All Publications

  • Postsynaptic neuronal activity promotes regeneration of retinal axons. Cell reports Varadarajan, S. G., Wang, F., Dhande, O. S., Le, P., Duan, X., Huberman, A. D. 2023; 42 (5): 112476


    The wiring of visual circuits requires that retinal neurons functionally connect to specific brain targets, a process that involves activity-dependent signaling between retinal axons and their postsynaptic targets. Vision loss in various ophthalmological and neurological diseases is caused by damage to the connections from the eye to the brain. How postsynaptic brain targets influence retinal ganglion cell (RGC) axon regeneration and functional reconnection with the brain targets remains poorly understood. Here, we established a paradigm in which the enhancement of neural activity in the distal optic pathway, where the postsynaptic visual target neurons reside, promotes RGC axon regeneration and target reinnervation and leads to the rescue of optomotor function. Furthermore, selective activation of retinorecipient neuron subsets is sufficient to promote RGC axon regeneration. Our findings reveal a key role for postsynaptic neuronal activity in the repair of neural circuits and highlight the potential to restore damaged sensory inputs via proper brain stimulation.

    View details for DOI 10.1016/j.celrep.2023.112476

    View details for PubMedID 37141093

  • Central nervous system regeneration. Cell Varadarajan, S. G., Hunyara, J. L., Hamilton, N. R., Kolodkin, A. L., Huberman, A. D. 2022; 185 (1): 77-94


    Neurons of the mammalian central nervous system fail to regenerate. Substantial progress has been made toward identifying the cellular and molecular mechanisms that underlie regenerative failure and how altering those pathways can promote cell survival and/or axon regeneration. Here, we summarize those findings while comparing the regenerative process in the central versus the peripheral nervous system. We also highlight studies that advance our understanding of the mechanisms underlying neural degeneration in response to injury, as many of these mechanisms represent primary targets for restoring functional neural circuits.

    View details for DOI 10.1016/j.cell.2021.10.029

    View details for PubMedID 34995518

  • Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord NEURON Varadarajan, S. G., Kong, J. H., Phan, K. D., Kao, T., Panaitof, S. C., Cardin, J., Eltzschig, H., Kania, A., Novitch, B. G., Butler, S. J. 2017; 94 (4): 790-?


    Netrin1 has been proposed to act from the floor plate (FP) as a long-range diffusible chemoattractant for commissural axons in the embryonic spinal cord. However, netrin1 mRNA and protein are also present in neural progenitors within the ventricular zone (VZ), raising the question of which source of netrin1 promotes ventrally directed axon growth. Here, we use genetic approaches in mice to selectively remove netrin from different regions of the spinal cord. Our analyses show that the FP is not the source of netrin1 directing axons to the ventral midline, while local VZ-supplied netrin1 is required for this step. Furthermore, rather than being present in a gradient, netrin1 protein accumulates on the pial surface adjacent to the path of commissural axon extension. Thus, netrin1 does not act as a long-range secreted chemoattractant for commissural spinal axons but instead promotes ventrally directed axon outgrowth by haptotaxis, i.e., directed growth along an adhesive surface.

