dLGN

The dLGN receives, processes, and relays classical image-forming visual information and, for this reason, has received the most attention of all retinorecipient thalamic nuclei. In higher mammals, the dLGN has a distinctive cytoarchitecture with layers that receive eye- and function-specific retinal inputs. While cells in the dLGN of highly visual diurnal rodents, such as squirrels, are separated into at least five layers (Kaas et al., Reference Kaas, Guillery and Allman1972; Van Hooser & Nelson, Reference Van Hooser and Nelson2006), the dLGN of nocturnal rodents lacks gross cytoarchitecture lamination, despite having eye-specific domains (Reese & Cowey, Reference Reese and Cowey1983; Godement et al., Reference Godement, Salaün and Imbert1984; Muir-Robinson et al., Reference Muir-Robinson, Hwang and Feller2002; Jaubert-Miazza et al., Reference Jaubert-Miazza, Green, Lo, Bui, Mills and Guido2005) (Fig. 2A). Nevertheless, evidence that the dLGN of rats (Reese, Reference Reese1988), mice (Grubb & Thompson, Reference Grubb and Thompson2004; Krahe et al., Reference Krahe, El-Danaf, Dilger, Henderson and Guido2011), and hamsters (Emerson et al., Reference Emerson, Chalupa, Thompson and Talbot1982) are not anatomically homogenous emerged. The possibility that “hidden laminae” existed in rodent dLGN first arose from studies demonstrating the dorsolateral “shell” and ventromedial “core” regions of rodent dLGN contain populations of retinal terminals that are morphologically separable (Erzurumlu et al., Reference Erzurumlu, Jhaveri and Schneider1988; Reese, Reference Reese1988; Hammer et al., Reference Hammer, Monavarfeshani, Lemon, Su and Fox2015). Hidden laminae have become more apparent with techniques that label individual classes of RGCs, of which there are more than thirty (Sanes & Masland, Reference Sanes and Masland2015; Baden et al., Reference Baden, Berens, Franke, Rosón, Bethge and Euler2016). A series of studies in transgenic reporter mice (each of which labels a single class of RGCs) have demonstrated the existence of several RGC class-specific retinorecipient sublaminae in dLGN (Kim et al., Reference Kim, Zhang, Yamagata, Meister and Sanes2008; Huberman et al., Reference Huberman, Feller and Chapman2008a; Huberman et al., Reference Huberman, Wei, Elstrott, Stafford, Feller and Barres2009; Kim et al., Reference Kim, Zhang, Meister and Sanes2010; Hong & Chen, Reference Hong and Chen2011; Kay et al., Reference Kay, De la Huerta, Kim, Zhang, Yamagata, Chu, Meister and Sanes2011) (Fig. 2D).

In addition to a heterogeneous distribution of retinal afferents, neuronal subtypes within the rodent dLGN are differentially distributed. Two main types of neurons exist in dLGN, both of which are innervated by retinal afferents. Principal neurons, or thalamocortical (TC) relay cells, are excitatory projection neurons that originate from the caudal progenitor domain within the thalamic ventricular zone (i.e., prosomer 2) (Altman & Bayer, Reference Altman and Bayer1989; Puelles & Rubenstein, Reference Puelles and Rubenstein2003; Vue et al., Reference Vue, Aaker, Taniguchi, Kazemzadeh, Skidmore, Martin, Martin, Treier and Nakagawa2007) during rodent embryogenesis. Ultimately TC progenitor cells differentiate into at least three morphologically distinct classes in nocturnal rodents—biconical X-like cells, symmetrical Y-like cells, and hemispheric W-like TC cells (Krahe et al., Reference Krahe, El-Danaf, Dilger, Henderson and Guido2011; Ling et al., Reference Ling, Hendrickson and Kalil2012). These classes of TC relay cells closely resemble those reported in cats (Friedlander et al., Reference Friedlander, Lin, Stanford and Sherman1981) and higher mammals (Irvin et al., Reference Irvin, Casagrande and Norton1993). Just as classes of relay cells are differentially distributed in cat and primate dLGN (Sherman, Reference Sherman1985; Nassi & Callaway, Reference Nassi and Callaway2009), they are uniquely distributed in mouse dLGN: W-like cells occupy the dorsolateral shell of mouse dLGN and X- and Y-like cells occupy the ventromedial dLGN core (Krahe et al., Reference Krahe, El-Danaf, Dilger, Henderson and Guido2011). While all three classes of TC relay cells project axons to visual cortex, recent evidence has demonstrated that regionally restricted cell types participate in functionally distinct parallel visual pathways in mice (Cruz-Martín et al., Reference Cruz-Martín, El-Danaf, Osakada, Sriram, Dhande, Nguyen, Callaway, Ghosh and Huberman2014; Bickford et al., Reference Bickford, Zhou, Krahe, Govindaiah and Guido2015).

