-
[show abstract]
[hide abstract]
ABSTRACT: Brain connections are organized into topographic maps that are precisely aligned both within and across modalities. This alignment facilitates coherent integration of different categories of sensory inputs and allows for proper sensorimotor transformations. Topographic maps are established and aligned by multistep processes during development, including interactions of molecular guidance cues expressed in gradients; spontaneous activity-dependent axonal and dendritic remodeling; and sensory-evoked plasticity driven by experience. By focusing on the superior colliculus, a major site of topographic map alignment for different sensory modalities, this review summarizes current understanding of topographic map development in the mammalian visual system and highlights recent advances in map alignment studies. A major goal looking forward is to reveal the molecular and synaptic mechanisms underlying map alignment and to understand the physiological and behavioral consequences when these mechanisms are disrupted at various scales. Expected final online publication date for the Annual Review of Neuroscience Volume 36 is July 08, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Annual Review of Neuroscience 04/2013; · 25.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The convergence of eye-specific thalamic inputs to visual cortical neurons forms the basis of binocular vision. Inputs from the same eye that signal light increment (On) and decrement (Off) are spatially segregated into subregions, giving rise to cortical receptive fields (RFs) that are selective for stimulus orientation. Here we map RFs of binocular neurons in the mouse primary visual cortex using spike-triggered average. We find that subregions of the same sign (On-On and Off-Off) preferentially overlap between the 2 monocular RFs, leading to binocularly matched orientation tuning. We further demonstrate that such subregion correspondence and the consequent matching of RF orientation are disrupted in mice reared in darkness during development. Surprisingly, despite the lack of all postnatal visual experience, a substantial degree of subregion correspondence still remains. In addition, dark-reared mice show normal monocular RF structures and binocular overlap. These results thus reveal the specific roles of experience-dependent and -independent processes in binocular convergence and refinement of On and Off inputs onto single cortical neurons.
Cerebral Cortex 02/2013; · 6.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Purpose. Glaucoma is characterized by retinal ganglion cell (RGC) death and frequently associated with elevated intraocular pressure (IOP). How RGCs degenerate before death is little understood, so we sought to investigate RGC degeneration in a mouse model of ocular hypertension. Methods. A laser-induced mouse model of chronic ocular hypertension mimicked human high-tension glaucoma. Immunohistochemistry was used to characterize overall RGC loss and an optomotor behavioral test to measure corresponding changes in visual capacity. Changes in RGC functional properties were characterized by a large-scale multi-electrode array (MEA). The transgenic Thy-1-YFP mouse line, in which a small number of RGCs are labeled with yellow fluorescent protein (YFP), permitted investigation of whether sub-types of RGCs or RGCs from particular retinal areas were differentially vulnerable to elevated IOP. Results. Sustained IOP elevation in mice was achieved by laser photocoagulation. We confirmed RGC loss and decreased visual acuity in ocular hypertensive mice. Furthermore, these mice had fewer visually-responsive cells with smaller receptive field sizes compared to controls. We demonstrated that RGC dendritic shrinkage started from the vertical axis of hypertensive eyes and that mono-laminated ON cells were more susceptible to IOP elevation than bi-laminated ON-OFF cells. Moreover, a subgroup of ON RGCs labeled by the SMI-32 antibody exhibited significant dendritic atrophy in the superior quadrant of the hypertensive eyes. Conclusions. RGC degeneration depends on subtype and location in hypertensive eyes. This study introduces a valuable model to investigate how the structural and functional degeneration of RGCs leads to visual impairments.
Investigative ophthalmology & visual science 01/2013; · 3.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Precise connections in the brain result from elaborate processes during development. In the visual system, axonal projections from retinal ganglion cells (RGCs) onto the superior colliculus form a precise retinotopic map. Studies have revealed that the development of retinocollicular maps involves three main factors: graded expression of molecular guidance cues such as EphAs and ephrin-As, activity-dependent processes driven by spontaneous activity in RGCs, and different forms of axonal competition. In this study, we developed a new, versatile model including these factors. We first modeled the selective arborization of RGC axons, mediated by EphA/ephrin-A signaling, without assuming that this initial process instructed the map's final topology. We also derived an integro-differential equation modeling a second, dynamic phase in which activity-dependent plasticity of axonal arbors combined with their competition for collicular resources can deeply remodel the topology of immature maps. Our model hence challenges the view that retinotopic maps are instructed by matching molecular gradients and then merely refined by activity-dependent processes. We reproduce fine features of retinotopic map development in wild-type and various transgenic mice, allowing a new understanding of the underlying mechanisms. Our model predicts that competition is not based on comparisons of axonal EphA receptor levels but rather relies on the optimization of collicular resources mediated by neurotrophic receptors such as p75(NTR). Our model finally clarifies the elusive role of reverse signaling between retinal ephrin-As and collicular EphAs by reproducing for the first time the phenotypes of two mouse genotypes in which this function is altered.
