagues recorded from mechanically dissociated ipRGC somas to facilitate pharmacological manipulation. Isolated ipRGCs survive remarkably well in culture, generating robust light responses for up to 6 days. Using this system, Berson et al. showed that ipRGC phototransduction utilizes a rhabdomeric-like phosphoinositide cascade, requiring a member (or possibly members) of the Gq/11 family of G proteins and the effector enzyme phospholipase C (PLC) (Fig. 6) (Graham et al. 2008) (but see(Chew et al. 2014). In addition, the presence of specific Gq/11 and PLC isoforms was confirmed in ipRGCs using single-cell RT-PCR and immunocytochemistry, consistent with the pharmacological findings (Graham et al. 2008). Genetically knocking out the β4 isoform of PLC nearly eliminated the intrinsic light response of ipRGCs (Xue et al. 2011).
In rhabdomeric photoreceptors, breakdown of PIP2 by PLC generates two by-products: a membrane-bound component called diacylglycerol (DAG), and inositol-triphosphate (IP3), which is free to move about the cytosol (Hardie 2001). DAG can be broken down within the membrane into polyunsaturated faty acids (PUFAs), which have been shown to directly open Drosophila photoreceptors’ Transient Receptor Potential (TRP) channels (Chyb et al. 1999). IP3, on the other hand, can cause release of Ca2+ from intracellular stores, which can lead to the opening of so called “store-operated channels” in the plasma membrane. In Drosophila photoreceptors the downstream mechanism linking PIP2 breakdown to TRP channel opening is still unclear, although a membrane-associated pathway is likely (Acharya et al. 1997). In ipRGCs, the light-gated cation channels are also TRP channels, specifically, TRPM6 and TRPM7 (Xue et al. 2011), and data strongly suggest that the cytosolic IP3 pathway is not required for phototransduction, similar to Drosophila photoreceptors (Fig. 7) (Graham et al. 2008). Intracellular application of high concentrations of IP3 neither induced a current, nor did it occlude light responses in ipRGCs (Fig. 7A), although it did modulate certain response properties, suggesting a non-essential secondary role for IP3 and intracellular Ca2+. Likewise, ipRGC phototransduction survived blockade of IP3 receptors with intracellular heparin, or intracellular Ca2+ store depletion using thapsigargin (Fig. 7A). Only after extended exposure to very high (10mM) concentrations of the general Ca2+ chelator BAPTA, does one see significant attenuation of phototransduction (Graham et al. 2008), although this is probably a side effect of clamping resting intracellular Ca2+ levels so low that enzymes such as PLC are no longer able to function (Hardie 2005). The most compelling evidence that ipRGC phototransduction does not require the cytosolic IP3 branch is that excised patches of ipRGC membrane (both outside-out and inside-out) remained autonomously photosensitive (Fig. 7B), ruling out a vital role for highly diffusible cytosolic components (Graham et al. 2008). Based on these findings, all the necessary components for ipRGC phototransduction appear to be within, or tightly coupled to, the plasma membrane.
The exact channel-gating mechanism downstream of PLC activation is still not clear. Application of DAG or PUFAs, either to isolated ipRGC somas or to excised patches of ipRGC membrane, failed to evoke a current or to block light responses (Fig. 8A-D). An alternative hypothesis, and one in line with a membrane-associated transduction cascade, is that the breakdown of PIP2 itself (as opposed to production of DAG or PUFAs) is the critical signal that opens the light-gated TRP channels in ipRGCs. There is evidence that PIP2 can either open or close a variety of ion channels, including the light-gated channels in Drosophila photoreceptors (Hardie 2003; Suh et al. 2006). As a preliminary test of this hypothesis, Berson et al. pharmacologically interfered with PIP2 synthesis using wortmannin. This drug inhibits phosphoinositide 4-kinase (PI4-K), the synthetic enzyme for phosphatidylinositol 4-phosphate (PIP), which is an essential precursor of PIP2. According to the hypothesis, wortmannin should slow the termination of the photocurrent at light offset by delaying the restoration of resting levels of PIP2 and, hence, the closure of the light-gated channels. Indeed, when wortmannin was included in the recording pipette solution, response shutoff was dramatically delayed (Fig. 8E). Further and more direct evidence, however, is needed to resolve the gating mechanism of the light-modulated channels in ipRGCs.