In addition to principal relay cells, rodent dLGN contains a small percentage (10–20%) of inhibitory interneurons, a cell type absent from most other dorsal thalamic regions (Arcelli et al., Reference Arcelli, Frassoni, Regondi, Biasi and Spreafico1997; Jaubert-Miazza et al., Reference Jaubert-Miazza, Green, Lo, Bui, Mills and Guido2005). The arrival of these interneurons occurs postnatally, after retinal inputs have targeted dLGN, formed immature connections, and begun to undergo activity-dependent refinement (Jones & Rubenstein, Reference Jones and Rubenstein2004; Singh et al., Reference Singh, Su, Brooks, Terauchi, Umemori and Fox2012; Golding et al., Reference Golding, Pouchelon, Bellone, Murthy, Di Nardo, Govindan, Ogawa, Shimogori, Lüscher and Dayer2014; Jager et al., Reference Jager, Ye, Yu, Zagoraiou, Prekop, Partanen, Jessell, Wisden, Brickley and Delogu2016). The precise origin of these interneurons is currently under debate, with studies suggesting they arise from a rostral progenitor domain within the thalamus (i.e., prosomer 3) or from tectum (Virolainen et al., Reference Virolainen, Achim, Peltopuro, Salminen and Partanen2012; Golding et al., Reference Golding, Pouchelon, Bellone, Murthy, Di Nardo, Govindan, Ogawa, Shimogori, Lüscher and Dayer2014; Jager et al., Reference Jager, Ye, Yu, Zagoraiou, Prekop, Partanen, Jessell, Wisden, Brickley and Delogu2016). Evidence is also emerging that dLGN interneurons are not a homogeneous population in mice, and can instead be divided into at least two classes based on soma size, membrane capacitance, and neuronal nitric oxide synthase (nNOS) expression (Leist et al., Reference Leist, Datunashvilli, Kanyshkova, Zobeiri, Aissaoui, Cerina, Romanelli, Pape and Budde2016). Similar interneuron diversity has been reported in rats (Gabbott & Bacon, Reference Gabbott and Bacon1994b), cats (Montera & Zempel, Reference Montera and Zempel1985; Montero & Singer, Reference Montero and Singer1985), and primates (Braak & Bachmann, Reference Braak and Bachmann1985). At present, however, it remains unclear whether classes of local inhibitory interneurons exhibit regional preferences in the nocturnal rodent dLGN.

vLGN and IGL

Unlike dLGN, the vLGN of nocturnal rodents is organized into at least two easily identifiable laminae—the magnocellular external vLGN (vLGNe), which contains large cells and receives dense innervation from retina, and the parvocellular internal vLGN (vLGNi), which receives little, if any, retinal input (Niimi et al., Reference Niimi, Kanaseki and Takimoto1963; Hickey & Spear, Reference Hickey and Spear1976; Gabbott & Bacon, Reference Gabbott and Bacon1994a ; Harrington, Reference Harrington1997). These laminae are separated by a small neuron-free, fiber-rich neuropil. Cell types within vLGN are vastly different than those in dLGN resulting in a significant difference in the transcriptome of each region (Su et al., Reference Su, Haner, Imbery, Brooks, Morhardt, Gorse, Guido and Fox2011; Yuge et al., Reference Yuge, Kataoka, Yoshida, Itoh, Aggarwal, Mori, Blackshaw and Shimogori2011). Moreover, the vLGN lacks stereotypic TC relay cells, and has only a limited number of vesicular glutamate transporter-expressing glutamatergic neurons (Fremeau et al., Reference Fremeau, Troyer, Pahner, Nygaard, Tran, Reimer, Bellocchio, Fortin, Storm-Mathisen and Edwards2001; Yuge et al., Reference Yuge, Kataoka, Yoshida, Itoh, Aggarwal, Mori, Blackshaw and Shimogori2011). Thus, in contrast to dLGN where glutamatergic neurons are the major cell type, vLGN contains a vastly higher population of GABAergic neurons (Gabbott & Bacon, Reference Gabbott and Bacon1994b ; Harrington, Reference Harrington1997; Inamura et al., Reference Inamura, Ono, Takebayashi, Zalc and Ikenaka2011). These major cellular differences reflect distinct embryonic origins of cells in vLGN, which are derived from progenitors in the most caudal prethalamus, a rostral domain of the thalamic ventricular zone, and the zona limitans interthalamica (ZLI) (Vue et al., Reference Vue, Aaker, Taniguchi, Kazemzadeh, Skidmore, Martin, Martin, Treier and Nakagawa2007; Delaunay et al., Reference Delaunay, Heydon, Miguez, Schwab, Nave, Thomas, Spassky, Martinez and Zalc2009; Nakagawa & Shimogori, Reference Nakagawa and Shimogori2012; Virolainen et al., Reference Virolainen, Achim, Peltopuro, Salminen and Partanen2012). Although detailed studies of vLGN neurons lag behind similar characterizations of glutamatergic TC relay cells and local GABAergic interneurons in dLGN, expression studies and transgenic reporter mice strongly suggest that distinct classes of cells are distributed in a laminar arrangement in vLGNe, even if it is not apparent at the gross cytoarchitectural level (Moore & Card, Reference Moore and Card1994; http://www.brain-map.org).

Although vLGN and IGL likely serve different functions in nocturnal rodents and are anatomically distinguishable (Hickey & Spear, Reference Hickey and Spear1976; Moore & Card, Reference Moore and Card1994; Morin, Reference Morin2013), we have grouped them together throughout this review because of shared features that will be discussed. Like those in vLGNe, neurons in the IGL originate from a rostral region of the thalamic progenitor zone and the ZLI (Vue et al., Reference Vue, Aaker, Taniguchi, Kazemzadeh, Skidmore, Martin, Martin, Treier and Nakagawa2007; Delaunay et al., Reference Delaunay, Heydon, Miguez, Schwab, Nave, Thomas, Spassky, Martinez and Zalc2009). A large fraction of neurons in IGL generate GABA (Moore & Speh, Reference Moore and Speh1993), few are glutamatergic, and none project axons to visual cortex (Harrington, Reference Harrington1997). However, it is important to highlight that some classes of IGL neurons are absent from vLGN. This includes NPY-expressing neurons in rodent IGL that project axons to hypothalamic nuclei (Card & Moore, Reference Card and Moore1989; Moore & Card, Reference Moore and Card1994; Harrington, Reference Harrington1997). Based on available data, classes of morphologically and neurochemically distinct neurons do not appear to cluster into distinct layers or regions of IGL, except, perhaps, for coarse differences in their distribution between rostral and caudal regions of the IGL (Brauer et al., Reference Brauer, Schober, Leibnitz, Werner, Lüth and Winkelmann1983; Moore & Card, Reference Moore and Card1994; Morin, Reference Morin2013).

