Honors & Awards
Cogan Award for Research in Vision and Ophthalmology, ARVO (2017)
Pew Biomedical Scholar, Pew Charitable Trusts (2013-2017)
McKnight Scholar, McKnight Endowment Fund (2013-2016)
Catalyst for a Cure Investigator, Glaucoma Research Foundation (2012- present)
Helen Hay Whitney Postdoctoral Fellow, HHWF Foundation (2006-2009)
Current Research and Scholarly Interests
My lab is focused on brain function, development and repair with emphasis on regeneration to prevent and cure blindness.
We also study the neural circuits that merge perceptions with internal states, in particular, visual fear.
The specific conditions we aim to understand and develop therapeutic strategies for include: retinal and optic nerve damage in glaucoma, and disorders of sensory-limbic integration, such as chronic anxiety, phobias and PTSD.
Signal Integration in Thalamus: Labeled Lines Go Cross-Eyed and Blurry.
2017; 93 (4): 717-720
The brain uses sensory information from the periphery to create percepts. In this issue of Neuron, Rompani et al. (2017) show that visual signals are combined in unexpected ways that vastly expand the possible representations of the outside world.
View details for DOI 10.1016/j.neuron.2017.02.020
View details for PubMedID 28231456
Regenerating optic pathways from the eye to the brain.
Science (New York, N.Y.)
2017; 356 (6342): 1031–34
Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connect the eyes to the brain, fail to regenerate after damage, eventually leading to blindness. Here, we review research on regeneration and repair of the optic system. Intrinsic developmental growth programs can be reactivated in RGCs, neural activity can enhance RGC regeneration, and functional reformation of eye-to-brain connections is possible, even in the adult brain. Transplantation and gene therapy may serve to replace or resurrect dead or injured retinal neurons. Retinal prosthetics that can restore vision in animal models may too have practical power in the clinical setting. Functional restoration of sight in certain forms of blindness is likely to occur in human patients in the near future.
View details for DOI 10.1126/science.aal5060
View details for PubMedID 28596336
Cortico-fugal output from visual cortex promotes plasticity of innate motor behaviour.
2016; 538 (7625): 383-387
The mammalian visual cortex massively innervates the brainstem, a phylogenetically older structure, via cortico-fugal axonal projections. Many cortico-fugal projections target brainstem nuclei that mediate innate motor behaviours, but the function of these projections remains poorly understood. A prime example of such behaviours is the optokinetic reflex (OKR), an innate eye movement mediated by the brainstem accessory optic system, that stabilizes images on the retina as the animal moves through the environment and is thus crucial for vision. The OKR is plastic, allowing the amplitude of this reflex to be adaptively adjusted relative to other oculomotor reflexes and thereby ensuring image stability throughout life. Although the plasticity of the OKR is thought to involve subcortical structures such as the cerebellum and vestibular nuclei, cortical lesions have suggested that the visual cortex might also be involved. Here we show that projections from the mouse visual cortex to the accessory optic system promote the adaptive plasticity of the OKR. OKR potentiation, a compensatory plastic increase in the amplitude of the OKR in response to vestibular impairment, is diminished by silencing visual cortex. Furthermore, targeted ablation of a sparse population of cortico-fugal neurons that specifically project to the accessory optic system severely impairs OKR potentiation. Finally, OKR potentiation results from an enhanced drive exerted by the visual cortex onto the accessory optic system. Thus, cortico-fugal projections to the brainstem enable the visual cortex, an area that has been principally studied for its sensory processing function, to plastically adapt the execution of innate motor behaviours.
View details for DOI 10.1038/nature19818
View details for PubMedID 27732573
Neural activity promotes long-distance, target-specific regeneration of adult retinal axons.
2016; 19 (8): 1073-1084
Axons in the mammalian CNS fail to regenerate after injury. Here we show that if the activity of mouse retinal ganglion cells (RGCs) is increased by visual stimulation or using chemogenetics, their axons regenerate. We also show that if enhancement of neural activity is combined with elevation of the cell-growth-promoting pathway involving mammalian target of rapamycin (mTOR), RGC axons regenerate long distances and re-innervate the brain. Analysis of genetically labeled RGCs revealed that this regrowth can be target specific: RGC axons navigated back to their correct visual targets and avoided targets incorrect for their function. Moreover, these regenerated connections were successful in partially rescuing a subset of visual behaviors. Our findings indicate that combining neural activity with activation of mTOR can serve as powerful tool for enhancing axon regeneration, and they highlight the remarkable capacity of CNS neurons to re-establish accurate circuit connections in adulthood.
View details for DOI 10.1038/nn.4340
View details for PubMedID 27399843
- Life goes by: a visual circuit signals perceptual-motor mismatch NATURE NEUROSCIENCE 2016; 19 (2): 177-179
- BLINDNESS Assassins of eyesight NATURE 2015; 527 (7579): 456-457
Cell type-specific manipulation with GFP-dependent Cre recombinase
2015; 18 (9): 1334-?