5. Synaptic input
Although ipRGCs can function as photoreceptors, they nevertheless receive intraretinal synaptic input from rod/cone-driven circuits. Electron microscopy revealed synaptic contacts made by amacrine and bipolar cells onto melanopsin-immunopositive processes in the IPL (Belenky et al. 2003). Thus, ipRGCs respond to light not only directly through melanopsin, but also indirectly through synaptically mediated input from rods and cones (Dacey et al. 2005; Perez-Leon et al. 2006; Weng et al. 2013; Wong et al. 2007; Zhao et al. 2014). Both the intrinsic light response and the extrinsic, rod/cone-driven light response are remarkably tonic and can signal light continuously for at least 10 hours (Wong 2012). Moreover, the receptive fields for both response components are coextensive with each ipRGC’s dendritic field (Wong et al. 2007). However, these components are drastically different in two important ways. Firstly, whereas the intrinsic photoresponse is very sluggish, the extrinsic response is as rapid as the light responses of conventional RGCs (Fig. 9) (Wong et al. 2007). The intrinsic response integrates photons over many seconds, while the extrinsic response enables ipRGCs to track rapid changes in light intensity (Do et al. 2009; Wong et al. 2007). Secondly, the intensity thresholds for rod input, cone input and melanopsin phototransduction are vastly different, roughly 7 log photons cm-2 s-1, 9 log photons cm-2 s-1 and 11 log photons cm-2 s-1 , respectively (Dacey et al. 2005; Zhao et al. 2014). The different dynamic ranges of synaptic input and intrinsic photoreception enable ipRGCs to encode light intensities spanning at least 9 orders of magnitude (Dacey et al. 2005).
Using whole-cell voltage-clamp recordings combined with pharmacology, investigators demonstrated that SCN-projecting ipRGCs have spontaneous inhibitory and excitatory synaptic inputs in the dark, and that they express receptors for glutamate, GABA and glycine (Perez-Leon et al. 2006; Wong et al. 2007). Light stimulation increases both excitatory glutamatergic input and inhibitory GABA/glycinergic input, which are presumably mediated by bipolar and amacrine cells, respectively (Wong et al. 2007). Both inputs evoke primarily ON light responses, although comparatively weak OFF responses can also be seen under some conditions (Schmidt and Kofuji 2010; Wong et al. 2007; Zhao et al. 2014). This predominating ON-channel input was surprising because SCN-projecting ipRGCs’ dendrites are found mainly in the distal half of the IPL, which had been assumed for decades to be the “OFF” sublamina where RGCs receive input only from OFF bipolar cells but not ON bipolars (Famiglietti and Kolb 1976; Nelson et al. 1978). ON bipolar cells use two unconventional strategies to release glutamate onto the dendrites of SCN-projecting mouse ipRGCs in the “OFF” sublamina. Some ON bipolar cells’ axons extend lateral protrusions that contain synaptic vesicles (Fig. 10A), whereas others possess en passant (in passing) synaptic vesicles within their axonal shafts (Dumitrescu et al. 2009). Distally stratifying ipRGCs are also present in rabbit, marmoset and macaque retinas, and they likewise receive unconventional ON bipolar input in the “OFF” sublamina (Fig. 10C) (Grunert et al. 2011; Hoshi et al. 2009).
The mammalian retina contains about a dozen types of bipolar cells and over 20 types of amacrine cells (Kolb et al., 1981; Masland 2011) (and see webvision chapter “roles of amacrine cells). In mice, the ON bipolar cells that use axonal side branches to contact “OFF”-sublamina ipRGC dendrites appear to be type-6 cone bipolar cells (Fig. 10A) (Dumitrescu et al. 2009). Transsynaptic viral tracing has shown that these “OFF”-sublamina ipRGC dendrites are also directly postsynaptic from dopaminergic amacrine cells which costratify with these ipRGC dendrites (Viney et al. 2007). As will be discussed in detail in “Adaptation, neuromodulation, and circadian control” below, ipRGCs receive modulatory input from dopaminergic amacrine cells (Van Hook et al. 2012; Vugler et al. 2007b). Transsynaptic viral tracing also revealed that proximally stratifying mouse ipRGCs with dendrites in the “ON” sublamina (see “Morphological and physiological diversity” below) are directly postsynaptic from type-8 ON cone bipolar cells and another type of monostratified amacrine cell (Fig. 10B) (Viney et al. 2007). In rabbits and primates, distally stratifying ipRGCs are contacted by a type of calbindin-positive ON cone bipolar cell (Fig. 10C) (Hoshi et al. 2009) and DB6 ON cone bipolars (Fig. 10D) (Grunert et al. 2011), respectively. Besides receiving direct ON cone bipolar input, ipRGCs also receive ON rod bipolar input, albeit polysynaptically just like for all other mammalian RGCs (Grunert et al. 2011; Weng et al. 2013). Specifically, ipRGCs receive ON rod bipolar input through AII amacrine cells making gap junctions onto ON cone bipolars, which then synapse on ipRGCs. Another putative pathway that affects ipRGCs may be added by centrifugal fibers entering the retina. These centrifugal fibers are known to be histaminergic (Gastinger et al. 1999) and they have an effect on dopaminergic amacrine cells in mouse retina through H1 receptors (Frazao et al. 2011). The synaptic input to “OFF”-stratifying ipRGCs is summarized in Fig. 11.
