Retinocollicular Projection Research Articles

Monocular eye patching modulates ipsilesional reactive saccades and smooth pursuit in patients with left hemispatial neglect

Patients with hemispatial neglect show multiple oculomotor deficits like delayed contralesional saccade latencies, hypometric saccade amplitudes, and impaired smooth pursuit. We aimed to investigate whether modulation of superior colliculus (SC) activity via monocular eye patching improves neglect patients’ eye movements to the contralesional side of space. Thirteen neglect patients with left-hemispheric (LH) stroke, 22 neglect patients with right-hemispheric (RH) stroke, and 24 healthy controls completed a video-oculographic examination of horizontal smooth pursuit and reactive saccades twice, while the left or right eye was covered with an eye patch. Independent of the eye patch position, LH and RH patients showed enlarged saccade latencies toward contralesional stimuli. In addition, both during smooth pursuit and reactive saccades, RH patients made significantly fewer rightward saccades when the right than when the left eye was patched. Moreover, during reactive saccades, RH patients made significantly fewer right than left saccades, but only when the right eye was patched. These findings suggest that the ipsilesional eye patch modulated ipsilesional ocular performance in the RH group, presumably resulting from differences in SC activity. Yet, ipsilesional eye patching did not improve eye movements to the contralesional side of space, possibly due to the incomplete contralateral retinocollicular projection in humans.

Dynamic Alterations of Retinal EphA5 Expression in Retinocollicular Map Plasticity.

The topographically ordered retinocollicular projection is an excellent system for studying the mechanism of axon guidance. Gradients of EphA receptors in the retina and ephrin-As in the superior colliculus (SC) pattern the anteroposterior axis of the retinocollicular map, but whether they are involved in map plasticity after injury is unknown. Partial damage to the caudal SC at birth creates a compressed, complete retinotopic map in the remaining SC without affecting visual response properties. Previously, we found that the gradient of ephrin-A expression in compressed maps is steeper than normal, suggesting an instructive role in compression. Here we measured EphA5 mRNA and protein levels after caudal SC damage in order to test the hypothesis that changes in retinal EphA5 expression occur that are complementary to the changes in collicular ephrin-A expression. We find that the nasotemporal gradient of EphA5 receptor expression steepens in the retina and overall expression levels change dynamically, especially in temporal retina, supporting the hypothesis. This change in receptor expression occurs after the change in ephrin-A ligand expression. We propose that changes in the retinal EphA5 gradient guide recovery of the retinocollicular projection from early injury. This could occur directly through the change in EphA5 expression instructing retino-SC map compression, or through ephrin-A ligand signaling instructing a change in EphA5 receptor expression that in turn signals the retinocollicular map to compress. Understanding what molecular signals direct compensation for injury is essential to developing rehabilitative strategies and maximizing the potential for recovery.

Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice.

Eph receptors play pivotal roles in the axon guidance of retinal ganglion cells (RGCs) at the optic chiasm and the establishment of the topographic retinocollicular map. We previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) is specifically involved in the control of retinotectal projections in chicks through the dephosphorylation of EphA and EphB receptors. We subsequently revealed that all the mouse R3 subfamily members (PTPRB, PTPRH, PTPRJ, and PTPRO) of the receptor protein tyrosine phosphatase (RPTP) family inhibited Eph receptors as their substrates in cultured mammalian cells. We herein investigated the functional roles of R3 RPTPs in the projection of mouse retinal axon of both sexes. Ptpro and Ptprj were expressed in mouse RGCs; however, Ptprj expression levels were markedly higher than those of Ptpro Consistent with their expression levels, Eph receptor activity was significantly enhanced in Ptprj-knock-out (Ptprj-KO) retinas. In Ptprj-KO and Ptprj/Ptpro-double-KO (DKO) mice, the number of retinal axons that projected ipsilaterally or to the contralateral eye was significantly increased. Furthermore, retinal axons in Ptprj-KO and DKO mice formed anteriorly shifted ectopic terminal zones in the superior colliculus (SC). We found that c-Abl (Abelson tyrosine kinase) was downstream of ephrin-Eph signaling for the repulsion of retinal axons at the optic chiasm and in the SC. c-Abl was identified as a novel substrate for PTPRJ and PTPRO, and the phosphorylation of c-Abl was upregulated in Ptprj-KO and DKO retinas. Thus, PTPRJ regulates retinocollicular projections in mice by controlling the activity of Eph and c-Abl kinases.SIGNIFICANCE STATEMENT Correct retinocollicular projection is a prerequisite for proper vision. Eph receptors have been implicated in retinal axon guidance at the optic chiasm and the establishment of the topographic retinocollicular map. We herein demonstrated that protein tyrosine phosphatase receptor type J (PTPRJ) regulated retinal axonal projections by controlling Eph activities. The retinas of Ptprj-knock-out (KO) and Ptpro/Ptprj double-KO mice exhibited significantly enhanced Eph activities over those in wild-type mice, and their axons showed defects in pathfinding at the chiasm and retinocollicular topographic map formation. We also revealed that c-Abl (Abelson tyrosine kinase) downstream of Eph receptors was regulated by PTPRJ. These results indicate that the regulation of the ephrin-Eph-c-Abl axis by PTPRJ plays pivotal roles in the proper central projection of retinal axons during development.