There are many transgenic GFP reporter lines that allow the visualization of specific populations of cells. Using such lines for functional studies requires a method that transforms GFP into a molecule that enables genetic manipulation. We developed a method that exploits GFP for gene manipulation, Cre recombinase dependent on GFP (CRE-DOG), a split component system that uses GFP and its derivatives to directly induce Cre/loxP recombination. Using plasmid electroporation and AAV viral vectors, we delivered CRE-DOG to multiple GFP mouse lines, which led to effective recombination selectively in GFP-labeled cells. Furthermore, CRE-DOG enabled optogenetic control of these neurons. Beyond providing a new set of tools for manipulation of gene expression selectively in GFP(+) cells, we found that GFP can be used to reconstitute the activity of a protein not known to have a modular structure, suggesting that this strategy might be applicable to a wide range of proteins.
View details for DOI 10.1038/nn.4081
View details for Web of Science ID 000360292600024
View details for PubMedID 26258682
When Visual Circuits Collide: Motion Processing in the Brain.
2015; 162 (2): 241-243
How is sensory information transformed by each station of a synaptic circuit as it flows progressively deeper into the brain? In this issue of Cell, Mauss et al. describe a set of connections in the fly brain that combines opposing directional signals, and they hypothesize that this motif limits global motion noise as the fly moves through space.
View details for DOI 10.1016/j.cell.2015.06.051
View details for PubMedID 26186184
Cortical Cliques: A Few Plastic Neurons Get All the Action
2015; 86 (5): 1113-1116
Adjustments in neural activity can drive cortical plasticity, but the underlying circuit components remain unclear. In this issue of Neuron, Barnes et al. (2015) show that visual deprivation-induced homeostatic plasticity invokes specific changes among select categories of V1 neurons.
View details for DOI 10.1016/j.neuron.2015.05.039
View details for Web of Science ID 000355666400002
View details for PubMedID 26050030
Contactin-4 Mediates Axon-Target Specificity and Functional Development of the Accessory Optic System
2015; 86 (4): 985-999
The mammalian eye-to-brain pathway includes more than 20 parallel circuits, each consisting of precise long-range connections between specific sets of retinal ganglion cells (RGCs) and target structures in the brain. The mechanisms that drive assembly of these parallel connections and the functional implications of their specificity remain unresolved. Here we show that in the absence of contactin 4 (CNTN4) or one of its binding partners, amyloid precursor protein (APP), a subset of direction-selective RGCs fail to target the nucleus of the optic tract (NOT)--the accessory optic system (AOS) target controlling horizontal image stabilization. Conversely, ectopic expression of CNTN4 biases RGCs to arborize in the NOT, and that process also requires APP. Our data reveal critical and novel roles for CNTN4/APP in promoting target-specific axon arborization, and they highlight the importance of this process for functional development of a behaviorally relevant parallel visual pathway.
View details for DOI 10.1016/j.neuron.2015.04.005
View details for Web of Science ID 000354878400013
View details for PubMedID 25959733
Characteristic Patterns of Dendritic Remodeling in Early-Stage Glaucoma: Evidence from Genetically Identified Retinal Ganglion Cell Types
JOURNAL OF NEUROSCIENCE
2015; 35 (6): 2329-2343
Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and the second leading cause of blindness worldwide. The type and timing of cellular changes leading to RGC loss in glaucoma remain incompletely understood, including whether specific RGC subtypes are preferentially impacted at early stages of this disease. Here we applied the microbead occlusion model of glaucoma to different transgenic mouse lines, each expressing green fluorescent protein in 1-2 specific RGC subtypes. Targeted filling, reconstruction, and subsequent comparison of the genetically identified RGCs in control and bead-injected eyes revealed that some subtypes undergo significant dendritic rearrangements as early as 7 d following induction of elevated intraocular pressure (IOP). By comparing specific On-type, On-Off-type and Off-type RGCs, we found that RGCs that target the majority of their dendritic arbors to the scleral half or "Off" sublamina of the inner plexiform layer (IPL) undergo the greatest changes, whereas RGCs with the majority of their dendrites in the On sublamina did not alter their structure at this time point. Moreover, M1 intrinsically photosensitive RGCs, which functionally are On RGCs but structurally stratify their dendrites in the Off sublamina of the IPL, also underwent significant changes in dendritic structure 1 week after elevated IOP. Thus, our findings reveal that certain RGC subtypes manifest significant changes in dendritic structure after very brief exposure to elevated IOP. The observation that RGCs stratifying most of their dendrites in the Off sublamina are first to alter their structure may inform the development of new strategies to detect, monitor, and treat glaucoma in humans.
View details for DOI 10.1523/JNEUROSCI.1419-14.2015
View details for Web of Science ID 000349686500003
View details for PubMedID 25673829
Functional Assembly of Accessory Optic System Circuitry Critical for Compensatory Eye Movements.
Accurate motion detection requires neural circuitry that compensates for global visual field motion. Select subtypes of retinal ganglion cells perceive image motion and connect to the accessory optic system (AOS) in the brain, which generates compensatory eye movements that stabilize images during slow visual field motion. Here, we show that the murine transmembrane semaphorin 6A (Sema6A) is expressed in a subset of On direction-selective ganglion cells (On DSGCs) and is required for retinorecipient axonal targeting to the medial terminal nucleus (MTN) of the AOS. Plexin A2 and A4, two Sema6A binding partners, are expressed in MTN cells, attract Sema6A(+) On DSGC axons, and mediate MTN targeting of Sema6A(+) RGC projections. Furthermore, Sema6A/Plexin-A2/A4 signaling is required for the functional output of the AOS. These data reveal molecular mechanisms underlying the assembly of AOS circuits critical for moving image perception.