Journal of Neuroscience 07/2012; 32(28):9755-68. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dopaminergic amacrine (DA) cells play multiple and important roles in retinal function. Neurotrophins are known to modulate the number and morphology of DA cells, but the underlying regulatory mechanisms are unclear. Here, we investigate how neurotrophin-3 (NT-3) regulates DA cell density in the mouse retina. We demonstrate that overexpression of NT-3 upregulates DA cell number and leads to a consequent increase in the density of DA cell dendrites. To examine the mechanisms of DA cell density increase, we further investigate the effect of NT-3 overexpression on retinal apoptosis and mitosis during development. We find that NT-3 does not affect the well known wave of retinal cell apoptosis that normally occurs during the first 2 weeks after birth. Instead, overexpression of NT-3 promotes additional mitosis of DA cells at postnatal day 4, but does not affect cell mitosis before birth, the peak period of amacrine cell genesis in wild-type retinas. We next show that retinal explants cultured from birth to day 7 without extra NT-3 produced by lens exhibit similar number of DA cells as in wild type, further supporting the notion that postnatal overexpression of lens-derived NT-3 affects DA cell number. Moreover, the additional mitosis after birth in NT-3-overexpressing mice does not occur in calretinin-positive amacrine cells or PKC-positive rod ON bipolar cells. Thus, the NT-3-triggered wave of cell mitosis after birth is specific for the retinal DA cells.
Journal of Neuroscience 08/2011; 31(35):12663-73. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The DBA/2J mice have been used as an animal model for human pigmentary glaucoma. However, these mice develop various degrees of disease symptoms at different ages, making it difficult to detect pathological changes of retinal degeneration at glaucoma onset. The purpose of this study is to develop a non-invasive assay to identify individual mice that develop visual deficits.
We apply two behavioral tests, a swimming test of visual discrimination and a test of optomotor response, to identify glaucomatous DBA/2J mice. We then examine whether the elevation of intraocular pressure (IOP), the common risk factor for glaucoma, affects visual performances of the DBA/2J mice. We further compare the retinal ganglion cell death, one of the signature glaucoma symptoms, in mice with normal behavior with those with poor visual performances.
Our data demonstrate that (1) the onset of visual deficits in DBA/2J mice is around 7 months of age; (2) within each age group, there are various degrees of visual deficits; and (3) the percentage of mice exhibiting visual deficits increases with age and their visual capacities decrease gradually. Furthermore, the poor visual performances of DBA/2J mice do not correlate with the elevation of IOP. Importantly, compared to mice with normal visual performances in the same age group, mice with poor visual performances exhibit significant loss of retinal ganglion cells.
Our studies establish a reliable behavioral assay to identify glaucomatous DBA/2J mice, thus making it possible to examine subtle pathological changes and molecular mechanisms in glaucoma pathogenesis with a relatively small number of samples.
Current eye research 02/2011; 36(5):481-91. · 1.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The mouse is a promising model in the study of visual system function and development because of available genetic tools. However, a quantitative analysis of visual receptive field properties had not been performed in the mouse superior colliculus (SC) despite its importance in mouse vision and its usefulness in developmental studies. We have made single-unit extracellular recordings from superficial layers of the SC in urethane-anesthetized C57BL/6 mice. We first map receptive fields with flashing spot stimuli and show that most SC neurons have spatially overlapped ON and OFF subfields. With drifting sinusoidal gratings, we then determine the tuning properties of individual SC neurons, including selectivity for stimulus direction and orientation, spatial frequency tuning, temporal frequency tuning, response linearity, and size preference. A wide range of receptive field sizes and selectivity are observed across the population and in various subtypes of SC neurons identified morphologically. In particular, orientation-selective responses are discovered in the mouse SC, and they are not affected by cortical lesion or long-term visual deprivation. However, ON/OFF characteristics and spatial frequency tuning of SC neurons are influenced by cortical inputs and require visual experience during development. Together, our results provide essential information for future investigations on the functional development of the superior colliculus.