dLGN: Retinal afferents

In mammals, the primary excitatory drive onto TC relay cells is provided by retinal inputs (Sherman, Reference Sherman2005; Petrof & Sherman, Reference Petrof and Sherman2013). Anatomically, retinal projections to dLGN are spatially organized in (at least) three fundamental ways. First, retinal afferents are segregated into nonoverlapping eye-specific domains in an activity-dependent manner (Huberman et al., Reference Huberman, Feller and Chapman2008a ; Zhang et al., Reference Zhang, Ackman, Xu and Crair2012). The dLGN of nocturnal rodents receives a relatively small contribution (5–10%) of retinal afferents from the ipsilateral retina and these projections are confined to a ventromedial core region of the dLGN (Jaubert-Miazza et al., Reference Jaubert-Miazza, Green, Lo, Bui, Mills and Guido2005; Gaillard et al., Reference Gaillard, Karten and Sauvé2013; Morin & Studholme, Reference Morin and Studholme2014) (Fig. 2B). Second, retinal projections to dLGN are organized topographically-so that neighboring RGCs provide input to neighboring TC relay cells and provide a continuous and faithful representation of spatial information from retina to brain (Feldheim et al., Reference Feldheim, Vanderhaeghen, Hansen, Frisén, Lu, Barbacid and Flanagan1998; Pfeiffenberger et al., Reference Pfeiffenberger, Yamada and Feldheim2006; Huberman et al., Reference Huberman, Feller and Chapman2008a ; Cang & Feldheim, Reference Cang and Feldheim2013) (Fig. 2C). Third, and perhaps most remarkably, retinal projections undergo class-specific segregation in rodent dLGN (Fig. 2D). Although more than 30 classes of RGCs exist in nocturnal rodents only a subset innervate dLGN (Sanes & Masland, Reference Sanes and Masland2015; Baden et al., Reference Baden, Berens, Franke, Rosón, Bethge and Euler2016; Ellis et al., Reference Ellis, Gauvain, Sivyer and Murphy2016). This suggests that targeting mechanisms exist that guide some classes of RGC axons into dLGN and exclude others. Once appropriate classes of retinal axons enter dLGN, they are further segregated into a newly-appreciated laminar organization (Hong & Chen, Reference Hong and Chen2011; Dhande & Huberman, Reference Dhande and Huberman2014; Sanes & Masland, Reference Sanes and Masland2015). The presence of these stereotyped class-specific retinal projections has been elegantly revealed by transgenic reporter mice in which individual RGC classes are labeled with reporter proteins (Hattar et al., Reference Hattar, Kumar, Park, Tong, Tung, Yau and Berson2006; Kim et al., Reference Kim, Zhang, Yamagata, Meister and Sanes2008; Huberman et al., Reference Huberman, Manu, Koch, Susman, Lutz, Ullian, Baccus and Barres2008b ; Huberman et al., Reference Huberman, Wei, Elstrott, Stafford, Feller and Barres2009; Kim et al., Reference Kim, Zhang, Meister and Sanes2010; Kay et al., Reference Kay, De la Huerta, Kim, Zhang, Yamagata, Chu, Meister and Sanes2011; Rivlin-Etzion et al., Reference Rivlin-Etzion, Zhou, Wei, Elstrott, Nguyen, Barres, Huberman and Feller2011; Dhande et al., Reference Dhande, Estevez, Quattrochi, El-Danaf, Nguyen, Berson and Huberman2013; Triplett et al., Reference Triplett, Wei, Gonzalez, Sweeney, Huberman, Feller and Feldheim2014). While only a small set of individual RGC projections have been mapped with this approach, some rules are beginning to emerge. First, projections of direction-selective classes of RGCs arborize in more dorsolateral regions of dLGN, including the shell of dLGN (Kim et al., Reference Kim, Zhang, Yamagata, Meister and Sanes2008; Huberman et al., Reference Huberman, Wei, Elstrott, Stafford, Feller and Barres2009; Rivlin-Etzion et al., Reference Rivlin-Etzion, Zhou, Wei, Elstrott, Nguyen, Barres, Huberman and Feller2011; Cruz-Martín et al., Reference Cruz-Martín, El-Danaf, Osakada, Sriram, Dhande, Nguyen, Callaway, Ghosh and Huberman2014). Second, there is considerable overlap in the laminar termination zones of RGC axons (Fig. 2D), and taken in the context of recent ultrastructural and circuit tracing experiments in dLGN (Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016; Rompani et al., Reference Rompani, Müllner, Wanner, Zhang, Roth, Yonehara and Roska2017), this raises the possibility that individual TC relay cells may receive inputs from multiple classes of RGCs.