    View details for DOI 10.1016/j.neuron.2017.03.007

    View details for PubMedID 28434801

  • Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium. Molecular neurodegeneration Soucy, J. R., Aguzzi, E. A., Cho, J., Gilhooley, M. J., Keuthan, C., Luo, Z., Monavarfeshani, A., Saleem, M. A., Wang, X., Wohlschlegel, J., RReSTORe Consortium, Baranov, P., Di Polo, A., Fortune, B., Gokoffski, K. K., Goldberg, J. L., Guido, W., Kolodkin, A. L., Mason, C. A., Ou, Y., Reh, T. A., Ross, A. G., Samuels, B. C., Welsbie, D., Zack, D. J., Johnson, T. V., Fouda, A. Y., Ashok, A., Moshiri, A., Chedotal, A., Reed, A. A., Askary, A., Su, A. A., La Torre, A., Jalligampala, A., Silva-Lepe, A., Das, A., Wirostko, B., Frankfort, B. J., Sivyer, B., Alapure, B., Young, B., Clark, B., Jones, B. W., Hellmer, C., Mitchell, C., Ufongene, C., Goldman, D., Feldheim, D., Gutmann, D. H., Calkins, D. J., Krizaj, D., Gamm, D. M., Lozano, D. C., Bovenkamp, D. E., Chen, D. F., Cordero, E. V., Trakhtenberg, E. F., Tian, F., Zhou, F., McLellan, G. J., Quigley, H. A., Serhan, H. A., Tribble, J. R., Meyer, J., Gross, J., Mumm, J. S., Sivak, J. M., Zhang, J. S., Do, J. L., Crowston, J., Chen, J., McGregor, J., Vinnakota, K. C., Huang, K., Peynshaert, K., Uyhazi, K. E., Martin, K., Muller, K., Park, K. K., Cho, K., Chang, K., Benowitz, L., Levin, L. A., Todd, L., De Groef, L., Moons, L., Alarcon-Martinez, L., Singh, M. S., Vidal-Sanz, M., Silveira, M. S., Pavlou, M., Veldman, M. B., Van Hook, M., Samuel, M., Hu, M., Peng, M., Young, M., Cayouette, M., Geranmayeh, M. H., Woodworth, M., Vetter, M., Marsh-Armstrong, N. R., Williams, P. A., Rasiah, P. K., Subramanian, P., Cui, Q. N., Sappington, R. M., Amine, R., Eva, R., Johnston, R. J., Giger, R. J., Ethier, R., Abed, S., Momin, S. N., Blackshaw, S., Liddelow, S. A., Mary, S., Atolagbe, S., Varadarajan, S., Nabhan, T. I., Khatib, T., Sharma, T. P., Brunner, T., Greenwell, T., Rex, T. S., Watkins, T., Badea, T. C., Vrathasha, V., Chavali, V. R., Oliveira-Valenca, V. M., Tai, W. L., Batchelor, W. M., Yang, X., Park, Y., Pan, Y. 2023; 18 (1): 64


    Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

    View details for DOI 10.1186/s13024-023-00655-y

    View details for PubMedID 37735444

  • Corrigendum to "Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function". Experimental neurology Hunyara, J. L., Foshe, S., Varadarajan, S. G., Gribble, K. D., Huberman, A. D., Kolodkin, A. L. 2023; 359: 114256

    View details for DOI 10.1016/j.expneurol.2022.114256

    View details for PubMedID 36457222

  • Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function. Experimental neurology Hunyara, J. L., Foshe, S., Varadarajan, S. G., Gribble, K. D., Huberman, A. D., Kolodkin, A. L. 2022: 114176


    Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.

    View details for DOI 10.1016/j.expneurol.2022.114176

    View details for PubMedID 35870522

  • Probing the role of retinorecipient target cells in visual circuit regeneration Varadarajan, S., Dhande, O., Le, P., Huberman, A. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022
  • Dorsal commissural axon guidance in the developing spinal cord. Current topics in developmental biology Alvarez, S., Varadarajan, S. G., Butler, S. J. 2021; 142: 197–231


    Commissural axons have been a key model system for identifying axon guidance signals in vertebrates. This review summarizes the current thinking about the molecular and cellular mechanisms that establish a specific commissural neural circuit: the dI1 neurons in the developing spinal cord. We assess the contribution of long- and short-range signaling while sequentially following the developmental timeline from the birth of dI1 neurons, to the extension of commissural axons first circumferentially and then contralaterally into the ventral funiculus.

    View details for DOI 10.1016/bs.ctdb.2020.10.009

    View details for PubMedID 33706918

  • Assembly and repair of eye-to-brain connections. Current opinion in neurobiology Varadarajan, S. G., Huberman, A. D. 2018; 53: 198–209


    Vision is the sense humans rely on most to navigate the world and survive. A tremendous amount of research has focused on understanding the neural circuits for vision and the developmental mechanisms that establish them. The eye-to-brain, or 'retinofugal' pathway remains a particularly important model in these contexts because it is essential for sight, its overt anatomical features relate to distinct functional attributes and those features develop in a tractable sequence. Much progress has been made in understanding the growth of retinal axons out of the eye, their selection of targets in the brain, the development of laminar and cell type-specific connectivity within those targets, and also dendritic connectivity within the retina itself. Moreover, because the retinofugal pathway is prone to degeneration in many common blinding diseases, understanding the cellular and molecular mechanisms that establish connectivity early in life stands to provide valuable insights into approaches that re-wire this pathway after damage or loss. Here we review recent progress in understanding the development of retinofugal pathways and how this information is important for improving visual circuit regeneration.