Journal of Neuroscience 12/2010; 30(49):16573-84. · 7.11 Impact Factor
-
Nature Neuroscience 03/2010; 13(3):277-9. · 15.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ocular dominance plasticity (ODP) following monocular deprivation (MD) is a model of activity-dependent neural plasticity that is restricted to an early critical period regulated by maturation of inhibition. Unique developmental plasticity mechanisms may improve outcomes following early brain injury. Our objective was to determine the effects of neonatal cerebral hypoxia-ischemia (HI) on ODP. The rationale extends from observations that neonatal HI results in death of subplate neurons, a transient population known to influence development of inhibition. In rodents subjected to neonatal HI and controls, maps of visual response were derived from optical imaging during the critical period for ODP and changes in the balance of eye-specific response following MD were measured. In controls, MD results in a shift of the ocular dominance index (ODI) from a baseline of 0.15 to -0.10 (p < 0.001). Neonatal HI with moderate cortical injury impairs this shift, ODI = 0.14 (p < 0.01). Plasticity was intact in animals with mild injury and in those exposed to hypoxia alone. Neonatal HI resulted in decreased parvalbumin expression in hemispheres receiving HI compared with hypoxia alone: 23.4 versus 35.0 cells/high-power field (p = 0.01), with no change in other markers of inhibitory or excitatory neurons. Despite abnormal inhibitory neuron phenotype, spontaneous activity of single units and development of orientation selective responses were intact following neonatal HI, while overall visual responses were reduced. Our data suggest that specific plasticity mechanisms are impaired following early brain injury and that the impairment is associated with altered inhibitory neuronal development and cortical activation.
Journal of Neuroscience 01/2010; 30(1):81-92. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The functional separation of ON and OFF pathways, one of the fundamental features of the visual system, starts in the retina. During postnatal development, some retinal ganglion cells (RGCs) whose dendrites arborize in both ON and OFF sublaminae of the inner plexiform layer transform into RGCs with dendrites that monostratify in either the ON or OFF sublamina, acquiring final dendritic morphology in a subtype-dependent manner. Little is known about how the receptive field (RF) properties of ON, OFF, and ON-OFF RGCs mature during this time because of the lack of a reliable and efficient method to classify RGCs into these subtypes. To address this deficiency, we developed an innovative variant of Spike Triggered Covariance (STC) analysis, which we term Spike Triggered Covariance - Non-Centered (STC-NC) analysis. Using a multi-electrode array (MEA), we recorded the responses of a large population of mouse RGCs to a Gaussian white noise stimulus. As expected, the Spike-Triggered Average (STA) fails to identify responses driven by symmetric static nonlinearities such as those that underlie ON-OFF center RGC behavior. The STC-NC technique, in contrast, provides an efficient means to identify ON-OFF responses and quantify their RF center sizes accurately. Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller. Importantly, we demonstrate for the first time that neurotrophin-3 (NT-3) regulates the development of physiological properties of ON-OFF center RGCs. Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells. In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.
PLoS Computational Biology 01/2010; 6(10):e1000967. · 5.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Changes of ocular dominance in the visual cortex can be induced by visual manipulations during a critical period in early life. However, the role of critical period plasticity in normal development is unknown. Here we show that at the onset of this time window, the preferred orientations of individual cortical cells in the mouse are mismatched through the two eyes and the mismatch decreases and reaches adult levels by the end of the period. Deprivation of visual experience during this period irreversibly blocks the binocular matching of orientation preference, but has no effect in adulthood. The critical period of binocular matching can be delayed by long-term visual deprivation from birth, like that of ocular dominance plasticity. These results demonstrate that activity-dependent changes induced by normal visual experience during the well-studied critical period serve to match eye-specific inputs in the cortex, thus revealing a physiological role for critical period plasticity during normal development.
