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Zhang, Z., Zhou, J., Tan, P., Pang, Y., Rivkin, A.C., Kirchgessner, M.A., Williams, E., Lee, C.T., Liu, H., Franklin, A.D., Miyazaki, P.A., Bartlett, A., Aldridge, A.I., Vu, M., Boggeman, L., Fitzpatrick, C., Nery, J.R., Castanon, R.G., Rashid, M., Jacobs, M.W., Ito-Cole, T., O’Connor, C., Pinto-Duartec, A., Dominguez, B., Smith, J.B., Niu, S.Y., Lee, K.F., Jin, X., Mukamel, E.A., Behrens, M.M., Ecker, J.R., Callaway, E.M. Epigenomic diversity of cortical projection neurons in the mouse brain. (2021) Nature. 598(7879):167-173. DOI: 10.1038/s41586-021-03223-w

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Neuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To improve our understanding of the relationship between molecular and anatomical features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing to link neural epigenomic properties to projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical and cortico-subcortical long-distance projections. Our results showed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. On the basis of their epigenomes, intra-telencephalic cells that project to different cortical targets could be further distinguished, and some layer 5 neurons that project to extra-telencephalic targets (L5 ET) formed separate clusters that aligned with their axonal projections. Such separation varied between cortical areas, which suggests that there are area-specific differences in L5 ET subtypes, which were further validated by anatomical studies. Notably, a population of cortico-cortical projection neurons clustered with L5 ET rather than intra-telencephalic neurons, which suggests that a population of L5 ET cortical neurons projects to both targets. We verified the existence of these neurons by dual retrograde labelling and anterograde tracing of cortico-cortical projection neurons, which revealed axon terminals in extra-telencephalic targets including the thalamus, superior colliculus and pons. These findings highlight the power of single-cell epigenomic approaches to connect the molecular properties of neurons with their anatomical and projection properties.

Kirchgessner, M.A., Franklin, A.D., Callaway, E.M. Distinct “driving” versus “modulatory” influences of different visual corticothalamic pathways. (2021) Current Biology. DOI: 10.1016/j.cub.2021.09.025

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Faulkner, R.L., Wall, N.R., Callaway, E.M., Cline, H.T. Application of Recombinant Rabies Virus to Xenopus Tadpole Brain. (2021) eNeuro. DOI: 10.1523/ENEURO.0477-20.2021

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The Xenopus laevis experimental system has provided significant insight into the development and plasticity of neural circuits. Xenopus neuroscience research would be enhanced by additional tools to study neural circuit structure and function. Rabies viruses are powerful tools to label and manipulate neural circuits and have been widely used to study mesoscale connectomics. Whether rabies virus can be used to transduce neurons and express transgenes in Xenopus has not been systematically investigated. Glycoprotein-deleted rabies virus transduces neurons at the axon terminal and retrogradely labels their cell bodies. We show that glycoprotein-deleted rabies virus infects local and projection neurons in the Xenopus tadpole when directly injected into brain tissue. Pseudotyping glycoprotein-deleted rabies with EnvA restricts infection to cells with exogenous expression of the EnvA receptor, TVA. EnvA pseudotyped virus specifically infects tadpole neurons with promoter-driven expression of TVA, demonstrating its utility to label targeted neuronal populations. Neuronal cell types are defined by a combination of features including anatomical location, expression of genetic markers, axon projection sites, morphology, and physiological properties. We show that driving TVA expression in one hemisphere and injecting EnvA pseudotyped virus into the contralateral hemisphere, retrogradely labels neurons defined by cell body location and axon projection site. Using this approach, rabies can be used to identify cell types in Xenopus brain and simultaneously to express transgenes which enable monitoring or manipulation of neuronal activity. This makes rabies a valuable tool to study the structure and function of neural circuits in Xenopus.Studies in Xenopus have contributed a great deal to our understanding of brain circuit development and plasticity, regeneration, and hormonal regulation of behavior and metamorphosis. Here, we show that recombinant rabies virus transduces neurons in the Xenopus tadpole, enlarging the toolbox that can be applied to studying Xenopus brain. Rabies can be used for retrograde labeling and expression of a broad range of transgenes including fluorescent proteins for anatomical tracing and studying neuronal morphology, voltage or calcium indicators to visualize neuronal activity, and photo- or chemosensitive channels to control neuronal activity. The versatility of these tools enables diverse experiments to analyze and manipulate Xenopus brain structure and function, including mesoscale connectivity.