Developmental retinal ganglion cell death and retinotopicity of the murine retinocollicular projection.

During mammalian visual system development, retinal ganglion cells (RGCs) undergo extensive apoptotic death. In mouse retina, approximately 50% of RGCs present at birth (postnatal day 0; P0) die by P5, at a time when axons innervate central targets such as the superior colliculus (SC). We examined whether RGCs that make short-range axonal targeting errors within the contralateral SC are more likely to be eliminated during the peak period of RGC death (P1-P5), compared with RGCs initially making more accurate retinotopic connections. A small volume (2.3 nL) of the retrograde nucleophilic dye Hoechst 33342 was injected into the superficial left SC of anesthetized neonatal C57Bl/6J mice at P1 (n = 5) or P4 (n = 8), and the contralateral retina wholemounted 12 hr later. Retrogradely labelled healthy and dying (pyknotic) RGCs were identified by morphological criteria and counted. The percentage of pyknotic RGCs was analyzed in relation to distance from the area of highest density RGC labelling, presumed to represent the most topographically accurate population. As expected, pyknotic RGC density at P1 was significantly greater than P4 (p < 0.05). At P4, the density of healthy RGCs 500-750 µm away from the central region was significantly less, although this was not reflected in altered pyknotic rates. However, at P1 there was a trend (p = 0.08) for an increased proportion of pyknotic RGCs, specifically in temporal parts of the retina outside the densely labelled center. Overall, the lack of consistent association between short-range targeting errors and cell death suggests that most postnatal RGC loss is not directly related to topographic accuracy. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 51-60, 2018.

The effects of left and right monocular viewing on hemispheric activation

ABSTRACTBackground/Objectives: Prior research has revealed that whereas activation of the left hemisphere primarily increases the activity of the parasympathetic division of the autonomic nervous system, right-hemisphere activation increases the activity of the sympathetic division. In addition, each hemisphere primarily receives retinocollicular projections from the contralateral eye. A prior study reported that pupillary dilation was greater with left- than with right-eye monocular viewing. The goal of this study was to test the alternative hypotheses that this asymmetric pupil dilation with left-eye viewing was induced by activation of the right-hemispheric-mediated sympathetic activity, versus a reduction of left-hemisphere-mediated parasympathetic activity. Thus, this study was designed to learn whether there are changes in hemispheric activation, as measured by alteration of spontaneous alpha activity, during right versus left monocular viewing.Method: High-density electroencephalography (EEG) was recorded from healthy participants viewing a crosshair with their right, left, or both eyes.Results: There was a significantly less alpha power over the right hemisphere’s parietal-occipital area with left and binocular viewing than with right-eye monocular viewing.Conclusions: The greater relative reduction of right-hemisphere alpha activity during left than during right monocular viewing provides further evidence that left-eye viewing induces greater increase in right-hemisphere activation than does right-eye viewing.

