Superior Colliculus Does Play Dice
Authors: Daniel Kerschensteiner
Journal: Neuron (2015)

Random is not a word often used in describing nervous system organization and its development. Yet, in this issue of Neuron, Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar identify stochastic interactions of molecular and activity-dependent forces that can produce heterogeneous retinocollicular maps. Random is not a word often used in describing nervous system organization and its development. Yet, in this issue of Neuron, Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar identify stochastic interactions of molecular and activity-dependent forces that can produce heterogeneous retinocollicular maps. Topographic maps, in which neighboring neurons have similar functional properties (e.g., adjacent visual receptive fields), are a fundamental feature of sensory and motor systems. To produce topographic maps, nearby neurons in an input region need to connect to nearby neurons in a target region. How developing neurons establish such spatially ordered connectivity, particularly when targets are far away and intervening axons disorganized, is an intriguing question, addressed by Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar for projections from the retina to superior colliculus (SC). Retinal ganglion cell (RGC) axons innervate superficial layers of SC (Dhande et al., 2011Dhande O.S. Hua E.W. Guh E. Yeh J. Bhatt S. Zhang Y. Ruthazer E.S. Feller M.B. Crair M.C. J. Neurosci. 2011; 31: 3384-3399Crossref PubMed Scopus (87) Google Scholar), a midbrain structure, which integrates visual input with auditory and somatosensory information and generates commands that direct head and eye movements toward salient features of the environment (May, 2006May P.J. Prog. Brain Res. 2006; 151: 321-378Crossref PubMed Scopus (436) Google Scholar). In the retinocollicular projection, the naso-temporal (N-T) axis of the retina is mapped onto the anterior-posterior (A-P) axis of SC, and the dorso-ventral axis of the retina is mapped onto the medio-lateral axis of SC. This superficial map of visual space is aligned with sensory and motor maps in intermediate and deep layers of SC, such that activity in motor layers directs an animal’s gaze to the location represented in the overlying visual map (Schiller and Stryker, 1972Schiller P.H. Stryker M. J. Neurophysiol. 1972; 35: 915-924Crossref PubMed Scopus (469) Google Scholar). In this issue of Neuron, Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar examine how RGC axons achieve ordered distributions along the A-P axis of SC. This projection has long served as a model system for studies of topographic mapping (Cang and Feldheim, 2013Cang J. Feldheim D.A. Annu. Rev. Neurosci. 2013; 36: 51-77Crossref PubMed Scopus (168) Google Scholar). As part of his chemoaffinity hypothesis, Sperry proposed that “cytochemical gradients” on RGC axons and SC neurons define the positions of their connections (Sperry, 1963Sperry R.W. Proc. Natl. Acad. Sci. USA. 1963; 50: 703-710Crossref PubMed Scopus (1371) Google Scholar). Matching this prediction, EphA receptors were found to be expressed in a low-nasal to high-temporal gradient in RGCs, while SC neurons present high levels of ephrin-A ligands near the posterior and low levels near the anterior pole (McLaughlin and O’Leary, 2005McLaughlin T. O’Leary D.D. Annu. Rev. Neurosci. 2005; 28: 327-355Crossref PubMed Scopus (332) Google Scholar). In addition, RGCs express high levels of ephrin-As in the nasal and low levels of ephrin-As in the temporal retina, whereas posterior and anterior SC neurons contain low and high levels of EphAs, respectively (McLaughlin and O’Leary, 2005McLaughlin T. O’Leary D.D. Annu. Rev. Neurosci. 2005; 28: 327-355Crossref PubMed Scopus (332) Google Scholar). Because EphA/ephrin-A interactions mediate bidirectional repulsive signals, these opposing bilateral gradients are ideally suited to guide the mapping of RGC axons in SC. Consistent with this notion, in mice lacking EphAs or ephrin-As, RGC axons establish termination zones that are normal in structure and function but randomly positioned along the A-P axis of SC (Cang and Feldheim, 2013Cang J. Feldheim D.A. Annu. Rev. Neurosci. 2013; 36: 51-77Crossref PubMed Scopus (168) Google Scholar). While receptor and ligand knockout mice demonstrate the importance of EphA/ephrin-A signaling, they do not reveal how gradients are used to sort RGC axons into precise maps. One critical question is whether each axon finds a unique place of least repulsion independent of other axons, or whether neighboring RGC axons compete for limited resources in SC (e.g., neurotrophic factors) based on their relative EphA/ephrin-A signaling levels. Greg Lemke’s group generated mice in which these alternatives could be distinguished (Brown et al., 2000Brown A. Yates P.A. Burrola P. Ortuño D. Vaidya A. Jessell T.M. Pfaff S.L. O’Leary D.D. Lemke G. Cell. 2000; 102: 77-88Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). EphA and ephrin-A families have multiple members, which interact with similar affinities in different receptor-ligand combinations (McLaughlin and O’Leary, 2005McLaughlin T. O’Leary D.D. Annu. Rev. Neurosci. 