Abbott, L.F., Bock, D.D., Callaway, E.M., Denk, W., Dulac, C., Fairhall, A.L., Fiete, I., Harris, K.M., Helmstaedter, M., Jain, V., Kasthuri, N., LeCun, Y., Lichtman, J.W., Littlewood, P.B., Luo, L., Maunsell, J.H.R., Reid, R.C., Rosen, B.R., Rubin, G.M., Sejnowski, T.J., Seung, H.S., Svoboda, K., Tank, D.W., Tsao, D., Van Essen, D.C. The Mind of a Mouse. (2020) Cell. 182(6):1372-1376. DOI: 10.1016/j.cell.2020.08.010

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Yang, C.F., Kim, E.J., Callaway, E.M., Feldman, J.L. Monosynaptic Projections to Excitatory and Inhibitory preBötzinger Complex Neurons. (2020) Frontiers in Neuroanatomy. 14:58. DOI: 10.3389/fnana.2020.00058

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Kim, E.J., Zhang, Z., Huang, L., Ito-Cole, T., Jacobs, M.W., Juavinett, A.L., Senturk, G., Hu, M., Ku, M., Ecker, J.R., Callaway, E.M. Extraction of Distinct Neuronal Cell Types from within a Genetically Continuous Population. (2020) Neuron. DOI: 10.1016/j.neuron.2020.04.018

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Kirchgessner, M.A., Franklin, A.D., Callaway, E.M. Context-dependent and dynamic functional influence of corticothalamic pathways to first- and higher-order visual thalamus. (2020) Proceedings of the National Academy of Sciences of the United States of America. DOI: 10.1073/pnas.2002080117

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Garg, A.K., Li, P., Rashid, M.S., Callaway, E.M. Color and orientation are jointly coded and spatially organized in primate primary visual cortex. (2019) Science. 364(6447):1275-1279. DOI: 10.1126/science.aaw5868

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McBride, E.G., Lee, S.J., Callaway, E.M. Local and Global Influences of Visual Spatial Selection and Locomotion in Mouse Primary Visual Cortex. (2019) Current Biology. 29(10):1592-1605. DOI: 10.1016/j.cub.2019.03.065

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Padmanabhan, K., Osakada, F., Tarabrina, A., Kizer, E., Callaway, E.M., Gage, F.H., Sejnowski, T.J. Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping. (2019) Frontiers in Neuroanatomy. 12:115. DOI: 10.3389/fnana.2018.00115

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Suzuki, K., Tsunekawa, Y., Hernandez-Benitez, R., Wu, J., Zhu, J., Kim, E.J., Hatanaka, F., Yamamoto, M., Araoka, T., Li, Z., Kurita, M., Hishida, T., Li, M., Aizawa, E., Guo, S., Chen, S., Goebl, A., Soligalla, R.D., Qu, J., Jiang, T., Fu, X., Jafari, M., Esteban, C.R., Berggren, W.T., Lajara, J., Nuñez-Delicado, E., Guillen, P., Campistol, J.M., Matsuzaki, F., Liu, G.H., Magistretti, P., Zhang, K., Callaway, E.M., Zhang, K., Belmonte, J.C. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. (2016) Nature. 540(7631):144-149. DOI: 10.1038/nature20565

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Dimidschstein, J., Chen, Q., Tremblay, R., Rogers, S.L., Saldi, G.A., Guo, L., Xu, Q., Liu, R., Lu, C., Chu, J., Grimley, J.S., Krostag, A.R., Kaykas, A., Avery, M.C., Rashid, M.S., Baek, M., Jacob, A.L., Smith, G.B., Wilson, D.E., Kosche, G., Kruglikov, I., Rusielewicz, T., Kotak, V.C., Mowery, T.M., Anderson, S.A., Callaway, E.M., Dasen, J.S., Fitzpatrick, D., Fossati, V., Long, M.A., Noggle, S., Reynolds, J.H., Sanes, D.H., Rudy, B., Feng, G., Fishell, G. A viral strategy for targeting and manipulating interneurons across vertebrate species. (2016) Nature Neuroscience. 19(12):1743-1749. DOI: 10.1038/nn.4430