6. Intraretinal synaptic output
Besides receiving intraretinal synaptic input, ipRGCs mediate intraretinal synaptic output. For many decades, RGCs were thought to function strictly as retinal output neurons, signaling only to higher visual centers of the brain. But there is electron microscopy evidence that RGC dendrites are presynaptic in catfish (Sakai et al. 1986), and more recent work by Douglas McMahon and coauthors yielded evidence that ipRGCs signal to a subpopulation of dopaminergic amacrine cells (DA cells). Dopamine released by DA cells diffuses throughout the retina and reshapes the functional properties of retinal circuits according to current lighting conditions and time of day, and thus allow the retina to be a more dynamic system (Dowling 2012). DA cells come in three flavors showing transient, sustained and null responses to light (Zhang et al. 2007). The light responses of the transient DA cells were eliminated by L-AP4, which blocks rod/cone signaling to ON bipolar cells (Fig. 12A). By contrast, the sustained DA cells remained light-responsive in the presence of L-AP4 (Fig. 12B), or in rod/cone degenerate retinas (Zhang et al. 2008). In the presence of L-AP4, the sustained DA cells’ light responses peaked at a wavelength near 480nm (Fig. 12C), matching very well with a melanopsin-based input (Zhang et al. 2008; Zhang et al. 2007). In melanopsin-knockout mice, blocking ON bipolar input with L-AP4 abolished all DA cells’ light responses, confirming that the L-AP4-resistant photoresponse originates from ipRGCs (Zhang et al. 2012).
In addition, staining for cFos, an immediate early gene used to mark activated neurons, showed that roughly the same percentage of DA cells was activated by sustained light in rod/cone degenerate retinas as retinas injected with L-AP4 (Fig. 13) (Zhang et al. 2008). Knocking out melanopsin suppressed light-induced dopamine release (Dkhissi-Benyahya et al. 2013). These observations strongly suggest that sustained DA cells receive input from ipRGCs. Both DA cells and SCN-projecting ipRGCs have dendrites stratifying in the outermost sublayer of the IPL, raising the possibility that these ipRGC dendrites signal directly to the DA dendrites (Viney et al. 2007; Vugler et al. 2007b).
Another plausible transmission route has been suggested by the observation that some ipRGCs extend axon collaterals toward the IPL (Fig. 14) (Joo et al. 2013). In support of the latter possibility, blocking voltage-gated Na+ channels (which are present in RGC axons) with tetrodotoxin suppressed ipRGC signaling to DA cells (Prigge and Zhang 2015). Antagonizing AMPA/kainate receptors also disrupted ipRGC output to DA cells (Zhang et al. 2012) , suggesting ipRGCs signal to DA cells by releasing glutamate in a Na+ spike-dependent manner.
IpRGC signaling to sustained DA cells can account for the light-induced secretion of dopamine in rat retinas with severe rod/cone degeneration (Morgan and Kamp 1980; Vugler et al. 2007a) (but see(Cameron et al. 2009). Because dopamine is known to play myriad modulatory roles throughout the retina, intraretinal output from ipRGCs to DA cells could influence image-forming retinal circuits, and several studies have reinforced this possibility. Using a non-invasive field-potential recording technique called the electroretinogram, Mark Hankins and Rob Lucas found that prolonged nocturnal light exposure altered the photoresponse kinetics of ON bipolar cells in human subjects (Fig. 15). This effect exhibited a remarkably long integration time and was most optimally induced by 483 nm light, implicating a melanopsin-based mechanism (Hankins and Lucas 2002). The same researchers later observed diurnal rhythms in the amplitude and kinetics of the mouse electroretinogram, which were abolished upon knocking out melanopsin (Barnard et al. 2006). Additional evidence for ipRGC regulation of retinal function came from a study by Ouria Dkhissi-Benyahya et al. examining clock gene expression in rods and cones. In wild-type mice, the expression of these clock genes (which are thought to drive circadian rhythms within the retina) exhibits a daily rhythm, but when melanopsin was knocked out, this rhythm was dampened substantially (Dkhissi-Benyahya et al. 2013).