Monocular denervation of visual nuclei modulates APP processing and sAPPα production: A possible role on neural plasticity

Amyloid precursor protein (APP) is essential to physiological processes such as synapse formation and neural plasticity. Sequential proteolysis of APP by beta- and gamma-secretases generates amyloid-beta peptide (Aβ), the main component of senile plaques in Alzheimer Disease. Alternative APP cleavage by alpha-secretase occurs within Aβ domain, releasing soluble α-APP (sAPPα), a neurotrophic fragment. Among other functions, sAPPα is important to synaptogenesis, neural survival and axonal growth. APP and sAPPα levels are increased in models of neuroplasticity, which suggests an important role for APP and its metabolites, especially sAPPα, in the rearranging brain. In this work we analyzed the effects of monocular enucleation (ME), a classical model of lesion-induced plasticity, upon APP content, processing and also in secretases levels. Besides, we addressed whether α-secretase activity is crucial for retinotectal remodeling after ME. Our results showed that ME induced a transient reduction in total APP content. We also detected an increase in α-secretase expression and in sAPP production concomitant with a reduction in Aβ and β-secretase contents. These data suggest that ME facilitates APP processing by the non-amyloidogenic pathway, increasing sAPPα levels. Indeed, the pharmacological inhibition of α-secretase activity reduced the axonal sprouting of ipsilateral retinocollicular projections from the intact eye after ME, suggesting that sAPPα is necessary for synaptic structural rearrangement. Understanding how APP processing is regulated under lesion conditions may provide new insights into APP physiological role on neural plasticity.

Nicotine-induced plasticity in the retinocollicular pathway: Evidence for involvement of amyloid precursor protein

During early postnatal development retinocollicular projections undergo activity-dependent synaptic refinement that results in the formation of precise topographical maps in the visual layers of the superior colliculus (SC). Amyloid Precursor Protein (APP) is a widely expressed transmembrane glycoprotein involved in the regulation of several aspects of neural development, such as neurite outgrowth, synapse formation and plasticity. Stimulation of cholinergic system has been found to alter the expression and processing of APP in different cell lines. Herein, we investigated the effect of nicotine on the development of retinocollicular pathway and on APP metabolism in the SC of pigmented rats. Animals were submitted to intracranial Elvax implants loaded with nicotine or phosphate-buffered saline (vehicle) at postnatal day (PND) 7. The ipsilateral retinocollicular pathway of control and experimental groups was anterogradely labeled either 1 or 3weeks after surgery (PND 14 or PND 28). Local nicotine exposure produces a transitory sprouting of uncrossed retinal axons outside their main terminal zones. Nicotine also increases APP content and its soluble neurotrophic fragment sAPPα. Furthermore, nicotine treatment upregulates nicotinic acetylcholine receptor α7 and β2 subunits. Taken together, these data indicate that nicotine disrupts the ordering and topographic mapping of axons in the retinocollicular pathway and facilitates APP processing through the nonamyloidogenic pathway, suggesting that sAPPα may act as a trophic agent that mediates nicotine-induced morphological plasticity.

Ephrin-As are required for the topographic mapping but not laminar choice of physiologically distinct RGC types.

In the retinocollicular projection, the axons from functionally distinct retinal ganglion cell (RGC) types form synapses in a stereotypical manner along the superficial to deep axis of the superior colliculus (SC). Each lamina contains an orderly topographic map of the visual scene but different laminae receive inputs from distinct sets of RGCs, and inputs to each lamina are aligned with the others to integrate parallel streams of visual information. To determine the relationship between laminar organization and topography of physiologically defined RGC types, we used genetic and anatomical axon tracing techniques in wild type and ephrin-A mutant mice. We find that adjacent RGCs of the same physiological type can send axons to both ectopic and normal topographic locations, supporting a penetrance model for ephrin-A independent mapping cues. While the overall laminar organization in the SC is unaffected in ephrin-A2/A5 double mutant mice, analysis of the laminar locations of ectopic terminations shows that the topographic maps of different RGC types are misaligned. These data lend support to the hypothesis that the retinocollicular projection is a superimposition of a number of individual two-dimensional topographic maps that originate from specific types of RGCs, require ephrin-A signaling, and form independently of the other maps.