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Smith, J.B., Klug, J.R., Ross, D.L., Howard, C.D., Hollon, N.G., Ko, V.I., Hoffman, H., Callaway, E.M., Gerfen, C.R., Jin, X. Genetic-Based Dissection Unveils the Inputs and Outputs of Striatal Patch and Matrix Compartments. (2016) Neuron. 91(5):1069-1084. DOI: 10.1016/j.neuron.2016.07.046

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Padmanabhan, K., Osakada, F., Tarabrina, A., Kizer, E., Callaway, E.M., Gage, F.H., Sejnowski, T.J. Diverse Representations of Olfactory Information in Centrifugal Feedback Projections. (2016) Journal of Neuroscience. 36(28):7535-45. DOI: 10.1523/JNEUROSCI.3358-15.2016

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Tuncdemir, S.N., Wamsley, B., Stam, F.J., Osakada, F., Goulding, M., Callaway, E.M., Rudy, B., Fishell, G. Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits. (2016) Neuron. 89(3):521-35. DOI: 10.1016/j.neuron.2015.11.020

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Izpisua Belmonte, J.C., Callaway, E.M., Caddick, S.J., Churchland, P., Feng, G., Homanics, G.E., Lee, K.F., Leopold, D.A., Miller, C.T., Mitchell, J.F., Mitalipov, S., Moutri, A.R., Movshon, J.A., Okano, H., Reynolds, J.H., Ringach, D., Sejnowski, T.J., Silva, A.C., Strick, P.L., Wu, J., Zhang, F. Brains, genes, and primates. (2015) Neuron. 86(3):617-31. DOI: 10.1016/j.neuron.2015.03.021

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Ruiz, O., Lustig, B.R., Nassi, J.J., Cetin, A., Reynolds, J.H., Albright, T.D., Callaway, E.M., Stoner, G.R., Roe, A.W. Optogenetics through windows on the brain in the nonhuman primate. (2013) Journal of Neurophysiology. 110(6):1455-67. DOI: 10.1152/jn.00153.2013

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Li, Y., Stam, F.J., Aimone, J.B., Goulding, M., Callaway, E.M., Gage, F.H. Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus. (2013) Proceedings of the National Academy of Sciences of the United States of America. 110(22):9106-11. DOI: 10.1073/pnas.1306912110

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Li, Y., Aimone, J.B., Xu, X., Callaway, E.M., Gage, F.H. Development of GABAergic inputs controls the contribution of maturing neurons to the adult hippocampal network. (2012) Proceedings of the National Academy of Sciences of the United States of America. 109(11):4290-5. DOI: 10.1073/pnas.1120754109

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Vivar, C., Potter, M.C., Choi, J., Lee, J.Y., Stringer, T.P., Callaway, E.M., Gage, F.H., Suh, H., van Praag, H. Monosynaptic inputs to new neurons in the dentate gyrus. (2012) Nature Communications. 3:1107. DOI: 10.1038/ncomms2101

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Borrell, V., Kaspar, B.K., Gage, F.H., Callaway, E.M. In vivo evidence for radial migration of neurons by long-distance somal translocation in the developing ferret visual cortex. (2006) Cereb. Cortex. 16(11):1571-83. DOI: 10.1093/cercor/bhj094

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Tan, E.M., Yamaguchi, Y., Horwitz, G.D., Gosgnach, S., Lein, E.S., Goulding, M., Albright, T.D., Callaway, E.M. Selective and quickly reversible inactivation of mammalian neurons in vivo using the Drosophila allatostatin receptor. (2006) Neuron. 51(2):157-70. DOI: 10.1016/j.neuron.2006.06.018

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Gosgnach, S., Lanuza, G.M., Butt, S.J., Saueressig, H., Zhang, Y., Velasquez, T., Riethmacher, D., Callaway, E.M., Kiehn, O., Goulding, M. V1 spinal neurons regulate the speed of vertebrate locomotor outputs. (2006) Nature. 440(7081):215-9. DOI: 10.1038/nature04545

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Lein, E.S., Callaway, E.M., Albright, T.D., Gage, F.H. Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. (2005) Journal of Comparative Neurology. 485(1):1-10. DOI: 10.1002/cne.20426

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