One goal of systems neuroscience is a structure-function model of nervous system organization that would allow mechanistic linking of mind, brain, and behavior. A necessary but not sufficient foundation is a connectome, a complete matrix of structural connections between the nodes of a nervous system. Connections between two nodes can be described at four nested levels of analysis: macroconnections between gray matter regions, mesoconnections between neuron types, microconnections between individual neurons, and nanoconnections at synapses. A long history of attempts to understand how the brain operates as a system began at the macrolevel in the fifth century, was revolutionized at the meso- and microlevels by Cajal and others in the late nineteenth century, and reached the nanolevel in the mid-twentieth century with the advent of electron microscopy. The greatest challenge today is extracting knowledge and understanding of nervous system structure-function architecture from vast amounts of data.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Al-Awami AK, Beyer J, Strobelt H, Kasthuri N, Lichtman JW. et al. 2014. NeuroLines: a subway map metaphor for visualizing nanoscale neuronal connectivity. IEEE Trans. Vis. Comput. Graph. 20:2369–78 [Google Scholar]
  2. Alvarez-Bolado G, Swanson LW. 1996. Developmental Brain Maps: Structure of the Embryonic Rat Brain Amsterdam: Elsevier [Google Scholar]
  3. Barabási AL, Bonabeau E. 2003. Scale-free networks. Sci. Am. 288:60–69 [Google Scholar]
  4. Birnbaum R, Weinberger DR. 2013. Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk. Dialogues Clin. Neurosci. 15:279–89 [Google Scholar]
  5. Bohland JW, Wu C, Barbas H, Bokil H, Bota M. et al. 2009. A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale. PLOS Comput. Biol. 5:e1000334 [Google Scholar]
  6. Bota M, Dong H-W, Swanson LW. 2003. From gene networks to brain networks. Nat. Neurosci. 6:795–99 [Google Scholar]
  7. Bota M, Dong H-W, Swanson LW. 2012. Combining collation and annotation efforts toward completion of the rat and mouse connectomes in BAMS. Front. Neuroinformatics 6:2 [Google Scholar]
  8. Bota M, Sporns O, Swanson LW. 2015. Architecture of the cerebral cortical association connectome underlying cognition. PNAS 112:E2093–101 [Google Scholar]
  9. Bota M, Swanson LW. 2007. The neuron classification problem. Brain Res. Rev. 56:79–88 [Google Scholar]
  10. Boulina M, Samarajeewa H, Baker JD, Kim MD, Chiba A. 2013. Live imaging of multicolor-labeled cells in Drosophila. Development 140:1605–13 [Google Scholar]
  11. Brown RA, Swanson LW. 2013. Neural systems language: a formal modeling language for the systematic description, unambiguous communication, and automated digital curation of neural connectivity. J. Comp. Neurol. 521:2889–906 [Google Scholar]
  12. Brown RA, Swanson LW. 2015. Golgi: interactive online brain mapping. Front. Neuroinformatics 9:26 [Google Scholar]
  13. Bullmore E, Sporns O. 2009. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 10:186–98 [Google Scholar]
  14. Bullmore E, Sporns O. 2012. The economy of brain network organization. Nat. Rev. Neurosci. 13:336–49 [Google Scholar]
  15. Cai D, Cohen KB, Luo T, Lichtman JW, Sanes JR. 2013. Improved tools for the Brainbow toolbox. Nat. Methods 10:540–47 [Google Scholar]