View details for DOI 10.1016/j.neuron.2015.03.064
View details for PubMedID 25959730
So many pieces, one puzzle: cell type specification and visual circuitry in flies and mice
GENES & DEVELOPMENT
2014; 28 (23): 2565-2584
The visual system is a powerful model for probing the development, connectivity, and function of neural circuits. Two genetically tractable species, mice and flies, are together providing a great deal of understanding of these processes. Current efforts focus on integrating knowledge gained from three cross-fostering fields of research: (1) understanding how the fates of different cell types are specified during development, (2) revealing the synaptic connections between identified cell types ("connectomics") by high-resolution three-dimensional circuit anatomy, and (3) causal testing of how identified circuit elements contribute to visual perception and behavior. Here we discuss representative examples from fly and mouse models to illustrate the ongoing success of this tripartite strategy, focusing on the ways it is enhancing our understanding of visual processing and other sensory systems.
View details for DOI 10.1101/gad.248245.114
View details for Web of Science ID 000345812000001
View details for PubMedID 25452270
Birthdate and Outgrowth Timing Predict Cellular Mechanisms of Axon Target Matching in the Developing Visual Pathway
2014; 8 (4): 1006-1017
How axons select their appropriate targets in the brain remains poorly understood. Here, we explore the cellular mechanisms of axon target matching in the developing visual system by comparing four transgenic mouse lines, each with a different population of genetically labeled retinal ganglion cells (RGCs) that connect to unique combinations of brain targets. We find that the time when an RGC axon arrives in the brain is correlated with its target selection strategy. Early-born, early-arriving RGC axons initially innervate multiple targets. Subsequently, most of those connections are removed. By contrast, later-born, later-arriving RGC axons are highly accurate in their initial target choices. These data reveal the diversity of cellular mechanisms that mammalian CNS axons use to pick their targets and highlight the key role of birthdate and outgrowth timing in influencing this precision. Timing-based mechanisms may underlie the assembly of the other sensory pathways and complex neural circuitry in the brain.
View details for DOI 10.1016/j.celrep.2014.06.063
View details for Web of Science ID 000341573500011
View details for PubMedID 25088424
A dedicated circuit links direction-selective retinal ganglion cells to the primary visual cortex
2014; 507 (7492): 358-?
How specific features in the environment are represented within the brain is an important unanswered question in neuroscience. A subset of retinal neurons, called direction-selective ganglion cells (DSGCs), are specialized for detecting motion along specific axes of the visual field. Despite extensive study of the retinal circuitry that endows DSGCs with their unique tuning properties, their downstream circuitry in the brain and thus their contribution to visual processing has remained unclear. In mice, several different types of DSGCs connect to the dorsal lateral geniculate nucleus (dLGN), the visual thalamic structure that harbours cortical relay neurons. Whether direction-selective information computed at the level of the retina is routed to cortical circuits and integrated with other visual channels, however, is unknown. Here we show that there is a di-synaptic circuit linking DSGCs with the superficial layers of the primary visual cortex (V1) by using viral trans-synaptic circuit mapping and functional imaging of visually driven calcium signals in thalamocortical axons. This circuit pools information from several types of DSGCs, converges in a specialized subdivision of the dLGN, and delivers direction-tuned and orientation-tuned signals to superficial V1. Notably, this circuit is anatomically segregated from the retino-geniculo-cortical pathway carrying non-direction-tuned visual information to deeper layers of V1, such as layer 4. Thus, the mouse harbours several functionally specialized, parallel retino-geniculo-cortical pathways, one of which originates with retinal DSGCs and delivers direction- and orientation-tuned information specifically to the superficial layers of the primary visual cortex. These data provide evidence that direction and orientation selectivity of some V1 neurons may be influenced by the activation of DSGCs.
View details for DOI 10.1038/nature12989
View details for Web of Science ID 000333029000034
View details for PubMedID 24572358
Visual Circuits: Mouse Retina No Longer a Level Playing Field
2014; 24 (4): R155-R156
Unlike humans, monkeys, or carnivores, mice are thought to lack a retinal subregion devoted to high-resolution vision; systematic analysis has now shown that mice encode visual space non-uniformly, increasing their spatial sampling of the binocular visual field.
View details for DOI 10.1016/j.cub.2013.12.045
View details for Web of Science ID 000331718900010
View details for PubMedID 24556437
Retinal ganglion cell maps in the brain: implications for visual processing
CURRENT OPINION IN NEUROBIOLOGY
2014; 24: 133-142
Everything the brain knows about the content of the visual world is built from the spiking activity of retinal ganglion cells (RGCs). As the output neurons of the eye, RGCs include ∼20 different subtypes, each responding best to a specific feature in the visual scene. Here we discuss recent advances in identifying where different RGC subtypes route visual information in the brain, including which targets they connect to and how their organization within those targets influences visual processing. We also highlight examples where causal links have been established between specific RGC subtypes, their maps of central connections and defined aspects of light-mediated behavior and we suggest the use of techniques that stand to extend these sorts of analyses to circuits underlying visual perception.