Ca2+ imaging has suggested an additional potential pathway for intraretinal signaling by ipRGCs. Under normal physiological conditions, about 3% of ganglion cell layer (GCL) cells in rodless coneless mouse retinas showed increases in Ca2+ dye signals in response to light, but in the presence of the gap junction blocker carbenoxolone, this percentage dropped to ~1%, leading the authors to propose that ipRGCs propagate their light responses to amacrine cells in the GCL (“displaced amacrine cells”) via gap junctions (Sekaran et al. 2003). But subsequent research showed that carbenoxolone has various non-specific effects, and can abolish light-driven increases in Ca2+ signals even in mechanically dissociated ipRGCs (Bramley et al. 2011). Nonetheless, tracer dye coupling between ipRGCs and displaced amacrines has been observed (Muller et al. 2010), and so gap-junction-mediated intraretinal signaling by ipRGCs remains a possibility.
7. Morphological and physiological diversity
The SCN-projecting rat and mouse ipRGCs appear to be morphologically homogeneous, suggesting they constitute a single cell type (but see(Baver et al. 2008). All such cells have somas medium in size among GCL neurons and sparse dendrites terminating in the outermost sublayer (“S1”) of the IPL, corresponding to the main plexus of melanopsin-immunoreactive dendrites (Fig. 16A-C,G) (Berson et al. 2002; Hannibal et al. 2002; Hattar et al. 2002). However, a number of studies from the early 2000s implicated the existence of multiple types of ipRGCs. For example, there is an additional plexus of melanopsin-positive dendrites in the innermost sublayer (“S5”) of the IPL (Provencio et al. 2002). Ca2+ imaging and “blind” multielectrode-array extracellular spike recording also revealed diverse melanopsin-mediated light responses in the GCL (Sekaran et al. 2003; Tu et al. 2005).
Using various fluorescent labeling techniques, subsequent work revealed the existence of five morphological types of melanopsin-expressing ipRGCs in the mouse retina. The SCN-projecting type originally described by David Berson is now called “M1”, whereas the new types are called M2, M3, M4 and M5 (Ecker et al. 2010; Schmidt et al. 2008; Viney et al. 2007). Examples of mouse M2 cells are shown in Fig. 16D-F,H. By whole-cell-recording from a large sample of randomly selected RGCs, all five morphological types of ipRGCs were also found in the rat (Reifler et al. 2015); representative examples are shown in Fig. 17. Among these ipRGC types, M1 is the only one that stratifies exclusively in S1 of the IPL. M3 is the only bistratified type, extending dendrites toward both S1 and S5. The remaining ipRGC types are all monostratified in S5, with M2 having relatively sparse dendrites, M4 having denser and radiate dendrites similar to the previously described alpha cell (Estevez et al. 2012; Schmidt et al. 2014), and M5 having the densest dendrites covering the smallest fields (Fig. 17).
The five types of ipRGCs exhibit diverse physiological properties, suggesting they perform different functions. In both mouse and rat, the five ipRGC types spike spontaneously at different frequencies (Reifler et al. 2015; Zhao et al. 2014). The various types of mouse ipRGCs also differ significantly in various basic biophysical properties such as membrane resistance, membrane capacitance, Na+ spike waveform, Na+ spike threshold, and voltage-gated Ca2+ and K+ currents (Hu et al. 2013; Schmidt and Kofuji 2009). Under dark-adapted conditions, the five mouse ipRGC types respond fairly similarly to full-field light, generating sustained depolarizing responses that last for the duration of the light (Zhao et al. 2014). Under light-adapted conditions, however, M1’s and M2’s cone-driven full-field light responses are significantly different, with the former’s responses being far more transient and much lower in amplitude (Schmidt and Kofuji 2010). Diversity was also observed in the various cell types’ responses to moving lights, and to light spots of different sizes, even under dark-adapted conditions. All five cell types responded more strongly to moving lights than to static lights; however, different cell types appeared tuned to different speeds of motion (Fig. 18A).
Furthermore, whereas M1’s receptive field consists of just an ON-center region, the non-M1 ipRGCs’ receptive fields display ON-center/OFF-surround antagonism, so that a large light spot illuminating the entire receptive field induces a weaker response than a smaller spot covering just the center region (Fig. 18B) (Zhao et al. 2014). Under conditions blocking rod/cone signaling, the five types of rat and mouse ipRGCs generate melanopsin-based light responses that differ in kinetics, amplitude, and threshold, with M1 cells’ intrinsic photoresponses being the fastest, largest, and most sensitive (Fig. 19) (Ecker et al. 2010; Estevez et al. 2012; Reifler et al. 2015; Schmidt and Kofuji 2009; Zhao et al. 2014).