Neuron 01/2010; 65(2):246-56. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Retinotopic mapping is a basic feature of visual system organization, but its role in processing visual information is unknown. Mutant mice lacking the beta2 subunit of nicotinic acetylcholine receptor have imprecise maps in both visual cortex (V1) and the superior colliculus (SC) due to the disruption of spontaneous retinal activity during development. Here, we use behavioral and physiological approaches to study their visual functions. We find that beta2-/- mice fail to track visual stimuli moving along the nasotemporal axis in a subcortical optomotor behavior, but track normally along the dorsoventral axis. In contrast, these mice display normal acuity along both axes in the visual water task, a behavioral test of cortical functions. Consistent with the behavioral results, we find that V1 neurons in beta2-/- mice have normal response properties, while SC neurons have disrupted receptive fields, including enlarged structure and decreased direction and orientation selectivity along the nasotemporal axis. The subcortical-specific deficits indicate that retinotopic map disruption has different impacts on the development of functional properties in V1 and the SC.
Journal of Neuroscience 10/2009; 29(41):12909-18. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sensory information is represented in the brain in the form of topographic maps, in which neighboring neurons respond to adjacent external stimuli. In the visual system, the superior colliculus receives topographic projections from the retina and primary visual cortex (V1) that are aligned. Alignment may be achieved through the use of a gradient of shared axon guidance molecules, or through a retinal-matching mechanism in which axons that monitor identical regions of visual space align. To distinguish between these possibilities, we take advantage of genetically engineered mice that we show have a duplicated functional retinocollicular map but only a single map in V1. Anatomical tracing revealed that the corticocollicular projection bifurcates to align with the duplicated retinocollicular map in a manner dependent on the normal pattern of spontaneous activity during development. These data suggest a general model in which convergent maps use coincident activity patterns to achieve alignment.
Cell 10/2009; 139(1):175-85. · 32.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The morphology of dendrites constrains and reflects the nature of synaptic inputs to neurons. The visual system has served as a useful model to show how visual function is determined by the arborization patterns of neuronal processes. In retina, light ON and light OFF responding ganglion cells selectively elaborate their dendritic arbors in distinct sublamina, where they receive, respectively, inputs from ON and OFF bipolar cells. During neonatal maturation, the bilaminarly distributed dendritic arbors of ON-OFF retinal ganglion cells (RGCs) are refined to more narrowly localized monolaminar structures characteristic of ON or OFF RGCs. Recently, brain-derived neurotrophic factor (BDNF) has been shown to regulate this laminar refinement, and to enhance the development of dendritic branches selectively of ON RGCs. Although other related neurotrophins are known to regulate neuronal process formation in the central nervous system, little is known about their action in maturing retina. Here, we report that overexpression of neurotrophin-3 (NT-3) in the eye accelerates RGC laminar refinement before eye opening. Furthermore, NT-3 overexpression increases dendritic branch number but reduces dendritic elongation preferentially in ON-OFF RGCs, a process that also occurs before eye opening. NT-3 overexpression does affect dendritic maturation in ON RGCs, but to a much less degree. Taken together, our results suggest that NT-3 and BDNF exhibit overlapping effects in laminar refinement but distinct RGC-cell-type specific effects in shaping dendritic arborization during postnatal development.
The Journal of Comparative Neurology 03/2009; 514(5):449-58. · 3.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The orderly projections from retina to superior colliculus (SC) preserve a continuous retinotopic representation of the visual world. The development of retinocollicular maps depend on a combination of molecular guidance cues and patterned neural activity. Here, we characterize the functional retinocollicular maps in mice lacking the guidance molecules ephrin-A2, -A3, and -A5 and in mice deficient in both ephrin-As and structured spontaneous retinal activity, using a method of Fourier imaging of intrinsic signals. We find that the SC of ephrin-A2/A3/A5 triple knock-out mice contains functional maps that are disrupted selectively along the nasotemporal (azimuth) axis of the visual space. These maps are discontinuous, with patches of SC responding to topographically incorrect locations. The patches disappear in mice that are deficient in both ephrin-As and structured activity, resulting in a near-absence of azimuth map in the SC. These results indicate that ephrin-As guide the formation of functional topography in the SC, and patterned retinal activity clusters cells based on their correlated firing patterns. Comparison of the SC and visual cortical mapping defects in these mice suggests that although ephrin-As are required for mapping in both SC and visual cortex, ephrin-A-independent mapping mechanisms are more important in visual cortex than in the SC.