Supraliminal but No Subliminal Priming by High-Spatial Frequency Faces in a Face-Sex Discrimination Task

It has been argued that visual subliminal processing of face-inherent sex information might depend on the retino-collicular projection. In the current study, we tested this possibility. Based on the known exclusive sensitivity of the retino-collicular projection for low spatial frequencies (LSF), we derived the following predictions. First, masked and, therefore, subliminal high-spatial frequency (HSF) face primes would not be processed, but, secondly, masked unfiltered face primes, thirdly, masked LSF face primes, and, fourthly, unmasked HSF primes should be processed and should lead to a congruence effect—that is, faster responses (better performance) in congruent conditions, with face primes and face targets of the same sex, as compared to incongruent conditions, with face primes and face targets of different sexes. These predictions were borne out in altogether three experiments. In Experiment 1, we observed that masked unfiltered primes created a congruence effect and that masked HSF primes failed to do so. In Experiment 2, we found that masked unfiltered primes and masked LSF primes both created significant congruence effects of about the same size. Finally, in Experiment 3, we demonstrated that unmasked HSF primes led to a congruence effect, whereas masked HSF primes failed to do so. Also, masking led to the subliminal presentation of the primes, as indicated by the fact that our participants were unaware of the masked but not the unmasked face primes. Together, these findings are in general agreement with an assumed origin of subliminal (or unaware) face processing along the magno-cellular projection of the human visual system.

Target-Independent EphrinA/EphA-Mediated Axon-Axon Repulsion as a Novel Element in Retinocollicular Mapping

SummaryEphrinAs and EphAs play critical roles during topographic map formation in the retinocollicular projection; however, their complex expression patterns in both the retina and superior colliculus (SC) have made it difficult to uncover their precise mechanisms of action. We demonstrate here that growth cones of temporal axons collapse when contacting nasal axons in vitro, and removing ephrinAs from axonal membranes by PI-PLC treatment abolishes this response. In conditional knockout mice, temporal axons display no major targeting defects when ephrinA5 is removed only from the SC, but substantial mapping defects were observed when ephrinA5 expression was removed from both the SC and from the retina, with temporal axons invading the target areas of nasal axons. Together, these data indicate that ephrinA5 drives repellent interactions between temporal and nasal axons within the SC, and demonstrates for the first time that target-independent mechanisms play an essential role in retinocollicular map formation in vivo.

The effects of constrained left versus right monocular viewing on the autonomic nervous system

Asymmetrical activation of right and left hemispheres differentially influences the autonomic nervous system. Additionally, each hemisphere primarily receives retinocollicular projections from the contralateral eye. To learn if asymmetrical hemispheric activation induced by monocular viewing would influence relative pupillary size and respiratory hippus variability (RHV), a measure of parasympathetic activity, healthy participants had their left, right or neither eye patched. Pupillary sizes were then recorded with infrared pupillography. Pupillary dilation was significantly greater with left than right eye viewing. RHV, however, was not different between eye viewing conditions. These differences in pupil dilatation may have been caused by relatively greater activation of the right hemispheric-mediated sympathetic activity induced by left monocular viewing or relatively greater deactivation of the left hemispheric-mediated parasympathetic activity induced by right eye patching. The absence of an asymmetry in RHV, however, suggests that hemispheric asymmetry of sympathetic activation was primarily responsible for this ocular asymmetry of pupil dilation.

Different roles of axon guidance cues and patterned spontaneous activity in establishing receptive fields in the mouse superior colliculus.