View details for DOI 10.1016/j.conb.2013.08.006
View details for Web of Science ID 000331509500020
View details for PubMedID 24492089
Genetic Dissection of Retinal Inputs to Brainstem Nuclei Controlling Image Stabilization
JOURNAL OF NEUROSCIENCE
2013; 33 (45): 17797-17813
When the head rotates, the image of the visual world slips across the retina. A dedicated set of retinal ganglion cells (RGCs) and brainstem visual nuclei termed the "accessory optic system" (AOS) generate slip-compensating eye movements that stabilize visual images on the retina and improve visual performance. Which types of RGCs project to each of the various AOS nuclei remain unresolved. Here we report a new transgenic mouse line, Hoxd10-GFP, in which the RGCs projecting to all the AOS nuclei are fluorescently labeled. Electrophysiological recordings of Hoxd10-GFP RGCs revealed that they include all three subtypes of On direction-selective RGCs (On-DSGCs), responding to upward, downward, or forward motion. Hoxd10-GFP RGCs also include one subtype of On-Off DSGCs tuned for forward motion. Retrograde circuit mapping with modified rabies viruses revealed that the On-DSGCs project to the brainstem centers involved in both horizontal and vertical retinal slip compensation. In contrast, the On-Off DSGCs labeled in Hoxd10-GFP mice projected to AOS nuclei controlling horizontal but not vertical image stabilization. Moreover, the forward tuned On-Off DSGCs appear physiologically and molecularly distinct from all previously genetically identified On-Off DSGCs. These data begin to clarify the cell types and circuits underlying image stabilization during self-motion, and they support an unexpected diversity of DSGC subtypes.
View details for DOI 10.1523/JNEUROSCI.2778-13.2013
View details for Web of Science ID 000327019100027
View details for PubMedID 24198370
Diverse Visual Features Encoded in Mouse Lateral Geniculate Nucleus
JOURNAL OF NEUROSCIENCE
2013; 33 (11): 4642-4656
The thalamus is crucial in determining the sensory information conveyed to cortex. In the visual system, the thalamic lateral geniculate nucleus (LGN) is generally thought to encode simple center-surround receptive fields, which are combined into more sophisticated features in cortex, such as orientation and direction selectivity. However, recent evidence suggests that a more diverse set of retinal ganglion cells projects to the LGN. We therefore used multisite extracellular recordings to define the repertoire of visual features represented in the LGN of mouse, an emerging model for visual processing. In addition to center-surround cells, we discovered a substantial population with more selective coding properties, including direction and orientation selectivity, as well as neurons that signal absence of contrast in a visual scene. The direction and orientation selective neurons were enriched in regions that match the termination zones of direction selective ganglion cells from the retina, suggesting a source for their tuning. Together, these data demonstrate that the mouse LGN contains a far more elaborate representation of the visual scene than current models posit. These findings should therefore have a significant impact on our understanding of the computations performed in mouse visual cortex.
View details for DOI 10.1523/JNEUROSCI.5187-12.2013
View details for Web of Science ID 000316119200003
View details for PubMedID 23486939
Transsynaptic Tracing with Vesicular Stomatitis Virus Reveals Novel Retinal Circuitry
JOURNAL OF NEUROSCIENCE
2013; 33 (1): 35-51
The use of neurotropic viruses as transsynaptic tracers was first described in the 1960s, but only recently have such viruses gained popularity as a method for labeling neural circuits. The development of retrograde monosynaptic tracing vectors has enabled visualization of the presynaptic sources onto defined sets of postsynaptic neurons. Here, we describe the first application of a novel viral tracer, based on vesicular stomatitis virus (VSV), which directs retrograde transsynaptic viral spread between defined cell types. We use this virus in the mouse retina to show connectivity between starburst amacrine cells (SACs) and their known synaptic partners, direction-selective retinal ganglion cells, as well as to discover previously unknown connectivity between SACs and other retinal ganglion cell types. These novel connections were confirmed using physiological recordings. VSV transsynaptic tracing enables cell type-specific dissection of neural circuitry and can reveal synaptic relationships among neurons that are otherwise obscured due to the complexity and density of neuropil.
View details for DOI 10.1523/JNEUROSCI.0245-12.2013
View details for Web of Science ID 000313046500006
View details for PubMedID 23283320
- Wiring visual circuits, one eye at a time NATURE NEUROSCIENCE 2012; 15 (2): 172-174
Visual Cognition: Rats Compare Shapes Among the Crowd
2012; 22 (1): R18-R20
Rats can discriminate simple shapes visually, even if they are moved around, made smaller, or partially covered up; the strategy they use may help shed light on human brain mechanisms for discriminating complex features, such as faces.
View details for DOI 10.1016/j.cub.2011.11.047
View details for Web of Science ID 000299144200009
View details for PubMedID 22240473
What can mice tell us about how vision works?
TRENDS IN NEUROSCIENCES
2011; 34 (9): 464-473
Understanding the neural basis of visual perception is a long-standing fundamental goal of neuroscience. Historically, most vision studies were carried out on humans, macaques and cats. Over the past 5 years, however, a growing number of researchers have begun using mice to parse the mechanisms underlying visual processing; the rationale is that, despite having relatively poor acuity, mice are unmatched in terms of the variety and sophistication of tools available to label, monitor and manipulate specific cell types and circuits. In this review, we discuss recent advances in understanding the mouse visual system at the anatomical, receptive field and perceptual level, focusing on the opportunities and constraints those features provide toward the goal of understanding how vision works.