Besides mice and rats, many other species that have been examined also possess multiple morphological and/or physiological types of ipRGCs, although it is unknown whether these other species also have five ipRGC types. In primates including humans, only two morphological types of melanopsin-expressing RGCs have been documented (Fig. 20). Both cell types have giant somas and sparse, monostratifying dendrites. The outer-stratifying type stratifies in S1 whereas the inner-stratifying type stratifies in S5, and so they could be homologous to the M1 and M2 types found in rodents (Dacey et al. 2005; Grunert et al. 2011; Hannibal et al. 2014; Jusuf et al. 2007; Neumann et al. 2011). The dendritic fields of the outer-stratifying cells tile the retina with little overlap, but they overlap substantially with the dendritic fields of the inner-stratifying cells, suggesting they constitute two distinct cell types (Jusuf et al. 2007). The receptive fields of both outer- and inner-stratifying primate ipRGCs consist only of an ON-center region, and both cell types appear to generate remarkably similar rod-driven, cone-driven and melanopsin-mediated light responses (Fig. 21) (Dacey et al. 2005). Moreover, both types project to the lateral geniculate nucleus and olivary pretectal nucleus (see “Central Projections” below for further information) (Dacey et al. 2005; Dacey et al. 2003). Thus, functional differences between the outer- and inner-stratifying primate ipRGCs remain elusive, although there is anatomical evidence that they receive different synaptic inputs (Jusuf et al. 2007; Neumann et al. 2011).
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8. Central Projections
Using a transgenic mouse line whose ipRGCs express the marker enzyme β-galactosidase, Samer Hattar et al. visualized the axons of M1-type ipRGCs and characterized their projections throughout the brain. As expected for cells that regulate non-image-forming visual behaviors, Hattar and colleagues found M1-type ipRGCs sent dense projections to the SCN, the intergeniculate leaflet (IGL), and the olivary pretectal nucleus (OPN) (Fig. 22A–C ) (Hattar et al. 2006). The SCN and IGL are parts of the circadian system, while the OPN mediates the pupillary light reflex. In addition to these expected sites, the same study discovered a number of other central targets. Within the hypothalamus, M1 cells sent axonal fibers to the ventral portion of the subparaventricular zone, a region controlling the autonomic nervous system. Rostrolateral to the SCN, a number of scattered fibers reach the lateral and ventrolateral preoptic areas, which influence release of reproductive hormones from the pituitary (Hattar et al. 2006). The brain targets identified in this study are summarized in Fig. 22D. These central projections suggest that M1 cells regulate a diverse array of non-image forming visual functions.
More recently, using a more sensitive Cre-based melanopsin reporter mouse line to label all five ipRGC types, Hattar and colleagues detected pronounced ipRGC projection to two additional visual nuclei: the dorsal division of the lateral geniculate nucleus (LGN), which is the primary thalamic relay site of retinal input to the visual cortex, and the superior colliculus (SC), a sensorimotor nucleus that detects novel visual stimuli (Fig. 22E,F). Retrograde and anterograde labeling has shown that primate ipRGCs also project to both the LGN and SC (Dacey et al. 2005; Hannibal et al. 2014). These findings suggest that in addition to their well-known role in regulating subconscious visual reflexes, ipRGCs may contribute to conscious visual perception, a possibility that has received strong support from electrophysiological and behavioral studies (see “Behavioral aspects of ipRGC function” below).
9. Adaptation, neuromodulation and circadian control
IpRGC photosensitivity displays various forms of plasticity. The gain of melanopsin phototransduction is influenced by background light level and prior lighting history. IpRGCs’ light responses are also modulated by neuromodulators released endogenously within the retina. Moreover, these neurons’ photoresponse amplitude depends on the time of day, suggesting it is under circadian control. All three aspects of ipRGC plasticity are considered in this section.
The image-forming visual system can operate over a wide spectrum of ambient light intensities covering more than ten orders of magnitude. While much of this range is due to the existence of two separate photoreceptor systems (rods and cones) that operate over different light intensity ranges, some of the capacity is due to the ability of both rods and cones to change their sensitivity to light, a process called adaptation (Perlman and Normann 1998). When presented with a constant background light, rods and cones generate an initial peak response which relaxes during the steady illumination, indicating desensitization to the light over time. This desensitization allows the photoreceptors to increase their dynamic range, so they can respond to light intensities that would otherwise be saturating. This is termed “light adaptation”. Conversely, when placed back into a dark environment, rods and cones gradually regain their sensitivity, a process called “dark adaptation”. Both light and dark adaptation are a direct consequence of changes in the phototransduction cascade. While rods have a relatively limited ability to adapt to background illumination, saturating at high light levels, cones exhibit an almost infinite capacity to adapt to light levels (Fain et al. 2001; Knox and Solessio 2006).
Due to their role in stable representations of absolute light levels, and their unusually tonic response properties, it was initially not clear whether ipRGCs’ intrinsic photosensitivity would display similar adaptation mechanisms as rods and cones. David Berson and colleagues found that when ipRGCs were exposed to a nearly saturating background light, these cells gradually became desensitized, while responses to a brighter pulse of light on top of the background light became larger over time (Fig. 23).