Visual neurons in the superior colliculus (SC) respond to both bright (On) and dark (Off) stimuli in their receptive fields. This receptive field property is due to proper convergence of On- and Off-centered retinal ganglion cells to their target cells in the SC. In this study, we have compared the receptive field structure of individual SC neurons in two lines of mutant mice that are deficient in retinotopic mapping: the ephrin-A knockouts that lack important retinocollicular axonal guidance cues and the nAChR-β2 knockouts that have altered activity-dependent refinement of retinocollicular projections. We find that even though the receptive fields are much larger in the ephrin-A knockouts, their On–Off overlap remains unchanged. These neurons also display normal level of selectivity for stimulus direction and orientation. In contrast, the On–Off overlap is disrupted in the β2 knockouts. Together with the previous finding of disrupted direction and orientation selectivity in the β2 knockout mice, our results indicate that molecular guidance cues and activity-dependent processes play different roles in the development of receptive field properties in the SC.

Характеристики квантового вивільнення глутамату та гамк у синапсах між кокультивованими гангліозними клітинами сітківки та нейронами superior colliculus

We investigated features of quantal release of glutamate and GABA in synapses between retinal ganglion cells (RGC) and superior colliculus (SC) neurons in coculture using dual patch-clamp technique. The main quantal characteristics of neurotransmitters release were defined on the basic of quantal analysis. Number of released quanta distributions for both neurotransmitters were corresponded to the binomial law. It was shown that evoked postsynaptic currents (PSC) in SC neurons as response to generation of action potential (AP) in RGC were mediated by simultaneous release at least from 2 to 14 quanta of glutamate and 2 quanta of GABA. Thereby high efficacy of excitatory and inhibitory signals transmission is guaranteed in retinocollicular projections. It is supposed that multiquantal character of the neurotransmitters release can be related to simultaneous involvement of several closely adjacent excited terminals, each of which possesses one active zone, or by one terminal with several.

Overexpression of Ten-m3 in the retina alters ipsilateral retinocollicular projections in the wallaby (Macropus eugenii)

Retinal projections to the superior colliculus are organised into retinotopic maps. Binocular vision requires that inputs from the two eyes map in register with each other. Studies in mice lacking Ten-m3, a homophilic transmembrane protein, indicate that it plays a key role in this process by influencing ipsilateral projections. The postnatal, ex utero development of the wallaby allows the targeted manipulation of molecules of interest during development. The distribution of mRNA for Ten-m3 in the retina and superior colliculus of the wallaby, and the effects of its spatiotemporally restricted retinal overexpression was investigated, in particular on the mapping of ipsilateral projections. Quantitative polymerase chain reaction found that Ten-m3 mRNA is expressed at relatively higher levels in the retina and colliculus early in development. Further, it is higher in ventral than dorsal retina, and increased in the retinotopically corresponding medial compared to lateral superior colliculus. In situ hybridisation demonstrated an increasing dorsoventral gradient in retinal ganglion cells was matched to an increasing lateromedial gradient in the superior colliculus. Overexpression of Ten-m3 by in vivo retinal electroporation produced an increase in ipsilateral projections to the binocular rostromedial colliculus, fitting with the proposal that Ten-m3 mediates mapping by attractant homophilic interactions. Retrograde labelling of the projection from this region suggested that overexpression produces a shift in the axons of existing ipsilaterally projecting ganglion cells rather than a rerouting of the axons of contralaterally projecting cells. Retinal manipulation of Ten-m3 levels produces changes in ipsilateral mapping, supporting a role for it in binocular mapping.

Subcortical human face processing? Evidence from masked priming.

Face processing without awareness might depend on subcortical structures (retino-collicular projection), cortical structures, or a combination of the two. The present study was designed to tease apart these possibilities. Because the retino-collicular projection is more sensitive to low spatial frequencies, we used masked (subliminal) face prime images that were spatially low-pass filtered, or high-pass filtered. The masked primes were presented in the periphery prior to clearly visible target faces. Participants had to discriminate between male and female target faces and we recorded prime-target congruence effects--that is, the difference in discrimination speed between congruent pairs (with prime and target of the same sex) and incongruent pairs (with prime and target of different sexes). In two experiments, we consistently find that masked low-pass filtered face primes produce a congruence effect and that masked high-pass filtered face primes do not. Together our results support the assumption that the retino-collicular route which carries the low spatial frequencies also conveys sex specific features of face images contributing to subliminal face processing.