View details for DOI 10.1016/j.tins.2011.07.002
View details for Web of Science ID 000294941300003
View details for PubMedID 21840069
Cadherin-6 Mediates Axon-Target Matching in a Non-Image-Forming Visual Circuit
2011; 71 (4): 632-639
Neural circuits consist of highly precise connections among specific types of neurons that serve a common functional goal. How neurons distinguish among different synaptic targets to form functionally precise circuits remains largely unknown. Here, we show that during development, the adhesion molecule cadherin-6 (Cdh6) is expressed by a subset of retinal ganglion cells (RGCs) and also by their targets in the brain. All of the Cdh6-expressing retinorecipient nuclei mediate non-image-forming visual functions. A screen of mice expressing GFP in specific subsets of RGCs revealed that Cdh3-RGCs which also express Cdh6 selectively innervate Cdh6-expressing retinorecipient targets. Moreover, in Cdh6-deficient mice, the axons of Cdh3-RGCs fail to properly innervate their targets and instead project to other visual nuclei. These findings provide functional evidence that classical cadherins promote mammalian CNS circuit development by ensuring that axons of specific cell types connect to their appropriate synaptic targets.
View details for DOI 10.1016/j.neuron.2011.07.006
View details for Web of Science ID 000294521600009
View details for PubMedID 21867880
Pathway-Specific Genetic Attenuation of Glutamate Release Alters Select Features of Competition-Based Visual Circuit Refinement
2011; 71 (2): 235-242
A hallmark of mammalian neural circuit development is the refinement of initially imprecise connections by competitive activity-dependent processes. In the developing visual system retinal ganglion cell (RGC) axons from the two eyes undergo activity-dependent competition for territory in the dorsal lateral geniculate nucleus (dLGN). The direct contributions of synaptic transmission to this process, however, remain unclear. We used a genetic approach to reduce glutamate release selectively from ipsilateral-projecting RGCs and found that their release-deficient axons failed to exclude competing axons from the ipsilateral eye territory in the dLGN. Nevertheless, the release-deficient axons consolidated and maintained their normal amount of dLGN territory, even in the face of fully active competing axons. These results show that during visual circuit refinement glutamatergic transmission plays a direct role in excluding competing axons from inappropriate target regions, but they argue that consolidation and maintenance of axonal territory are largely insensitive to alterations in synaptic activity levels.
View details for DOI 10.1016/j.neuron.2011.05.045
View details for Web of Science ID 000293433900008
View details for PubMedID 21791283
Transgenic Mice Reveal Unexpected Diversity of On-Off Direction-Selective Retinal Ganglion Cell Subtypes and Brain Structures Involved in Motion Processing
JOURNAL OF NEUROSCIENCE
2011; 31 (24): 8760-8769
On-Off direction-selective retinal ganglion cells (DSGCs) encode the axis of visual motion. They respond strongly to an object moving in a preferred direction and weakly to an object moving in the opposite, "null," direction. Historically, On-Off DSGCs were classified into four subtypes according to their directional preference (anterior, posterior, superior, or inferior). Here, we compare two genetically identified populations of On-Off DSGCs: dopamine receptor 4 (DRD4)-DSGCs and thyrotropin-releasing hormone receptor (TRHR)-DSGCs. We find that although both populations are tuned for posterior motion, they can be distinguished by a variety of physiological and anatomical criteria. First, the directional tuning of TRHR-DSGCs is broader than that of DRD4-DSGCs. Second, whereas both populations project similarly to the dorsal lateral geniculate nucleus, they project differently to the ventral lateral geniculate nucleus and the superior colliculus. Moreover, TRHR-DSGCs, but not DRD4-DSGCs, also project to the zona incerta, a thalamic area not previously known to receive direction-tuned visual information. Our findings reveal unexpected diversity among mouse On-Off DSGC subtypes that uniquely process and convey image motion to the brain.
View details for DOI 10.1523/JNEUROSCI.0564-11.2011
View details for Web of Science ID 000291642800009
View details for PubMedID 21677160
View details for PubMedCentralID PMC3139540
The Down Syndrome Critical Region Regulates Retinogeniculate Refinement
JOURNAL OF NEUROSCIENCE
2011; 31 (15): 5764-5776
Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the "Down syndrome critical region" (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.
View details for DOI 10.1523/JNEUROSCI.6015-10.2011
View details for Web of Science ID 000289472400026
View details for PubMedID 21490218
Emergence of Lamina-Specific Retinal Ganglion Cell Connectivity by Axon Arbor Retraction and Synapse Elimination
JOURNAL OF NEUROSCIENCE
2010; 30 (48): 16376-16382
Throughout the nervous system, neurons restrict their connections to specific depths or "layers" of their targets to constrain the type and number of synapses they make. Despite the importance of lamina-specific synaptic connectivity, the mechanisms that give rise to this feature in mammals remain poorly understood. Here we examined the cellular events underlying the formation of lamina-specific retinal ganglion cell (RGC) axonal projections to the superior colliculus (SC) of the mouse. By combining a genetically encoded marker of a defined RGC subtype (OFF-αRGCs) with serial immunoelectron microscopy, we resolved the ultrastructure of axon terminals fated for laminar stabilization versus those fated for removal. We found that OFF-αRGCs form synapses across the full depth of the retinorecipient SC before undergoing lamina-specific arbor retraction and synapse elimination to arrive at their mature, restricted pattern of connectivity. Interestingly, we did not observe evidence of axon degeneration or glia-induced synapse engulfment during this process. These findings indicate that lamina-specific visual connections are generated through the selective stabilization of correctly targeted axon arbors and suggest that the decision to maintain or eliminate an axonal projection reflects the molecular compatibility of presynaptic and postsynaptic neurons at a given laminar depth.