In addition to being segregated based on eye of origin, topography, and RGC class, retinal inputs in dLGN are structurally and functionally distinct from retinal inputs in other retinorecipient nuclei, even other thalamic nuclei (Sherman, Reference Sherman2005; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014). Specifically, retinal terminals onto dLGN TC relay cells are significantly larger than all other terminals in dLGN (and larger than retinal terminals in all other retinorecipient nuclei), and exhibit unique ultrastructural morphology and function (Guillery, Reference Guillery1969; Lund & Cunningham, Reference Lund and Cunningham1972; Sherman, Reference Sherman2004; Guido, Reference Guido2008; Bickford et al., Reference Bickford, Slusarczyk, Dilger, Krahe, Kucuk and Guido2010; Hong & Chen, Reference Hong and Chen2011). It is worth pointing out, however, that at least two distinct types of RG synapses have been identified in rodent dLGN: “simple encapsulated” RG synapses, in which a single retinal terminal synapses onto a TC relay cell dendrite, and “complex encapsulated” RG synapses in which axons from numerous RGCs converge to innervate adjacent regions of a TC relay cell dendrite (Lund & Cunningham, Reference Lund and Cunningham1972; Hammer et al., Reference Hammer, Monavarfeshani, Lemon, Su and Fox2015; Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016). Finally, it is important to point out that retinal projections not only innervate TC relay cells, but also local interneurons in nocturnal rodents (Sherman, Reference Sherman2004; Seabrook et al., Reference Seabrook, Krahe, Govindaiah and Guido2013b ).

dLGN: Nonretinal afferents

While retinal inputs provide the excitatory drive to TC relay cells, they account for only 5–10% of the total inputs onto a relay cell and are far outnumbered by nonretinal inputs (Sherman & Guillery, Reference Sherman and Guillery2002; Bickford et al., Reference Bickford, Slusarczyk, Dilger, Krahe, Kucuk and Guido2010; Cetin & Callaway, Reference Cetin and Callaway2014). A summary of the main inputs to rodent dLGN is depicted in Fig. 3.

Fig. 3. Afferent and efferent projections of rodent dLGN. (A) Sources of afferent projections to dLGN are colored green. (B) Brain regions innervated by dLGN efferents are colored in orange. dLGN, dorsal lateral geniculate nucleus; vLGN, ventral lateral geniculate nucleus; TRN, thalamic reticular nucleus; SC, superior colliculus; PRT, pretectal region; MRN, midbrain reticular nucleus; DR, dorsal raphe nucleus; PPN, pedunculopontine nucleus; PBG, parabigeminal nucleus; PB, parabrachial nucleus; LC, locus coeruleus; VIS1, visual cortex, layer I; VIS4, visual cortex, layer IV; VIS6, visual cortex, layer VI; RGC, retinal ganglion cell.

While many nonretinal inputs onto dLGN TC relay cells have modulatory or inhibitory roles, a recent study identified a novel glutamatergic nonretinal source of “driver-like” input onto dLGN TC relay cells (Bickford et al., Reference Bickford, Zhou, Krahe, Govindaiah and Guido2015). These inputs arise from the ipsilateral superior colliculus (SC) and terminate onto W-like TC relay cells in the dorsolateral shell of dLGN (Harting et al., Reference Harting, Huerta, Hashikawa and van Lieshout1991a ; Bickford et al., Reference Bickford, Zhou, Krahe, Govindaiah and Guido2015). Circuit tracing experiments indicate these excitatory tectogeniculate connections contribute to the processing and transmission of direction-selective visual information (Bickford et al., Reference Bickford, Zhou, Krahe, Govindaiah and Guido2015).

While tectogeniculate inputs represent a minor source of inputs to dLGN, a more significant portion of nonretinal glutamatergic inputs arise from cortical projection neurons in layer VI of primary visual cortex (Sherman, Reference Sherman2016). Corticothalamic inputs are small, located on distal portions of TC relay cell dendrites, and generate weak excitatory postsynaptic potentials (EPSPs) in relay cells (Sherman & Guillery, Reference Sherman and Guillery2002; Petrof & Sherman, Reference Petrof and Sherman2013). For this reason, it is likely that these inputs are insufficient for the relay of information alone and are, therefore, modulatory in nature (Petrof & Sherman, Reference Petrof and Sherman2013). Despite these features, corticothalamic inputs do significantly influence RG transmission by affecting the gain of signal transmission and sharpening of receptive field properties of TC relay cells (Sherman & Guillery, Reference Sherman and Guillery2002; Briggs & Usrey, Reference Briggs and Usrey2008; Olsen et al., Reference Olsen, Bortone, Adesnik and Scanziani2012; Bickford, Reference Bickford2015).

In addition to tectal and cortical glutamatergic inputs, TC relay cells in higher mammals receive modulatory cholinergic, serotonergic, noradrenergic, and dopaminergic inputs from a variety of sources in the brainstem including parabigeminal nucleus, pedunculopontine region, locus coeruleus, dorsal raphe nucleus of the midbrain, and the midbrain reticular formation (Mackay-Sim et al., Reference Mackay-Sim, Sefton and Martin1983; de Lima et al., Reference de Lima, Montero and Singer1985; De Lima & Singer, Reference De Lima and Singer1987; Papadopoulos & Parnavelas, Reference Papadopoulos and Parnavelas1990a , Reference Papadopoulos and Parnavelas b ; McCormick, Reference McCormick1992; Jones, Reference Jones2012). At present, some of these afferent projections have been demonstrated in nocturnal rodents (Hallanger et al., Reference Hallanger, Levey, Lee, Rye and Wainer1987; Harting et al., Reference Harting, Van Lieshout, Hashikawa and Weber1991b ), but additional studies are needed to map specific sources of these inputs and to understand their role in signal processing in rodents.