Creb is modulated in the mouse superior colliculus in developmental and experimentally-induced models of plasticity

In the central nervous system long-term plastic processes need the activation of specific gene expression programs and the synthesis of new protein in order to occur. A transcription factor fundamental for several plasticity mechanisms in various CNS areas is the cAMP response element-binding protein, CREB. This factor is activated through phosphorylation at its Serine 133 residue by multiple signaling pathways. Little is known about CREB role in the superior colliculus, a midbrain area considered an experimentally useful model for the study of neuronal plasticity processes. In the present work we studied by Western blot analysis the modulation of CREB expression and activation in the mouse superior colliculus in three models of neuronal plasticity: (1) developmental plasticity; (2) lesion-induced plasticity; (3) and fluoxetine-induced restored plasticity. We used an antibody that detects endogenous level of the total CREB protein (anti-TCREB) to identify possible modulations at CREB expression level, and a second antibody (anti-PCREB) that detects endogenous level of CREB only when it is phosphorylated at Ser133, to identify modifications of CREB activation state. The results showed that: (1) the expression and activation of CREB increase during the development of the superior colliculus in temporal correlation with the plastic process of refinement of retino-collicular projections; (2) the activation of CREB is induced by a monocular lesion performed during the critical period for plasticity in young animals but not when performed in less plastic juvenile mice; (3) the expression and activation of CREB increase in adult animals treated with fluoxetine, known to restore high levels of plasticity in adult animals. These results suggest that CREB transcription factor plays a fundamental role in plasticity processes also at the level of the mouse superior colliculus.

Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity

Although the organization of neuronal circuitry is shaped by activity patterns, the capacity to modify and/or optimize the structure and function of whole projection pathways using external stimuli is poorly defined. We investigate whether neuronal activity induced by pulsed magnetic fields (PMFs) alters brain structure and function. We delivered low-intensity PMFs to the posterior cranium of awake, unrestrained mice (wild-type and ephrin-A2A5(-/-)) that have disorganized retinocollicular circuitry and associated visuomotor deficits. Control groups of each genotype received sham stimulation. Following daily stimulation for 14 d, we measured biochemical, structural (anterograde tracing), and functional (electrophysiology and behavior) changes in the retinocollicular projection. PMFs induced BDNF, GABA, and nNOS expression in the superior colliculus and retina of wild-type and ephrin-A2A5(-/-) mice. Furthermore, in ephrin-A2A5(-/-) mice, PMFs corrected abnormal neuronal responses and selectively removed inaccurate ectopic axon terminals to improve structural and functional organization of their retinocollicular projection and restore normal visual tracking behavior. In contrast, PMFs did not alter the structure or function of the normal projection in wild-type mice. Sham PMF stimulation had no effect on any mice. Thus, PMF-induced biochemical changes are congruent with its capacity to facilitate beneficial reorganization of abnormal neural circuits without disrupting normal connectivity and function.

Nutritional restriction of omega-3 fatty acids alters topographical fine tuning and leads to a delay in the critical period in the rodent visual system

The development and maturation of sensory systems depends on the correct pattern of connections which occurs during a critical period when axonal elimination and synaptic plasticity are involved in the formation of topographical maps. Among the mechanisms involved in synaptic stabilization, essential fatty acids (EFAs), available only through diet, appear as precursors of signaling molecules involved in modulation of gene expression and neurotransmitter release. Omega-3 fatty acids, such as docosahexaenoic acid (DHA), are considered EFAs and are accumulated in the brain during fetal period and neonatal development. In this study, we demonstrated the effect of omega-3/DHA nutritional restriction in the long-term stabilization of connections in the visual system. Female rats were fed 5weeks before mating with either a control (soy oil) or a restricted (coconut oil) diet. Litters were fed until postnatal day 13 (PND13), PND28 or PND42 with the same diets when they received an intraocular injection of HRP. Another group received a single retinal lesion at the temporal periphery at PND21. Omega-3 restriction induced an increase in the optical density in the superficial layers of the SC, as a result of axonal sprouting outside the main terminal zones. This effect was observed throughout the SGS, including the ventral and intermediate sub-layers at PND13 and also at PND28 and PND42. The quantification of optical densities strongly suggests a delay in axonal elimination in the omega3− groups. The supplementation with fish oil (DHA) was able to completely reverse the abnormal expansion of the retinocollicular projection. The same pattern of expanded terminal fields was also observed in the ipsilateral retinogeniculate pathway. The critical period window was studied in lesion experiments in either control or omega-3/DHA restricted groups. DHA restriction induced an increased sprouting of intact, ipsilateral axons at the deafferented region of the superior colliculus compared to the control group, revealing an abnormal extension of the critical period. Finally, in omega-3 restricted group we observed in the collicular visual layers normal levels of GAP-43 with decreased levels of its phosphorylated form, p-GAP-43, consistent with a reduction in synaptic stabilization. The data indicate, therefore, that chronic dietary restriction of omega-3 results in a reduction in DHA levels which delays axonal elimination and critical period closure, interfering with the maintenance of terminal fields in the visual system.