View details for DOI 10.1523/JNEUROSCI.3455-10.2010
View details for Web of Science ID 000284999900031
View details for PubMedID 21123583
View details for PubMedCentralID PMC3073606
Molecular and Cellular Mechanisms of Lamina-specific Axon Targeting
COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY
2010; 2 (3)
The specificity of synaptic connections is directly related to the functional integrity of neural circuits. Long-range axon guidance and topographic mapping mechanisms bring axons into spatial proximity of target cells and thus limit the number of potential synaptic partners. Synaptic specificity is then achieved by extracellular short-range guidance cues and cell-surface recognition cues. Neural activity may enhance the precision and strength of specific circuit connections. Here, we focus on one of the final steps of synaptic matchmaking: the targeting of synaptic layers and the mutual recognition of axons and dendrites within these layers.
View details for DOI 10.1101/cshperspect.a001743
View details for Web of Science ID 000279881700009
View details for PubMedID 20300211
MILESTONES AND MECHANISMS FOR GENERATING SPECIFIC SYNAPTIC CONNECTIONS BETWEEN THE EYES AND THE BRAIN
INVERTEBRATE AND VERTEBRATE EYE DEVELOPMENT
2010; 93: 229-259
All information about the visual world is conveyed to the brain by a single type of neurons at the back of the eye called retinal ganglion cells (RGCs). Understanding how RGC axons locate and wire up with their targets is therefore critical to understanding visual development. In recent years, several important technological and conceptual advances have been made in this area, and yet, many fundamental questions remain unanswered. Indeed, while much is now known about how RGC axons pathfind at the optic chiasm and form retinotopic maps within their targets, how RGCs select their overall targets in the first place is poorly understood. Moreover, the signals that direct mammalian RGC axons to their appropriate layer within those targets remain unknown. The recent advent of genetic tools to selectively label and manipulate defined groups of RGCs is starting to provide a way to resolve these and other important questions about RGC wiring specificity. This field is therefore positioned to reveal new principles of visual circuit development that no doubt will extend to other regions of the CNS.
View details for DOI 10.1016/S0070-2153(10)93008-1
View details for Web of Science ID 000283820000008
View details for PubMedID 20959168
Genetic Identification of an On-Off Direction-Selective Retinal Ganglion Cell Subtype Reveals a Layer-Specific Subcortical Map of Posterior Motion
2009; 62 (3): 327-334
Motion detection is an essential component of visual processing. On-Off direction-selective retinal ganglion cells (On-Off DSGCs) detect objects moving along specific axes of the visual field due to their precise retinal circuitry. The brain circuitry of On-Off DSGCs, however, is largely unknown. We report a mouse with GFP expressed selectively by the On-Off DSGCs that detect posterior motion (On-Off pDSGCs), allowing two-photon targeted recordings of their light responses and delineation of their complete map of central connections. On-Off pDSGCs project exclusively to the dorsal lateral geniculate nucleus and superior colliculus and in both targets form synaptic lamina that are separate from a lamina corresponding to non-DSGCs. Thus, individual On-Off DSGC subtypes are molecularly distinct and establish circuits that map specific qualities of directional motion to dedicated subcortical areas. This suggests that each RGC subtype represents a unique parallel pathway whose synaptic specificity in the retina is recapitulated in central targets.
View details for DOI 10.1016/j.neuron.2009.04.014
View details for Web of Science ID 000266146100005
View details for PubMedID 19447089
View details for PubMedCentralID PMC3140054
Architecture and activity-mediated refinement of axonal projections from a mosaic of genetically identified retinal ganglion cells
2008; 59 (3): 425-438
Our understanding of how mammalian sensory circuits are organized and develop has long been hindered by the lack of genetic markers of neurons with discrete functions. Here, we report a transgenic mouse selectively expressing GFP in a complete mosaic of transient OFF-alpha retinal ganglion cells (tOFF-alphaRGCs). This enabled us to relate the mosaic spacing, dendritic anatomy, and electrophysiology of these RGCs to their complete map of projections in the brain. We find that tOFF-alphaRGCs project exclusively to the superior colliculus (SC) and dorsal lateral geniculate nucleus and are restricted to a specific laminar depth within each of these targets. The axons of tOFF-alphaRGC are also organized into columns in the SC. Both laminar and columnar specificity develop through axon refinement. Disruption of cholinergic retinal waves prevents the emergence of columnar- but not laminar-specific tOFF-alphaRGC connections. Our findings reveal that in a genetically identified sensory map, spontaneous activity promotes synaptic specificity by segregating axons arising from RGCs of the same subtype.