Finally, the last significant source of nonretinal inputs to dLGN are inhibitory GABAergic inputs that arise from both local inhibitory neurons and projection neurons in the TRN, a region that forms a lateral shell around dorsal thalamus in nocturnal rodents (Hale et al., Reference Hale, Sefton, Baur and Cottee1982; Guillery & Harting, Reference Guillery and Harting2003; Pinault, Reference Pinault2004). Inhibitory neurons in the ipsilateral pretectum also project to dLGN (Born & Schmidt, Reference Born and Schmidt2007), however evidence suggests that these projections innervate dLGN interneurons not TC relay cells (Wang et al., Reference Wang, Eisenback, Datskovskaia, Boyce and Bickford2002; Born & Schmidt, Reference Born and Schmidt2007), adding further complexity to dLGN circuitry.

An interesting facet of the convergence of retinal and nonretinal inputs in dLGN is that their development appears tightly coordinated. Retinal axons target and innervate dLGN prior to the arrival of nonretinal inputs and play instructive roles in the establishment of nonretinal circuitry (Brooks et al., Reference Brooks, Su, Levy, Wang, Seabrook, Guido and Fox2013; Seabrook et al., Reference Seabrook, El-Danaf, Krahe, Fox and Guido2013a ; Golding et al., Reference Golding, Pouchelon, Bellone, Murthy, Di Nardo, Govindan, Ogawa, Shimogori, Lüscher and Dayer2014; Grant et al., Reference Grant, Hoerder-Suabedissen and Molnár2016). Likewise, nonretinal inputs contribute to the development and function of retinogeniculate synapses. For example, the presence of corticothalamic axons and corticogeniculate synapses play essential roles in the establishment, refinement, and maintenance of retinal inputs (Shanks et al., Reference Shanks, Ito, Schaevitz, Yamada, Chen, Litke and Feldheim2016; Thompson et al., Reference Thompson, Picard, Min, Fagiolini and Chen2016).

vLGN and IGL: Retinal afferents

Several features of retinal projections to vLGNe are similar to those in dLGN: retinal afferents provide a main excitatory drive to vLGNe; the arrival of retinal inputs in vLGNe occurs neonatally and precedes nonretinal inputs (Su et al., Reference Su, Haner, Imbery, Brooks, Morhardt, Gorse, Guido and Fox2011); retinal inputs are mapped topographically in vLGNe and these inputs are segregated into nonoverlapping eye-specific domains (Holcombe & Guillery, Reference Holcombe and Guillery1984; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014; Morin & Studholme, Reference Morin and Studholme2014). On this last point, it warrants mention that ipsilateral retinal projections occupy a region of vLGN that is more complex and less stereotyped than its counterparts in dLGN. For this reason, activity-dependent refinement of eye-specific retinal projections has not been thoroughly characterized in vLGNe, nor has it served as an anatomical readout of activity-dependent refinement as has been the case in dLGN (Jaubert-Miazza et al., Reference Jaubert-Miazza, Green, Lo, Bui, Mills and Guido2005; Demas et al., Reference Demas, Sagdullaev, Green, Jaubert-Miazza, McCall, Gregg, Wong and Guido2006; Stevens et al., Reference Stevens, Allen, Vazquez, Howell, Christopherson, Nouri, Micheva, Mehalow, Huberman and Stafford2007; Huberman et al., Reference Huberman, Manu, Koch, Susman, Lutz, Ullian, Baccus and Barres2008b ; Rebsam et al., Reference Rebsam, Petros and Mason2009; Xu et al., Reference Xu, Furman, Mineur, Chen, King, Zenisek, Zhou, Butts, Tian, Picciotto and Crair2011; Rebsam et al., Reference Rebsam, Bhansali and Mason2012; Dilger et al., Reference Dilger, Krahe, Morhardt, Seabrook, Shin and Guido2015).

There are, however, several dramatic differences between retinal projections in dLGN and vLGNe. First, the majority of dLGN-projecting classes of RGCs fail to send collateral axon branches into vLGNe despite having to pass by it (or through it) on the way to dLGN (Huberman et al., Reference Huberman, Manu, Koch, Susman, Lutz, Ullian, Baccus and Barres2008b ; Kim et al., Reference Kim, Zhang, Yamagata, Meister and Sanes2008; Huberman et al., Reference Huberman, Wei, Elstrott, Stafford, Feller and Barres2009; but see also; Rivlin-Etzion et al., Reference Rivlin-Etzion, Zhou, Wei, Elstrott, Nguyen, Barres, Huberman and Feller2011). Instead, sets of nonimage-forming classes of RGCs, including the M1 class of melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs; labeled in Opn4^{taulacz/taulacz} mice) and RGCs labeled in Cdh3-GFP mice, innervate vLGNe (Hattar et al., Reference Hattar, Kumar, Park, Tong, Tung, Yau and Berson2006; Osterhout et al., Reference Osterhout, Josten, Yamada, Pan, Wu, Nguyen, Panagiotakos, Inoue, Egusa and Volgyi2011). It is worth noting that a small subset of ipRGC terminals have been reported in the medial-most region of dLGN in Opn4^{taulacz/taulacz} mice. While these may reflect projections from M1 ipRGCs, it is also possible that they belong to axons from other ipRGCs, such as M3 ipRGCs (Schmidt et al., Reference Schmidt, Chen and Hattar2011). Indeed other classes of ipRGCs innervate dLGN and mediate image-forming visual signals in nocturnal rodents (Ecker et al., Reference Ecker, Dumitrescu, Wong, Alam, Chen, LeGates, Renna, Prusky, Berson and Hattar2010; Estevez et al., Reference Estevez, Fogerson, Ilardi, Borghuis, Chan, Weng, Auferkorte, Demb and Berson2012). Projections of M1 ipRGCs and Cdh3-GFP RGCs arborize broadly across all regions of vLGNe, raising questions as to whether hidden lamina exist in vLGNe. However, it is important to point out that studies in diurnal rats identified distinct lamination of retinal projections in this region (Gaillard et al., Reference Gaillard, Karten and Sauvé2013). Moreover, only a small set of the RGCs that likely innervate rodent vLGNe have been identified and studied to date, leaving open the possibility that additional RGC classes will be identified whose projections are regionally restricted to specific sublamina of vLGNe. In support of this, there is a small region of vLGNe underlying the optic tract (OT) that contains a region with morphologically distinct retinal arbors (Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014), much like that observed in the dorsolateral shell of dLGN (Reese, Reference Reese1988; Grubb & Thompson, Reference Grubb and Thompson2004).