2005; 28: 327-355Crossref PubMed Scopus (332) Google Scholar). In wild-type mice, RGCs express EphA5 and EphA6 in graded, and EphA4 in ungraded, fashion. Brown et al., 2000Brown A. Yates P.A. Burrola P. Ortuño D. Vaidya A. Jessell T.M. Pfaff S.L. O’Leary D.D. Lemke G. Cell. 2000; 102: 77-88Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar inserted a cassette expressing EphA3 from and internal ribosome entry site into the Islet2 gene. In Isl2EphA/EphA mice, approximately half the RGCs (Isl2−) express EphA4, EphA5, and EphA6 as in wild-type, whereas the other half (Isl2+) express EphA3 in addition. Isl2− and Isl2+ RGCs are distributed evenly in the retina, and levels of EphA3 in Isl2+ RGCs are constant across the retina. Anatomical tracings showed that retinocollicular maps of Isl2EphA/EphA mice are duplicated along the A-P axis (Brown et al., 2000Brown A. Yates P.A. Burrola P. Ortuño D. Vaidya A. Jessell T.M. Pfaff S.L. O’Leary D.D. Lemke G. Cell. 2000; 102: 77-88Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). This duplication, particularly the anterior shift of axons of temporal Isl2− RGCs, suggests that relative rather than absolute EphA/ephrin-A signaling levels influence the position of RGC axons in SC and led to the formulation of a deterministic model of topographic mapping (Reber et al., 2004Reber M. Burrola P. Lemke G. Nature. 2004; 431: 847-853Crossref PubMed Scopus (99) Google Scholar). In this issue of Neuron, Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar provide empirical and modeling evidence to suggest that topographic mapping of RGC axons instead emerges from a stochastic sorting process driven by relative EphA/ephrin-A signaling levels and spontaneous activity patterns. The authors use intrinsic signal imaging to analyze functional maps of visual space in SCs of wild-type (or Isl2+/+), Isl2EphA/+, and Isl2EphA/EphA mice. Consistent with previous results (Brown et al., 2000Brown A. Yates P.A. Burrola P. Ortuño D. Vaidya A. Jessell T.M. Pfaff S.L. O’Leary D.D. Lemke G. Cell. 2000; 102: 77-88Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, Triplett et al., 2009Triplett J.W. Owens M.T. Yamada J. Lemke G. Cang J. Stryker M.P. Feldheim D.A. Cell. 2009; 139: 175-185Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), they find that representations of visual azimuth in SC are always single in wild-type and always doubled in Isl2EphA/EphA mice (Figure 1). By contrast, retinocollicular development of Isl2EphA/+ mice appears to follow a probability distribution, generating single and doubled maps in about a quarter of the cases and partially duplicated (i.e., mixed) maps in the remaining half of SCs (Figure 1). Five of seven mice exhibited categorically different maps in left and right SCs, excluding variations in genetic background as a source of heterogeneity. The observation that disparate topographies can emerge from identical genetic starting points strongly suggests a stochastic mapping process. Previous anatomical studies of Isl2EphA/+ mice did not report heterogeneity in retinocollicular projections (Brown et al., 2000Brown A. Yates P.A. Burrola P. Ortuño D. Vaidya A. Jessell T.M. Pfaff S.L. O’Leary D.D. Lemke G. Cell. 2000; 102: 77-88Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, Reber et al., 2004Reber M. Burrola P. Lemke G. Nature. 2004; 431: 847-853Crossref PubMed Scopus (99) Google Scholar). To test whether the apparent discrepancy reflects differences in the sensitivity of functional and anatomical assays or may be caused by small sample sizes of previous studies, Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar correlate functional imaging and anatomical tracings in a larger cohort of Isl2EphA/+ mice. The tracing experiments reveal that axons from nasal RGCs form heterogeneous termination zones in Isl2EphA/+ mice: the majority are split in two (similar to previous observations), but a significant fraction are single. Importantly, single termination zones were mostly found in SCs with single functional maps, whereas split termination zones are distributed among SCs with mixed and duplicated functional maps. These results suggest that functional map heterogeneity in Isl2EphA/+ mice reflects variability in the order of RGC axons in SC. To quantitatively explore the axon sorting process, Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar adapt a stochastic model of retinocollicular development (Tsigankov and Koulakov, 2010Tsigankov D. Koulakov A.A. BMC Neurosci. 