  16. Cajal SRy. 1888. Estructura de los centros nerviosos de las aves. Rev. Trim. Histol. Norm. Patol. 1:1–10 [Google Scholar]
  17. Cajal SRy. 1892. El nuevo concepto de la histología de los centros nerviosos. Rev. Cien. Méd. Barc. 18:361–376, 457–476, 505–520, 529–541 [Google Scholar]
  18. Cajal SRy. 1893. Neue Darstellung vom histologischen Bau des Centralnervensystems. Arch. Anat. Physiol. Anat. Abth. 5–6:319–428 [Google Scholar]
  19. Cajal SRy. 1899–1904. Textura del Sistema Nervioso del Hombre y de los Vertebrados Madrid: Moya [Google Scholar]
  20. Cajal SRy. 1909–1911. Histologie du Systéme Nerveux de l'Homme et des Vertébrés 2 transl. L Azoulay Paris: Maloine [Google Scholar]
  21. Callaway EM, Luo L. 2015. Monosynaptic circuit tracing with glycoprotein-deleted rabies viruses. J. Neurosci. 35:8979–85 [Google Scholar]
  22. Canteras NS, Simerly RB, Swanson LW. 1992. The connections of the posterior nucleus of the amygdala. J. Comp. Neurol. 324:143–79 [Google Scholar]
  23. Chen BE, Kondo M, Garnier A, Watson FL, Püettmann-Holgado R. et al. 2006. The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila. Cell 125:607–20 [Google Scholar]
  24. Chiang A-S, Lin C-Y, Chuang C-C, Chang H-M, Hsieh C-H. et al. 2011. Three-dimensional reconstruction of brain-wide wiring networks in Drosophila at single-cell resolution. Curr. Biol. 21:1–11 [Google Scholar]
  25. Chitwood BG, Chitwood MB. 1974. Introduction to Nematology Baltimore: Univ. Park [Google Scholar]
  26. Clarke E, O'Malley CD. 1996. The Human Brain and Spinal Cord: A Historical Study Illustrated by Writings from Antiquity to the Twentieth Century San Francisco: Norman, 2nd ed.. [Google Scholar]
  27. Csete ME, Doyle JC. 2002. Reverse engineering of biological complexity. Science 295:1664–68 [Google Scholar]
  28. De Robertis E. 1959. Submicroscopic morphology and function of the synapse. Int. Rev. Cytol. 8:61–96 [Google Scholar]
  29. Dumas L, Heitz-Marchaland C, Fouquet S, Suter U, Livet J. et al. 2015. Multicolor analysis of oligodendrocyte morphology, interactions, and development with Brainbow. Glia 63:699–717 [Google Scholar]
  30. Eberle AL, Mikula S, Schalek R, Lichtman JW, Tate ML, Zeidler D. 2015. High-resolution, high-throughput imaging with a multibeam scanning electron microscope. J. Microsc. 259:114–20 [Google Scholar]
  31. Emmons SW. 2015. The beginning of connectomics: a commentary on White et al. 1986 ‘The structure of the nervous system of the nematode Caenorhabditis elegans.’. Philos. Trans. R. Soc. B 370:20140309 [Google Scholar]
  32. Eurocontrol 2015. Frequently asked questions (FAQ) on student controller recruitment Brussels: Eur. Organ. Saf. Air Navig https://www.eurocontrol.int/faq/air-traffic-controller-jobs [Google Scholar]
  33. Feinberg EH, Vanhoven MK, Bendesky A, Wang G, Fetter RD. et al. 2008. GFP Reconstitution Across Synaptic Partners (GRASP) defines cell contacts and synapses in living nervous systems. Neuron 57:353–63 [Google Scholar]
  34. Friston KJ. 1994. Functional and effective connectivity in neuroimaging: a synthesis. Hum. Brain Mapp. 2:56–78 [Google Scholar]
  35. Goldschmidt R. 1903. Histologische Untersuchungen an Nematoden. I. Die Sinnesorgane von Ascaris lumbricoides L. und Ascaris megalocephala (Clequ.). Zool. Zbl. 24:173–82 [Google Scholar]