Background light also accelerated photoresponse kinetics, so that the response to a light pulse peaked faster, and also decayed faster toward to the baseline after cessation of the pulse. These are hallmarks of light adaptation. Furthermore, when previously light-adapted ipRGCs were left in the dark for increasing periods of time, their responses to the same light stimulus intensity increased, a clear indication of dark adaptation (Fig. 24) (Wong et al. 2005). Although Wong et al.2005 found that ipRGCs light-adapt and dark-adapt much slower than do the classical photoreceptors, subsequent work revealed two important similarities between ipRGC and rod/cone adaptations: for all three photoreceptor classes, the flash sensitivity vs. background intensity relationship can be described by the Weber-Fechner law, and light adaptation is at least partly mediated by Ca2+ (Do and Yau 2013). These similarities are somewhat surprising, considering that ipRGCs use a phototransduction cascade that differs drastically from rods’ and cones’ (see the “Phototransduction” section above).
In addition to the above acute adaptational effects on ipRGCs’ intrinsic photosensitivity, prolonged exposure to light or darkness significantly modulates melanopsin mRNA levels. In rats maintained in constant darkness, melanopsin expression rose progressively for at least 5 days, whereas those kept in constant light became nearly completely devoid of melanopsin mRNA after 7 days (Hannibal et al. 2005).
As mentioned earlier in the “Intraretinal synaptic output” section, dopamine is an important neuromodulator that has widespread influences on retinal function. Thus, not surprisingly, it has been shown to modulate ipRGCs. Dopamine and an agonist for D1-class dopamine receptors were found to acutely attenuate the intrinsic light responses of dissociated ipRGCs (Van Hook et al. 2012). Moreover, prolonged application of a D2-class dopamine agonist enhanced the mRNA levels of melanopsin and pituitary adenylyl cyclase-activating peptide (PACAP), a peptide present in ipRGCs (Sakamoto et al. 2005). Adenosine, which appears to rise at night and during prolonged darkness (Ribelayga and Mangel 2005), has been reported to shorten the duration of ipRGCs’ intrinsic photoresponses, but unlike dopamine, it does not significantly reduce the peak amplitude of these responses (Sodhi and Hartwick 2014). Melatonin, which is also released primarily at night, has been reported to modulate the rod/cone-driven light responses of M4-type rat ipRGCs (Pack et al. 2015). Finally, these is indirect evidence that cholecystokinin released from amacrine cells modulates retinal input to the central circadian clock (Shimazoe et al. 2008).
IpRGCs are well known to mediate photoentrainment of the central circadian clock (see “Behavioral aspects of ipRGC function below”). But there is evidence that these RGCs are themselves under circadian regulation. In both light/dark (“LD”) and constant dark (“DD”) conditions, melanopsin mRNA levels in rat retinas display a daily rhythm. This rhythm disappeared in rod/cone degenerate rats, suggesting it is driven by the retinal circadian clock rather than the SCN’s central circadian clock (Sakamoto et al. 2004). Multielectrode-array extracellular recording indeed demonstrated a statistically significant increase in the amplitude of rat ipRGCs’ intrinsic photoresponse early in the subjective night compared to all the other circadian times examined (Weng et al. 2009), although this increase was much smaller than the amplitude of the circadian rhythm in melanopsin mRNA expression (Sakamoto et al. 2004).
10. Behavioral aspects of ipRGC function
Daily rhythms in mammalian physiology and behavior, collectively called circadian rhythms, are controlled by a tiny cluster of cells in the SCN of the hypothalamus. SCN neurons possess a transcription/translation-based molecular clock that allows them to autonomously regulate activity patterns in near 24-hour rhythms, which ultimately lead to daily changes in behaviors such as sleep/wake cycles and rhythms in core body temperature. However, the circadian clock is not tuned perfectly to 24 hours, and in order to adjust to changes in the animals’ environmental light/dark phases, the SCN must be reset periodically so that circadian rhythms are synchronized (or “entrained”) to the light/dark cycle. Light is by far the most potent circadian entrainment cue, and ipRGCs are the primary cells that carry this signal since eliminating these neurons abolished photoentrainment in mice (Goz et al. 2008; Guler et al. 2008; Hatori et al. 2008). Melanopsin-knockout animals have relatively normal circadian rhythms, and do not display any overt dysfunction in their ability to entrain to light. However, light pulses induced significantly smaller phase shifts in these animals’ circadian rhythms (Fig. 25), revealing a crucial role for melanopsin signaling (Panda et al. 2002; Ruby et al. 2002). On the other hand, rods are essential for photoentrainment to dim light (Altimus et al. 2010; Lall et al. 2010), whereas cones are important for proper responses of the photoentrainment system to short-duration light pulses (Dkhissi-Benyahya et al. 2007; Dollet et al. 2010).