View details for DOI 10.1016/j.neuron.2008.07.018
View details for Web of Science ID 000258565500011
View details for PubMedID 18701068
Mechanisms underlying development of visual maps and receptive fields
ANNUAL REVIEW OF NEUROSCIENCE
2008; 31: 479-509
Patterns of synaptic connections in the visual system are remarkably precise. These connections dictate the receptive field properties of individual visual neurons and ultimately determine the quality of visual perception. Spontaneous neural activity is necessary for the development of various receptive field properties and visual feature maps. In recent years, attention has shifted to understanding the mechanisms by which spontaneous activity in the developing retina, lateral geniculate nucleus, and visual cortex instruct the axonal and dendritic refinements that give rise to orderly connections in the visual system. Axon guidance cues and a growing list of other molecules, including immune system factors, have also recently been implicated in visual circuit wiring. A major goal now is to determine how these molecules cooperate with spontaneous and visually evoked activity to give rise to the circuits underlying precise receptive field tuning and orderly visual maps.
View details for DOI 10.1146/annurev.neuro.31.060407.125533
View details for Web of Science ID 000257992200020
View details for PubMedID 18558864
The classical complement cascade mediates CNS synapse elimination
2007; 131 (6): 1164-1178
During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.
View details for DOI 10.1016/j.cell.2007.10.036
View details for Web of Science ID 000252217100023
View details for PubMedID 18083105
Mechanisms of eye-specific visual circuit development
CURRENT OPINION IN NEUROBIOLOGY
2007; 17 (1): 73-80
Eye-specific visual connections are a prominent model system for exploring how precise circuits develop in the CNS and, in particular, for addressing the role of neural activity in synapse elimination and axon refinement. Recent experiments have identified the features of spontaneous retinal activity that mediate eye-specific retinogeniculate segregation, the synaptic events associated with this process, and the importance of axon guidance cues for organizing the overall layout of eye-specific maps. The classic model of ocular dominance column development, in which spontaneous retinal activity plays a crucial role, has also gained new support. Although many outstanding questions remain, the mechanisms that instruct eye-specific circuit development are becoming clear.
View details for DOI 10.1016/j.conb.2007.01.005
View details for Web of Science ID 000244771100011
View details for PubMedID 17254766
Spontaneous retinal activity mediates development of ocular dominance columns and binocular receptive fields in V1
2006; 52 (2): 247-254
The mechanisms that give rise to ocular dominance columns (ODCs) during development are controversial. Early experiments indicated a key role for retinal activity in ODC formation. However, later studies showed that in those early experiments, the retinal activity perturbation was initiated after ODCs had already formed. Moreover, recent studies concluded that early eye removals do not impact ODC segregation. Here we blocked spontaneous retinal activity during the very early stages of ODC development. This permanently disrupted the anatomical organization of ODCs and led to a dramatic increase in receptive field size for binocular cells in primary visual cortex. Our data suggest that early spontaneous retinal activity conveys crucial information about whether thalamocortical axons represent one or the other eye and that this activity mediates binocular competition important for shaping receptive fields in primary visual cortex.
View details for DOI 10.1016/j.neuron.2006.07.028
View details for Web of Science ID 000241799900006
View details for PubMedID 17046688
Neuronal pentraxins mediate synaptic refinement in the developing visual system
JOURNAL OF NEUROSCIENCE
2006; 26 (23): 6269-6281
Neuronal pentraxins (NPs) define a family of proteins that are homologous to C-reactive and acute-phase proteins in the immune system and have been hypothesized to be involved in activity-dependent synaptic plasticity. To investigate the role of NPs in vivo, we generated mice that lack one, two, or all three NPs. NP1/2 knock-out mice exhibited defects in the segregation of eye-specific retinal ganglion cell (RGC) projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation and elimination. Retinas from mice lacking NP1 and NP2 had cholinergically driven waves of activity that occurred at a frequency similar to that of wild-type mice, but several other parameters of retinal activity were altered. RGCs cultured from these mice exhibited a significant delay in functional maturation of glutamatergic synapses. Other developmental processes, such as pathfinding of RGCs at the optic chiasm and hippocampal long-term potentiation and long-term depression, appeared normal in NP-deficient mice. These data indicate that NPs are necessary for early synaptic refinements in the mammalian retina and dorsal lateral geniculate nucleus. We speculate that NPs exert their effects through mechanisms that parallel the known role of short pentraxins outside the CNS.
View details for DOI 10.1523/jneurosci.4212-05.2006
View details for Web of Science ID 000238174600017
View details for PubMedID 16763034
View details for PubMedCentralID PMC2579897
Dynamics of spontaneous activity in the fetal macaque retina during development of retinogeniculate pathways
JOURNAL OF NEUROSCIENCE
2006; 26 (19): 5190-5197
Correlated spontaneous activity in the form of retinal "waves" has been observed in a wide variety of developing animals, but whether retinal waves occur in the primate has not been determined previously. To address this issue, we recorded from isolated retinas using multielectrode arrays at six fetal ages: embryonic day 51 (E51), E55, E60, E67, E71, and E76. These recordings revealed that the fetal monkey retina is essentially silent at E51 and E55, with only few cells firing on rare occasions and without any obvious spatial or temporal order. Because previous work has shown that the magnocellular and parvocellular subdivisions of the dorsal lateral geniculate are selectively innervated during this early period, our results suggest that this process is unlikely to be regulated by retinal activity. Highly structured retinal waves were first observed at E60, >1 week before the segregation of eye-specific retinal dorsal lateral geniculate nucleus projections commences. The incidence of such waves decreased rapidly and progressively during the developmental period (E67-E76) when segregated eye-specific projections become established. Our findings indicate that retinal waves first occur in the fetal monkey at a remarkably early stage of development, >100 d before birth, and that this activity undergoes rapid changes in salient properties when eye-specific retinogeniculate projections are being formed.