  36. Goldschmidt R. 1908. Nervensystem von Ascaris lumbricoides und megalocephala. Ein Versuch, in den Aufbau eines einfachen Nervensystems einzudringen. Erster Teil. Zeitsch. Wissen. Zool. 90:73–136 [Google Scholar]
  37. Goldschmidt R. 1909. Nervensystem von Ascaris lumbricoides und megalocephala. Ein Versuch, in den Aufbau eines einfachen Nervensystems einzudringen. Zweite Teil. Zeitsch. Wissen. Zool. 92:306–57 [Google Scholar]
  38. Golgi C. 1873. Sulla struttura della grigia del cervello. Gaz. Med. Ital. Lomb. 6:244–46 [Google Scholar]
  39. Golgi C. 1885. Sulla Fina Anatomia degli Organi Centrali del Sistema Nervoso Reggio-Emilia: Stefano Calderini e Figlio [Google Scholar]
  40. Hahn JD, Swanson LW. 2015. Connections of the juxtaventromedial region of the lateral hypothalamic area in the male rat. Front. Sys. Neurosci. 9:66 [Google Scholar]
  41. Hampel S, Chung P, McKellar CE, Hall D, Looger LL, Simpson JH. 2011. Drosophila Brainbow: a recombinase-based fluorescence labeling technique to subdivide neural expression patterns. Nat. Methods 8:253–59 [Google Scholar]
  42. Hayworth KJ, Xu CS, Lu Z, Knott GW, Fetter RD. et al. 2015. Ultrastructurally smooth thick partitioning and volume stitching for large-scale connectomics. Nat. Methods 12:319–22 [Google Scholar]
  43. Herrick CJ. 1948. The Brain of the Tiger Salamander Ambystoma tigrinum Chicago: Univ. Chicago Press [Google Scholar]
  44. Hikosaka R, Takahashi M, Takahat M. 1996. Variability and invariability in the structure of an identified nonspiking interneuron of crayfish as revealed by three-dimensional morphometry. Zool. Sci. 131:69–78 [Google Scholar]
  45. Hodgkin AL. 1964. The Conduction of the Nerve Impulse Liverpool: Liverpool Univ. Press [Google Scholar]
  46. Horgan J. 1999. The Undiscovered Mind: How the Human Brain Defies Replication, Medication, and Explanation New York: Free [Google Scholar]
  47. Jarrell TA, Wang Y, Bloniarz AE, Brittin CA, Xu M. et al. 2012. The connectome of a decision-making neural network. Science 337:437–44 [Google Scholar]
  48. Jones DK, Knösche TR, Turner R. 2013. White matter integrity, fiber count, and other fallacies: the do's and don'ts of diffusion MRI. NeuroImage 73:239–54 [Google Scholar]
  49. Kasthuri N, Hayworth K, Berger DR, Schalek RL, Conchello JA. et al. 2015. Saturated reconstruction of a volume of neocortex. Cell 162:635–47 [Google Scholar]
  50. Kasthuri N, Lichtman JW. 2007. The rise of the “projectome.”. Nat. Methods 4:307–8 [Google Scholar]
  51. Kim J, Zhao T, Petralia RS, Yu Y, Peng H. et al. 2012. mGRASP enables mapping mammalian synaptic connectivity with light microscopy. Nat. Methods 9:96–102 [Google Scholar]
  52. Kim JS, Greene MJ, Zlateski A, Lee K, Richardson M. et al. 2014. Space-time wiring specificity supports direction selectivity in the retina. Nature 509:331–36 [Google Scholar]
  53. Kruger L, Otis TS. 2007. Whither withered Golgi? A retrospective evaluation of reticularist and synaptic constructs. Brain Res. Bull. 72:201–7 [Google Scholar]
  54. Lichtman JW, Colman H. 2000. Synapse elimination and indelible memory. Neuron 25:269–78 [Google Scholar]
  55. Lichtman JW, Pfister H, Shavit N. 2014. The big data challenges of connectomics. Nat. Neurosci. 17:1448–54 [Google Scholar]