The SCN signals through various neural circuits to coordinate circadian rhythms throughout the body. In one of these circuits, the SCN regulates secretion of the sleep-promoting hormone melatonin from the pineal gland into the bloodstream: SCN à paraventricular nucleus of the hypothalamus à intermediolateral nucleus of the spinal cord à superior cervical ganglion à pineal gland (Larsen et al. 1998). As a result of this SCN regulation, melatonin is released from the pineal only during subjective night. Upon exposure to sufficiently intense light, however, ipRGC input acutely suppresses this release of melatonin (Brainard et al. 2001; Thapan et al. 2001; Vartanian et al. 2015). Because ipRGCs remain photosensitive in the absence of rods and cones, rodless coneless mice and some blind patients continue to exhibit this non-image-forming visual response (Fig. 26) (Czeisler et al. 1995; Lucas et al. 1999; Zaidi et al. 2007).
IpRGCs are also responsible for light-evoked constriction of the pupil. Projections of ipRGC axons to the OPN, the retino-recipient site responsible for the pupillary light reflex, make them likely candidates for regulating this response. Indeed, melanopsin-knockout animals had diminished pupillary light reflexes at high irradiance levels (Fig. 27A,B) (Lucas et al. 2003). In addition, melanopsin-knockout mice without functional rods or cones were completely unable to constrict their pupils in response to light (Fig. 27C) (Hattar et al. 2003; Panda et al. 2003). Furthermore, killing ipRGCs using various methods dramatically attenuated the pupillary light reflex (Guler et al. 2008; Hatori et al. 2008).
Numerous additional non-image-forming photic responses have been reported to be at least partly mediated by ipRGCs. These include acute suppression of the nocturnal locomotor activity of mice (“negative masking”) (Mrosovsky and Hattar 2003), light-induction of sleep (“photosomnolence”) (Altimus et al. 2008; Lupi et al. 2008; Morin and Studholme 2011; Tsai et al. 2009) and maintenance of light-induced sleep in mice (Muindi et al. 2013), modulation of cognitive performance in humans (Vandewalle et al. 2013; Vandewalle et al. 2007), enhancement of alertness in humans (Viola et al. 2008), antidepressant effect in rats (Iyilikci et al. 2009) and humans (Meesters et al. 2011), light-induced exacerbation of headache in humans (Noseda et al. 2010), photophobia and light avoidance in mice (Johnson et al. 2010; Matynia et al. 2012), light-dependent relaxation of blood vessels (Sikka et al. 2014), and stimulation of the secretion of follicle-stimulating hormone (FSH) in women (Danilenko and Sergeeva 2015).
In addition, there is emerging evidence that melanopsin contributes to visual perception, which is probably mediated by ipRGC projection to the LGN and/or SC (Brown et al. 2010; Dacey et al. 2005; Ecker et al. 2010; Estevez et al. 2012; Zhao et al. 2014). Some blind patients with severe outer retinal degeneration but relatively normal ipRGCs possess a rudimentary ability to detect the presence of intense blue light (Zaidi et al. 2007), and fully sighted humans as well as mice appear to depend partly on melanopsin for brightness discrimination (Brown et al. 2012). Mice lacking rod/cone photoreception (but with intact melanopsin photoreception) were able to distinguish a computer screen displaying black and white stripes from a uniform gray screen of an equal mean intensity, suggesting melanopsin is sufficient for a certain degree of pattern vision (Ecker et al. 2010). There is also preliminary psychophysical evidence that melanopsin directly contributes to color vision in humans, challenging the trichromatic theory (Horiguchi et al. 2013). Most recently, mice lacking melanopsin were shown to have behavioral deficits in contrast sensitivity (Schmidt et al. 2014).
IpRGCs are likely to perform additional image-forming visual functions because under conditions preserving synaptic input, primate ipRGCs receive color-opponent (blue OFF, yellow ON) input from cones (Fig. 21B), implicating a capacity for color discrimination (Dacey et al. 2005). Furthermore, with the exception of M1 cells, all the other four types of mouse ipRGCs have receptive fields with antagonistic ON-center, OFF-surround regions (Fig. 18B), suggesting these cells perform spatial analysis (Estevez et al. 2012; Zhao et al. 2014). Finally, the five types of mouse ipRGCs are tuned to different speeds of motion (Fig. 18A), raising the possibility that they contribute to motion analysis (Zhao et al. 2014).