Significant differences also exist in the anatomy and physiology of retinal synapses in vLGN compared to dLGN. Retinal terminals in rodent vLGNe are remarkably smaller and less morphologically complex than those in dLGN, and this difference is reflected in their ability to elicit considerably weaker EPSPs (Mize & Horner, Reference Mize and Horner1984; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014). While several features of retinogeniculate synapses in vLGNe more closely resemble features of modulatory glutamatergic inputs (including their size, synaptic strength, and relative level of convergence on postsynaptic neurons), retinal inputs onto vLGN principal neurons exhibit paired-pulse depression and are likely to be “driver” inputs (Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014). Ultrastructural analysis further suggests that retinal terminals in vLGNe do not form “complex encapsulated” RG synapses and are not typically ensheathed by glial processes (Stelzner et al., Reference Stelzner, Baisden and Goodman1976; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014), both of which are features of RG synapses in rodent dLGN (Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014; Hammer et al., Reference Hammer, Monavarfeshani, Lemon, Su and Fox2015). These differences in retinal input type, synaptic morphology, and synaptic physiology suggest that light-derived information is processed differently in vLGNe.

Characteristics of retinal afferents in the nocturnal rodent IGL diverge even farther from their analogues in dLGN. Retinal projections to IGL are not segregated into nonoverlapping eye-specific domains (Su et al., Reference Su, Klemm, Josephson and Fox2013; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014; Morin & Studholme, Reference Morin and Studholme2014) nor are they topographically mapped (Harrington, Reference Harrington1997) (Fig. 2). These two features of retinal inputs distinguish IGL from vLGNe, which is surprising given that the only known classes of RGCs that project to IGL, M1 ipRGCs, and Cdh6-expressing RGCs, also project to vLGNe (Hattar et al., Reference Hattar, Kumar, Park, Tong, Tung, Yau and Berson2006; Osterhout et al., Reference Osterhout, Josten, Yamada, Pan, Wu, Nguyen, Panagiotakos, Inoue, Egusa and Volgyi2011). It is possible that subsets of RGCs in these classes differentially target IGL and vLGNe, or that each retinorecipient region has unique target-derived signals that allow for differential nonimage-forming RGC axon targeting mechanisms (Fox & Guido, Reference Fox and Guido2011).

Retinal terminals in IGL do share ultrastructural similarities with retinal terminals in dLGN and vLGNe, such as the presence of pale mitochondria and round synaptic vesicles (Moore & Card, Reference Moore and Card1994). In contrast to retinal terminals in dLGN, which reside on large proximal dendrites (Rafols & Valverde, Reference Rafols and Valverde1973; Wilson et al., Reference Wilson, Friedlander and Sherman1984), retinal inputs appear to contact small diameter, distal dendrites in IGL (Moore & Card, Reference Moore and Card1994). Analysis of retinal terminal size by anterograde labeling suggests that these terminals are similar in size to those in vLGNe, but are much less densely distributed than those in other major retinorecipient nuclei (Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014). Some peculiar features of retinal terminals in IGL have been noted in the literature and warrant mention here. For example, while retinal terminals in vLGNe, dLGN, and all other retinorecipient nuclei contain Vesicular Glutamate Transporter 2 (VGluT2), little, if any, of this transporter (or its closely related family member VGluT1) is present in IGL (Fujiyama et al., Reference Fujiyama, Hioki, Tomioka, Taki, Tamamaki, Nomura, Okamoto and Kaneko2003; Su et al., Reference Su, Klemm, Josephson and Fox2013; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014). The limited level of VGluT expression in IGL appears unchanged following surgical or genetic enucleation (Fujiyama et al., Reference Fujiyama, Hioki, Tomioka, Taki, Tamamaki, Nomura, Okamoto and Kaneko2003; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014), further suggesting retinal terminals in IGL may lack machinery for glutamate release. Despite this apparent lack of machinery for glutamate packaging and release, Blasiak et al. (Reference Blasiak, Blasiak and Lewandowski2009) showed that glutamate receptor antagonists impair excitatory responses to OT stimulation in IGL neurons. How do we reconcile such differences? It is possible that VGluT2 is present in retinal terminals in IGL but is below the limit of detection by immunostaining. Would such low levels of vGluT2 allow faithful transmission of signals at retinal synapses in IGL? Perhaps. Retinal terminals in IGL contain pituitary adenylate cyclase-activating peptide (PACAP) (Engelund et al., Reference Engelund, Fahrenkrug, Harrison and Hannibal2010), a neurotransmitter that can be co-released with glutamate and amplifies glutamatergic signaling (Kopp et al., Reference Kopp, Meissl, Dehghani and Korf2001; Michel et al., Reference Michel, Itri, Han, Gniotczynski and Colwell2006). Co-release of PACAP may reduce the necessity of retinal terminals to package and release large quantities of glutamate and therefore retinal terminals may require minimal levels of VGluTs.