    View details for PubMedID 30339988

  • Uniformity from Diversity: Vast-Range Light Sensing in a Single Neuron Type CELL Varadarajan, S. G., Huberman, A. D. 2017; 171 (4): 738–40


    The brightness of our visual environment varies tremendously from day to night. In this issue of Cell, Milner and Do describe how the population of retinal neurons responsible for entrainment of the brain's circadian clock cooperate to encode irradiance across a wide range of ambient-light intensities.

    View details for PubMedID 29100070

  • Netrin1 establishes multiple boundaries for axon growth in the developing spinal cord. Developmental biology Varadarajan, S. G., Butler, S. J. 2017


    The canonical model for netrin1 function proposed that it acted as a long-range chemotropic axon guidance cue. In the developing spinal cord, floor-plate (FP)-derived netrin1 was thought to act as a diffusible attractant to draw commissural axons to the ventral midline. However, our recent studies have shown that netrin1 is dispensable in the FP for axon guidance. We have rather found that netrin1 acts locally: netrin1 is produced by neural progenitor cells (NPCs) in the ventricular zone (VZ), and deposited on the pial surface as a haptotactic adhesive substrate that guides Dcc(+) axon growth. Here, we further demonstrate that this netrin1 pial-substrate has an early role orienting pioneering spinal axons, directing them to extend ventrally. However, as development proceeds, commissural axons choose to grow around a boundary of netrin1 expressing cells in VZ, instead of continuing to extend alongside the netrin1 pial-substrate in the ventral spinal cord. This observation suggests netrin1 may supply a more complex activity than pure adhesion, with netrin1-expressing cells also supplying a growth boundary for axons. Supporting this possibility, we have observed that additional domains of netrin1 expression arise adjacent to the dorsal root entry zone (DREZ) in E12.5 mice that are also required to sculpt axonal growth. Together, our studies suggest that netrin1 provides "hederal" boundaries: a local growth substrate that promotes axon extension, while also preventing local innervation of netrin1-expressing domains.

    View details for DOI 10.1016/j.ydbio.2017.08.001

    View details for PubMedID 28780049

  • Type Ib BMP receptors mediate the rate of commissural axon extension through inhibition of cofilin activity DEVELOPMENT Yamauchi, K., Varadarajan, S. G., Li, J. E., Butler, S. J. 2013; 140 (2): 333-342


    Bone morphogenetic proteins (BMPs) have unexpectedly diverse activities establishing different aspects of dorsal neural circuitry in the developing spinal cord. Our recent studies have shown that, in addition to spatially orienting dorsal commissural (dI1) axons, BMPs supply 'temporal' information to commissural axons to specify their rate of growth. This information ensures that commissural axons reach subsequent signals at particular times during development. However, it remains unresolved how commissural neurons specifically decode this activity of BMPs to result in their extending axons at a specific speed through the dorsal spinal cord. We have addressed this question by examining whether either of the type I BMP receptors (Bmpr), BmprIa and BmprIb, have a role controlling the rate of commissural axon growth. BmprIa and BmprIb exhibit a common function specifying the identity of dorsal cell fate in the spinal cord, whereas BmprIb alone mediates the ability of BMPs to orient axons. Here, we show that BmprIb, and not BmprIa, is additionally required to control the rate of commissural axon extension. We have also determined the intracellular effector by which BmprIb regulates commissural axon growth. We show that BmprIb has a novel role modulating the activity of the actin-severing protein cofilin. These studies reveal the mechanistic differences used by distinct components of the canonical Bmpr complex to mediate the diverse activities of the BMPs.

    View details for DOI 10.1242/dev.089524

    View details for Web of Science ID 000312741400009

    View details for PubMedID 23250207

    View details for PubMedCentralID PMC3597210