11. Roles in development
Melanopsin expression begins before birth (Tarttelin et al. 2003) and ipRGCs become photosensitive earlier than both rods and cones (Sekaran et al. 2005; Tu et al. 2005). One function for this early emergence of melanopsin-based photosensitivity is negative phototaxis, which causes mouse pups as young as P6 (postnatal day 6) to turn away from bright light (Johnson et al. 2010). Melanopsin has also been shown to regulate the early development of retinal neurons, retinal blood vessels and retinogeniculate circuits. In wild-type mice reared under normal light/dark conditions, embryonic hyaloid vasculature regresses and the retinal vasculature starts to form during early postnatal days. But in melanopsin-knockout mice or mice dark-reared from late gestation, the regression of the hyaloid vasculature was delayed and the retinal vasculature overgrew (Fig. 28A, bottom row). Furthermore, the number of RGCs and amacrine cells increased (Fig. 28B, blue). These observations suggest that during late gestation, melanopsin-mediated light detection activates a signaling pathway that suppresses the number of GCL neurons and regulates the timing of vasculature development (Rao et al. 2013).
As mentioned in the “Intraretinal synaptic output” section above, ipRGCs signal not only to the brain but also within the retina. Intraretinal signaling by ipRGCs is already apparent by P4. Besides participating in ion regulation (Berkowitz et al. 2010), such early signaling also controls the temporal properties of retinal waves. Retinal waves are spontaneous bursts of action potentials that propagate across RGCs during early postnatal development, and they contribute to the refinement of retinogeniculate projections. In wild-type mice, light increases the duration of each burst of spikes, and afferent axons from ipsilateral and contralateral retinas terminate in largely distinct parts of the dorsal LGN. In melanopsin-knockout mice, however, this effect of light on burst duration was absent, and ipsilateral and contralateral retinal inputs to the dorsal LGN became less segregated (Renna et al. 2011).
12. Conclusions
IpRGCs are mammalian photoreceptors whose morphological and physiological characteristics seem well suited for their primary role as light detectors for non-image forming visual reflexes. Because they were discovered so recently, many mysteries remain, and an untold number of functions for this rare and special type of ganglion cell should not be overlooked. Their invertebrate-like phototransduction cascade makes them unique among known vertebrate photoreceptors, and provides a window into possible mechanisms of the evolution of the retina. In addition to their intrinsic melanopsin-driven photosensitivity, ipRGCs receive rod and cone synaptic input and thus may provide the brain with different information in series, separated by complex spatial and temporal dynamics. Although they drive a number of tonic behaviors, requiring accurate representation of ambient light levels of long periods of time, ipRGCs can adapt to both light and darkness. They have an ability to communicate back to the retina, possibly changing the functional properties of image-forming retinal circuitry. Emerging evidence suggests that ipRGCs can also directly contribute to conscious visual perception. Finally, these RGCs regulate the early development of the retina and the retinogeniculate pathway. As the years catch up with this relatively young field of ganglion-cell photoreceptors, it is beginning to look like many RGC types are photoreceptive and perform diverse functional roles.
ABOUT THE AUTHORS
Dr. Dustin M. Graham was born and raised in Pleasanton, California and received his Ph.D. in neuroscience from Brown University. He began his research career at Santa Clara University in the lab of Dr. David Tauck, studying neural pathways of learning and memory in the pond snail Lymnaea stagnalis. His interests turned to the retina while working with Dr. Ralph Nelson at the National Institutes of Health. There he helped develop a rapid labeling technique to delineate morphological subtypes of retinal neurons in zebrafish. As a graduate student, Dustin studied mammalian circadian rhythms and the newly dicovered melanopsin ganglion cell activity in Dr. David Berson’s lab. He focussed on the phototransduction cascade in ipRGCs, and developed a dissociation and culturing procedure to identify and record light responses from isolated ipRGCs. Dustin is currently a research fellow in the Department of Neurobiology & Behavior, Stony Brook University, NY 11794.
Dr. Kwoon Wong grew up in Hong Kong, when it was still a British colony. His undergraduate major at the University of Texas at Austin was biochemistry, and as he started his PhD career at Harvard he was convinced that he wanted to study cancer biology. But an immensely satisfying rotation in Prof. John Dowling’s lab lured Kwoon into the world of neurophysiology, and he has been studying the visual system ever since. For his PhD thesis, he studied glutamate receptors and transporters at the photoreceptor-bipolar cell synapse in fish retinas. Then, at the 2002 Society for Neuroscience conference, he saw Prof. David Berson’s fascinating symposium presentation on melanopsin-expressing ganglion cells, a novel class of retinal photoreceptors involved in non-image-forming visual behaviors. Awestruck by this talk, Kwoon decided to do his postdoctoral work with Prof. Berson at Brown. During Kwoon’s six years in the Berson lab, he investigated melanopsin ganglion cells’ light responses and synaptic circuits. Since Jan 2010, he has been an Assistant Professor at the University of Michigan, where he has continued to study these exotic ganglion cells.
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