In addition to differences in synapse size and neurotransmitters released, a final asymmetry between retinal connections in IGL and other retinorecipient nuclei is that a considerable fraction of principle projection neurons in IGL (such as NPY + neurons) are not directly innervated by retinal inputs. Instead, the ability of these projection neurons to propagate light-derived signals requires yet-to-be identified interneurons (Thankachan & Rusak, Reference Thankachan and Rusak2005; Morin, Reference Morin2013), and suggests the existence of a unique circuitry for the transmission of sensory information in IGL.

vLGN and IGL: Nonretinal afferents

Despite some differences in retinal connectivity with vLGNe and IGL, there appears to be a high degree of similarity in the nonretinal afferents innervating these structures. It is worth noting three distinctions between sources of nonretinal afferents to vLGNe and IGL when compared with dLGN. First, the number of nuclei that project afferents to rodent vLGNe and IGL far exceed and are far more diverse than those to dLGN (Figs. 4 and 5). An incomplete list of these sources includes superior colliculus, visual cortex, olivary pretectal nucleus, anterior pretectal nucleus, posterior pretectal nucleus, locus coeruleus, dorsal raphe nucleus, subparafasicular thalamic nucleus, mesencephalic nucleus, lateral dorsal tegmental nucleus, medial and lateral terminal nuclei, supraoculomotor periaqueductal gray, retrorubral nucleus, pontine reticular nucleus, pararubral nucleus, and medial vestibular nucleus (Cosenza & Moore, Reference Cosenza and Moore1984; Moore & Card, Reference Moore and Card1994; Moore et al., Reference Moore, Weis and Moga2000; Vrang et al., Reference Vrang, Mrosovsky and Mikkelsen2003; Horowitz et al., Reference Horowitz, Blanchard and Morin2004) (Figs. 4 and 5). In addition, neurons in rodent IGL (but not vLGNe) receive afferents from a variety of sources which include (but are not limited to) prefrontal cortex, ZI, suprachiasmatic nucleus, cuneiform nucleus, and superior and lateral vestibular nuclei (Morin & Blanchard, Reference Morin and Blanchard1998, Reference Morin and Blanchard1999; Vrang et al., Reference Vrang, Mrosovsky and Mikkelsen2003; Horowitz et al., Reference Horowitz, Blanchard and Morin2004) (Fig. 5). Second, subcortical projections to vLGNe and IGL arise from both ipsilateral and contralateral sources in nocturnal rodents (Moore & Card, Reference Moore and Card1994; Vrang et al., Reference Vrang, Mrosovsky and Mikkelsen2003; Horowitz et al., Reference Horowitz, Blanchard and Morin2004). For example, IGL neurons receive bilateral input from the olivary pretectal nucleus (OPN) and suprachiasmatic nucleus (SCN), and contralateral inputs from the other IGL (Vrang et al., Reference Vrang, Mrosovsky and Mikkelsen2003); likewise, vLGNe neurons receive input from the contralateral vLGNe (Cosenza & Moore, Reference Cosenza and Moore1984). Third, few sources of afferents are shared with dLGN, strongly inferring diverse roles of these thalamic regions in processing light-derived information (Horowitz et al., Reference Horowitz, Blanchard and Morin2004). Even in cases when projections to all three regions of the lateral geniculate complex arise from a single brain region, they originate from different cellular sources. For example while dLGN, vLGNe, and IGL all receive input from corticothalamic cells in primary visual cortex, inputs to dLGN arise from layer VI cells whereas those innervating vLGNe and IGL arise from layer V (Cosenza & Moore, Reference Cosenza and Moore1984; Bourassa & Deschênes, Reference Bourassa and Deschênes1995; Jacobs et al., Reference Jacobs, Campagnoni, Kampf, Reyes, Kalra, Handley, Xie, Hong-Hu, Spreur and Fisher2007; Seabrook et al., Reference Seabrook, El-Danaf, Krahe, Fox and Guido2013a ; Hammer et al., Reference Hammer, Carrillo, Govindaiah, Monavarfeshani, Bircher, Su, Guido and Fox2014).

Fig. 4. Afferent and efferent projections of rodent vLGNe. (A) Sources of afferent projections to vLGNe are depicted in green. (B) Brain regions innervated by vLGNe neurons are depicted in orange. dLGN, dorsal lateral geniculate nucleus; vLGNe, ventral lateral geniculate nucleus, external division; LP, lateral posterior thalamic nucleus; LD, lateral dorsal nucleus; MD, medial dorsal nucleus; ZI, zona incerta; RH, rhomboid nucleus; RE, reuniens nucleus; SMT, submedial nucleus of the thalamus; LHA, lateral hypothalamic area; PH, posterior hypothalamic nucleus; SC, superior colliculus; PRT, pretectal region; MRN, midbrain reticular nucleus; PAG, periaqueductal gray; DR, dorsal raphe nucleus; PPN, pedunculopontine nucleus; RR, retrorubral nucleus; MT, medial terminal nucleus; LT, lateral terminal nucleus; DT, dorsal terminal nucleus; LC, locus coeruleus; PB, parabrachial nucleus; Bar, Barrington’s nucleus; MV, medial vestibular nucleus; LDT, laterodorsal tegmental nucleus; PRNc, pontine reticular nucleus; MDRN, medullary reticular nucleus; IO, accessory inferior olivary nucleus; VIS5, visual cortex, layer 5; RGC, retinal ganglion cell.