Journal of Neuroscience 11/2008; 28(43):11015-23. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The topographic representation of visual space is preserved from retina to thalamus to cortex. We have previously shown that precise mapping of thalamocortical projections requires both molecular cues and structured retinal activity. To probe the interaction between these two mechanisms, we studied mice deficient in both ephrin-As and retinal waves. Functional and anatomical cortical maps in these mice were nearly abolished along the nasotemporal (azimuth) axis of the visual space. Both the structure of single-cell receptive fields and large-scale topography were severely distorted. These results demonstrate that ephrin-As and structured neuronal activity are two distinct pathways that mediate map formation in the visual cortex and together account almost completely for the formation of the azimuth map. Despite the dramatic disruption of azimuthal topography, the dorsoventral (elevation) map was relatively normal, indicating that the two axes of the cortical map are organized by separate mechanisms.
Neuron 03/2008; 57(4):511-23. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Parallel ON and OFF pathways conduct visual signals from bipolar cells in the retina to higher centers in the brain. ON responses are thought to originate by exclusive use of metabotropic glutamate receptor 6 (mGluR6) expressed in retinal ON bipolar cells. Paradoxically, we find ON responses in retinal ganglion cells of mGluR6-null mice, but they occur at long latency. The long-latency ON responses are not blocked by metabotropic glutamate or cholinergic receptor antagonists and are not produced by activation of receptive field surrounds. We show that these longer-latency ON responses are initiated in the OFF pathways. Our results expose a previously unrecognized intrinsic property of OFF retinal pathways that generates responses to light onset. In mGluR6-null mice, long-latency ON responses are observed in the visual cortex, indicating that they can be conducted reliably to higher visual areas. In wild-type (WT) mice, APB (DL-2-amino-4-phosphonobutyric acid), an mGluR6 agonist, blocks normal, short-latency ON responses but unmasks longer-latency ones. We find that these potentially confusing ON responses in the OFF pathway are actively suppressed in WT mice via two pharmacologically separable retinal circuits that are activated by the ON system in the retina. Consequently, we propose that a major function of the signaling of the ON pathway to the OFF pathway is suppression of these mistimed, and therefore inappropriate, light-evoked responses.
Journal of Neuroscience 12/2006; 26(46):11857-69. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Intrinsic optical signal (IOS) imaging is a widely accepted technique for imaging brain activity. We propose an integrated device consisting of interleaved arrays of gallium arsenide (GaAs) based semiconductor light sources and detectors operating at telecommunications wavelengths in the near-infrared. Such a device will allow for long-term, minimally invasive monitoring of neural activity in freely behaving subjects, and will enable the use of structured illumination patterns to improve system performance. In this work we describe the proposed system and show that near-infrared IOS imaging at wavelengths compatible with semiconductor devices can produce physiologically significant images in mice, even through skull.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:1025-8.
-
[show abstract]
[hide abstract]
ABSTRACT: The visual cortex is organized into retinotopic maps that preserve an orderly representation of the visual world, achieved by topographically precise inputs from the lateral geniculate nucleus. We show here that geniculocortical mapping is imprecise when the waves of spontaneous activity in the retina during the first postnatal week are disrupted genetically. This anatomical mapping defect is present by postnatal day 8 and has functional consequences, as revealed by optical imaging and microelectrode recording in adults. Pharmacological disruption of these retinal waves during the first week phenocopies the mapping defect, confirming both the site and the timing of the disruption in neural activity responsible for the defect. Analysis shows that the geniculocortical miswiring is not a trivial or necessary consequence of the retinogeniculate defect. Our findings demonstrate that disrupting early spontaneous activity in the eye alters thalamic connections to the cortex.
Neuron 01/2006; 48(5):797-809. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ephrin-As and their receptors, EphAs, are expressed in the developing cortex where they may act to organize thalamic inputs. Here, we map the visual cortex (V1) in mice deficient for ephrin-A2, -A3, and -A5 functionally, using intrinsic signal optical imaging and microelectrode recording, and structurally, by anatomical tracing of thalamocortical projections. V1 is shifted medially, rotated, and compressed and its internal organization is degraded. Expressing ephrin-A5 ectopically by in utero electroporation in the lateral cortex shifts the map of V1 medially, and expression within V1 disrupts its internal organization. These findings indicate that interactions between gradients of EphA/ephrin-A in the cortex guide map formation, but that factors other than redundant ephrin-As are responsible for the remnant map. Together with earlier work on the retinogeniculate map, the current findings show that the same molecular interactions may operate at successive stages of the visual pathway to organize maps.
Neuron 12/2005; 48(4):577-89. · 14.74 Impact Factor