2010; 11: 155Crossref PubMed Scopus (21) Google Scholar). In this model, the probability that developing RGC axons switch positions depends on the resulting changes in repulsive signaling and local activity correlations. Retinocollicular maps develop prior to vision, when the retina generates spontaneous waves of activity that spread among RGCs and propagate forward through the visual system. As waves spread across the retina they correlate the activity of RGCs in a distance-dependent manner (Kerschensteiner, 2013Kerschensteiner D. Neuroscientist. 2013; 20: 272-290Crossref PubMed Scopus (47) Google Scholar). Seeded with parameters that mimic conditions in wild-type and Isl2EphA/EphA mice, the stochastic model reliably generates single and duplicated topographic maps, respectively. Importantly, when parameters are adjusted to reflect lower levels of EphA3 expression in Isl2EphA/+ compared to Isl2EphA/EphA mice, model runs produce heterogeneous outcomes including single, mixed, and duplicated maps. The parameter values that successfully replicate mapping phenotypes suggest that molecular and activity-dependent forces are roughly equal in strength. Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar therefore explore the contribution of activity patterns to map heterogeneity experimentally. During the period of retinocollicular refinement, retinal waves are mediated by cholinergic transmission. Deletion of the β2 subunit of nicotinic acetylcholine receptors (β2−/− mice) drastically reduces the frequency of waves in vivo and alters their spatiotemporal patterns (Burbridge et al., 2014Burbridge T.J. Xu H.P. Ackman J.B. Ge X. Zhang Y. Ye M.J. Zhou Z.J. Xu J. Contractor A. Crair M.C. Neuron. 2014; 84: 1049-1064Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar find that functional maps of Isl2EphA/+ β2−/− mice are uniformly single (Figure 1). Through correlation-based Hebbian plasticity mechanisms, retinal waves are thought to exert an attractive force, which drives neighboring RGCs to converge onto overlapping targets (Kerschensteiner, 2013Kerschensteiner D. Neuroscientist. 2013; 20: 272-290Crossref PubMed Scopus (47) Google Scholar). The observation that map coherence in SC is increased when wave frequency is reduced is thus unexpected. Given the broader spatial correlations of activity patterns in β2−/− compared to wild-type mice (Burbridge et al., 2014Burbridge T.J. Xu H.P. Ackman J.B. Ge X. Zhang Y. Ye M.J. Zhou Z.J. Xu J. Contractor A. Crair M.C. Neuron. 2014; 84: 1049-1064Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), it seems likely that rather than revealing hidden tendencies of waves to promote map duplication, the results of Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar reflect a broadened attractive force of abnormal activity patterns, which more effectively counteracts the molecular forces driving maps toward duplication in Isl2EphA/+ mice. It would be interesting, in the future, to test whether retinocollicular maps are heterogeneous in Isl2EphA/EphA β2−/− mice. Many neural processes are stochastic, including the will-they-won’t-they dynamics of vesicle fusion at axonal release sites and the trial-and-error approach of dendritic spines in search of synaptic partners. Probabilistic aspects of neural development so far were mostly thought to produce subtle differences in local wiring. The observations of Owens et al., 2015Owens M.T. Feldheim D.A. Stryker M.P. Triplett J.W. Neuron. 2015; 87 (this issue): 1261-1273Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, by contrast, demonstrate the potential of stochastic processes to generate large-scale heterogeneities in nervous system organization. Given the functional disruptions that may result (e.g., from mixed or duplicated retinocollicular maps), the question arises, what is the upside of stochasticity? The answer likely involves the increased adaptive potential of networks whose organization is shaped by dynamic interactions of multiple forces (e.g., molecular gradients and activity patterns). The need for developmental plasticity may be particularly high in structures like SC that register maps of different sensory modalities and/or establish overlapping representations of different response properties in a single map. In the future, it would thus be interesting to explore whether the heterogeneity of retinotopic maps in Isl2EphA/+ mice propagates to auditory, somatosensory, and motor maps deeper in SC (May, 2006May P.J. Prog. Brain Res. 2006; 151: 321-378Crossref PubMed Scopus (436) Google Scholar), and how it affects the overlapping map of orientation selectivity recently identified in visual SC (Feinberg and Meister, 2015Feinberg E.H. Meister M. Nature. 2015; 519: 229-232Crossref PubMed Scopus (70) Google Scholar). Stochastic Interaction between Neural Activity and Molecular Cues in the Formation of Topographic MapsOwens et al.NeuronSeptember 23, 2015In BriefIn this study, Owens et al. demonstrate variability in topographic map organization in a mouse model in which molecular- and activity-dependent forces are rendered nearly equal in balance. These findings suggest an inherent stochasticity in establishment of topography. Full-Text PDF Open Archive