Fig. 5. Afferent and efferent projections of rodent IGL. (A) Sources of afferent projections to IGL are colored green. (B) Brain regions innervated by IGL neurons are depicted in orange. IGL, intergeniculate leaflet; LP, lateral posterior thalamic nucleus; PP, PP; ZI, zona incerta; SPF, subparafascicular nucleus; RH, rhomboid nucleus; RE, reuniens nucleus; PVT, paraventricular nucleus; SCN, suprachiasmatic nucleus; RCH, retrochiasmatic area; SBPV, subparaventricular zone; AHN, anterior hypothalamic area; PH, posterior hypothalamic nucleus; VMH, ventromedial hypothalamic nucleus; DMH, dorsomedial nucleus of the hypothalamus; SC, superior colliculus; PRT, pretectal region; MT, medial terminal nucleus; LT, lateral terminal nucleus; DT, dorsal terminal nucleus; DR, dorsal raphe nucleus; PAG, periaqueductal gray; CUN, cuneiform nucleus; PPN, pedunculopontine nucleus; RR, retrorubral nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; Bar, Barrington’s nucleus; MV, medial vestibular nucleus; LAV, lateral vestibular nucleus; SUV, superior vestibular nucleus; PRNc, pontine reticular nucleus; VIS5, visual cortex, layer 5; ACA5/6, anterior cingulate area, layer 5 and 6; RGC, retinal ganglion cell.

dLGN efferents

Of the retinorecipient thalamic nuclei discussed here, the dLGN has by far the fewest targets of efferent projections. In fact, the relative simplicity of efferent projections from dLGN is striking and emphasizes a singular function of dLGN in processing and transferring image-forming visual information. TC relay cells project axons to only two ipsilateral regions in nocturnal rodents: primary visual cortex and TRN (Rafols & Valverde, Reference Rafols and Valverde1973; Towns et al., Reference Towns, Burton, Kimberly and Fetterman1982; Reese & Cowey, Reference Reese and Cowey1983; Crabtree & Killackey, Reference Crabtree and Killackey1989; López-Bendito & Molnár, Reference López-Bendito and Molnár2003; Jurgens et al., Reference Jurgens, Bell, McQuiston and Guido2012). Recent studies in mice have demonstrated that projections to visual cortex exhibit class-specificity, with W-like relay cells in the dorsolateral shell of dLGN, conveying direction-selective visual information to layer I and Y-like and X-like relay cells projecting to layer IV of primary visual cortex (Cruz-Martín et al., Reference Cruz-Martín, El-Danaf, Osakada, Sriram, Dhande, Nguyen, Callaway, Ghosh and Huberman2014; Bickford et al., Reference Bickford, Zhou, Krahe, Govindaiah and Guido2015). At present, it remains unclear whether these three classes of TC relay cells make unique connections with TRN neurons in nocturnal rodents. It is worth mentioning that, in cat, Y-cells provide the predominant dLGN input to the perigeniculate nucleus, the visual sector of cat TRN which overlies dLGN (Dubin & Cleland, Reference Dubin and Cleland1977; Friedlander et al., Reference Friedlander, Lin and Sherman1980).

vLGN and IGL efferents

Efferents from vLGNe and IGL target many of the same brain regions and, in contrast to the simplicity of the dLGN efferents, are diverse and far-reaching. Importantly, neither vLGNe nor IGL project efferents to visual cortex or any other cortical region (Harrington, Reference Harrington1997). Instead, their efferents innervate regions that regulate visuomotor function, eye movement, vestibular function, and circadian function (Moore et al., Reference Moore, Weis and Moga2000) (Figs. 4 and 5). A noteworthy and major target of efferents from vLGNe and IGL is the superior colliculus, a region intimately involved in multisensory integration, visuomotor function, and coordination of eye movements. Projections from vLGNe and IGL arborize in all layers of the ipsilateral SC and represent the largest thalamic source of afferents to SC in nocturnal rodents (Matute & Streit, Reference Matute and Streit1985; Taylor et al., Reference Taylor, Jeffery and Lieberman1986). However, whether these projections are excitatory, inhibitory, or modulatory remains unresolved. Efferents from both vLGNe and/or IGL also target other midbrain structures, including the ipsilateral OPN, the nucleus of the OT, and the anterior pretectal nucleus (Cadusseau & Roger, Reference Cadusseau and Roger1991; Harrington, Reference Harrington1997; Moore et al., Reference Moore, Weis and Moga2000). Other regions associated with eye movements, visuomotor function, and attention innervated by vLGNe and IGL include two of the accessory optic system nuclei (lateral terminal nucleus and medial terminal nucleus; Swanson et al., Reference Swanson, Cowan and Jones1974; Ribak & Peters, Reference Ribak and Peters1975), zona incerta (Brauer & Schober, Reference Brauer and Schober1982), and nuclei within the pons (Harrington, Reference Harrington1997).

In addition to visuomotor functions, vLGNe and IGL efferents project to both hypothalamic and thalamic regions (Moore et al., Reference Moore, Weis and Moga2000). The largest of these projections innervates the SCN, and is referred to as the geniculohypothalamic (GH) tract. GH projections are GABAergic, are important for modulating circadian function (Harrington, Reference Harrington1997), and originate from NPY⁺ or Enk⁺ neurons in the IGL (Card & Moore, Reference Card and Moore1982; Harrington et al., Reference Harrington, DeCoursey, Bruce and Buggy1987; Card & Moore, Reference Card and Moore1989). A separate set of neurons in vLGNe and IGL innervate contralateral vLGNe and IGL (Harrington, Reference Harrington1997), contralateral dLGN (Mikkelsen, Reference Mikkelsen1992; Kolmac et al., Reference Kolmac, Power and Mitrofanis2000), and, at least in higher mammals, pulvinar (Nakamura & Kawamura, Reference Nakamura and Kawamura1988).