Competition is a driving force in topographic mapping

Topographic maps are the primary means of relaying spatial information in the brain. Understanding the mechanisms by which they form has been a goal of experimental and theoretical neuroscientists for decades. The projection of the retina to the superior colliculus (SC)/tectum has been an important model used to show that graded molecular cues and patterned retinal activity are required for topographic map formation. Additionally, interaxon competition has been suggested to play a role in topographic map formation; however, this view has been recently challenged. Here we present experimental and computational evidence demonstrating that interaxon competition for target space is necessary to establish topography. To test this hypothesis experimentally, we determined the nature of the retinocollicular projection in Math5 (Atoh7) mutant mice, which have severely reduced numbers of retinal ganglion cell inputs into the SC. We find that in these mice, retinal axons project to the anteromedialj portion of the SC where repulsion from ephrin-A ligands is minimized and where their attraction to the midline is maximized. This observation is consistent with the chemoaffinity model that relies on axon-axon competition as a mapping mechanism. We conclude that chemical labels plus neural activity cannot alone specify the retinocollicular projection; instead axon-axon competition is necessary to create a map. Finally, we present a mathematical model for topographic mapping that incorporates molecular labels, neural activity, and axon competition.

In vivo evaluation of retinal and callosal projections in early postnatal development and plasticity using manganese-enhanced MRI and diffusion tensor imaging

The rodents are an excellent model for understanding the development and plasticity of the visual system. In this study, we explored the feasibility of Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) at 7 T for in vivo and longitudinal assessments of the retinal and callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Along the retinal pathways, unilateral intravitreal Mn2+ injection resulted in Mn2+ uptake and transport in normal neonatal visual brains at postnatal days (P) 1, 5 and 10 with faster Mn2+ clearance than the adult brains at P60. The reorganization of retinocollicular projections was also detected by significant Mn2+ enhancement by 2%-10% in the ipsilateral superior colliculus (SC) of normal neonatal rats, normal adult mice and adult rats after neonatal monocular enucleation (ME) but not in normal adult rats or adult rats after monocular deprivation (MD). DTI showed a significantly higher fractional anisotropy (FA) by 21% in the optic nerve projected from the remaining eye of ME rats compared to normal rats at 6 weeks old, likely as a result of the retention of axons from the ipsilaterally uncrossed retinal ganglion cells, whereas the anterior and posterior retinal pathways projected from the enucleated or deprived eyes possessed lower FA after neonatal binocular enucleation (BE), ME and MD by 22%-56%, 18%-46% and 11%-15% respectively compared to normal rats, indicative of neurodegeneration or immaturity of white matter tracts. Along the visual callosal pathways, intracortical Mn2+ injection to the visual cortex of BE rats enhanced a larger projection volume by about 74% in the V1/V2 transition zone of the contralateral hemisphere compared to normal rats, without apparent DTI parametric changes in the splenium of corpus callosum. This suggested an adaptive change in interhemispheric connections and spatial specificity in the visual cortex upon early blindness. The results of this study may help determine the mechanisms of axonal uptake and transport, microstructural reorganization and functional activities in the living visual brains during development, diseases, plasticity and early interventions in a global and longitudinal setting.