View details for DOI 10.1523/JNEUROSCI.0328-06.2006
View details for Web of Science ID 000237450300021
View details for PubMedID 16687510
Nob mice wave goodbye to eye-specific segregation
2006; 50 (2): 175-177
Spontaneous retinal activity is necessary to establish and maintain eye-specific projections to the LGN, but whether the spatial and temporal structure of this activity is important remains unclear. A new study by Demas et al. in the current issue of Neuron shows that when the frequency of spontaneous retinal waves is increased and waves abnormally persist past eye opening, eye-specific projections to the LGN desegregate. These results provide important new insight into the mechanisms that drive eye-specific refinement and stabilization.
View details for DOI 10.1016/j.neuron.2006.04.006
View details for Web of Science ID 000237176700002
View details for PubMedID 16630826
- Target-derived cues instruct synaptic differentiation JOURNAL OF NEUROSCIENCE 2006; 26 (4): 1063-1064
Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus
2005; 8 (8): 1013-1021
Axon guidance cues contributing to the development of eye-specific visual projections to the lateral geniculate nucleus (LGN) have not previously been identified. Here we show that gradients of ephrin-As and their receptors (EphAs) direct retinal ganglion cell (RGC) axons from the two eyes into their stereotyped pattern of layers in the LGN. Overexpression of EphAs in ferret RGCs using in vivo electroporation induced axons from both eyes to misproject within the LGN. The effects of EphA overexpression were competition-dependent and restricted to the early postnatal period. These findings represent the first demonstration of eye-specific pathfinding mediated by axon guidance cues and, taken with other reports, indicate that ephrin-As can mediate several mapping functions within individual target structures.
View details for DOI 10.1038/nn1505
View details for Web of Science ID 000230760200012
View details for PubMedID 16025110
Early and rapid targeting of eye-specific axonal projections to the dorsal lateral geniculate nucleus in the fetal macaque
JOURNAL OF NEUROSCIENCE
2005; 25 (16): 4014-4023
The emergence of eye-specific axonal projections to the dorsal lateral geniculate nucleus (dLGN) is a well established model system for exploring the mechanisms underlying afferent targeting during development. Using modern tract tracing methods, we examined the development of this feature in the macaque, an Old World Primate with a visual system similar to that of humans. Cholera toxin beta fragment conjugated to Alexa 488 was injected into the vitreous of one eye, and CTbeta conjugated to Alexa 594 into the other eye of embryos at known gestational ages. On embryonic day 69 (E69), which is approximately 100 d before birth, inputs from the two eyes were extensively intermingled in the dLGN. However, even at this early age, portions of the dLGN were preferentially innervated by the right or left eye, and segregation is complete within the dorsalmost layers 5 and 6. By E78, eye-specific segregation is clearly established throughout the parvocellular division of the dLGN, and substantial ocular segregation is present in the magnocellular division. By E84, segregation of left and right eye axons is essentially complete, and the six eye-specific domains that characterize the mature macaque dLGN are clearly discernable. These findings reveal that targeting of eye-specific axonal projections in the macaque occurs much earlier and more rapidly than previously reported. This segregation process is completed before the reported onset of ganglion cell axon loss and retino-dLGN synapse elimination, suggesting that, in the primate, eye-specific targeting occurs independent of traditional forms of synaptic plasticity.
View details for DOI 10.1523/JNEUROSCI.4292-04.2005
View details for Web of Science ID 000228542600003
View details for PubMedID 15843603
Decoupling eye-specific segregation from lamination in the lateral geniculate nucleus
JOURNAL OF NEUROSCIENCE
2002; 22 (21): 9419-9429
To determine whether there is a critical period for development of eye-specific layers in the lateral geniculate nucleus (LGN), we prevented the normal segregation of retinogeniculate afferents and then allowed an extended period of time for recovery. After recovery, both anatomy and physiology revealed strictly nonoverlapping territories of input from the two eyes. However, the normal stereotyped pattern of eye-specific afferent and cellular layers never developed. Instead, the eye-specific territories of afferent input emerged as variable and disorganized patches with no corresponding interlaminar spaces in the LGN. These findings reveal a critical period for coordinating the development of three processes in the LGN: the segregation of afferents from the two eyes, the spatial organization of those afferents into layers, and the alignment of postsynaptic cytoarchitecture with the afferent inputs. We also assessed the physiological consequences of preventing normal lamination and found normal single-cell responses and topographic representation of visual space in the LGN. Clusters of ON-center and OFF-center LGN cells were segregated from one another as in normal animals. However, the organization of ON and OFF sublaminas in the treated animals was disrupted.
View details for Web of Science ID 000179031600032
View details for PubMedID 12417667