  56. Lichtman JW, Sanes JR. 2008. Ome sweet ome: What can the genome tell us about the connectome?. Curr. Opin. Neurobiol. 18:346–53 [Google Scholar]
  57. Livet J, Weissman TA, Kang H, Draft RW, Lu J. et al. 2007. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450:56–62 [Google Scholar]
  58. Loulier K, Barry R, Mahou P, Le Franc Y, Supatto W. et al. 2014. Multiplex cell and lineage tracking with combinatorial labels. Neuron 81:505–20 [Google Scholar]
  59. Lu J, Tapia JC, White OL, Lichtman JW. 2009. The interscutularis muscle connectome. PLOS Biol. 7:e32 [Google Scholar]
  60. Luo L, Callaway EM, Svoboda K. 2008. Genetic dissection of neural circuits. Neuron 57:634–60 [Google Scholar]
  61. Macagno E, Honig B, Chasin L. 2014. Cyrus Levinthal, 1922–1970: A Biographical Memoir Washington, DC: Natl. Acad. Sci. [Google Scholar]
  62. Manzoni T. 1998. The cerebral ventricles, the animal spirits and the dawn of brain localization of function. Arch. Ital. Biol. 136:103–52 [Google Scholar]
  63. McCulloch WS, Pitts W. 1943. A logical calculus of the ideas immanent in nervous activity. Bull. Math. Biophys. 5:115–33 [Google Scholar]
  64. Meadows DH. 2008. Thinking in Systems: A Primer White River Junction, VT: Chelsea Green [Google Scholar]
  65. Meynert T. 1872. The brain of mammals. A Manual of Histology S Stricker 650–766 New York: William Wood [Google Scholar]
  66. Nikolenko V, Poskanzer KE, Yuste R. 2007. Two-photon photostimulation and imaging of neural circuits. Nat. Methods 4:943–50 [Google Scholar]
  67. Oberlaender M, de Kock CPJ, Bruno RM, Ramirez A, Meyer HS. et al. 2012. Cell type–specific three-dimensional structure of thalamocortical circuits in a column of rat vibrissal cortex. Cereb. Cortex 22:2375–91 [Google Scholar]
  68. Oh SW, Harris JA, Ng L, Winslow B, Cain N. et al. 2014. A mesoscale connectome of the mouse brain. Nature 508:207–14 [Google Scholar]
  69. Packer AM, Russell LE, Dalgleish HW, Hausser M. 2015. Simultaneous all-optical manipulation and recording of neural circuit activity with cellular resolution in vivo. Nat. Methods 12:140–46 [Google Scholar]
  70. Pan YA, Freundlich T, Weissman TA, Schoppik D, Wang XC. et al. 2013. Zebrabow: multispectral cell labeling for cell tracing and lineage analysis in zebrafish. Development 140:2835–46 [Google Scholar]
  71. Pechura CM, Martin JB. 1991. Mapping the Brain and its Functions: Integrating Enabling Technologies into Neuroscience Research Washington, DC: Natl. Acad. [Google Scholar]
  72. Pivetta C, Esposito MS, Sigrist M, Arber S. 2014. Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin. Cell 156:537–48 [Google Scholar]
  73. Randel N, Shahidi R, Verasztó C, Bezares-Calderón LA, Schmidt S, Jékely G. 2015. Inter-individual stereotypy of the Platynereis larval visual connectome. eLife 4e08069 [Google Scholar]
  74. Richier B, Salecker I. 2015. Versatile genetic paintbrushes: Brainbow technologies. Wiley Interdiscip. Rev. Dev. Biol. 4:161–80 [Google Scholar]
  75. Robertson JD. 1955. Recent electron microscope observations on the ultrastructure of the crayfish median-to-motor giant synapse. Exp. Cell Res. 8:226–29 [Google Scholar]
  76. Robertson JD. 1956. Some features of the ultrastructure of reptilian skeletal muscle. J. Biophys. Biochem. Cytol. 2:369–80 [Google Scholar]
  77. Robles E, Filosa A, Baier H. 2013. Precise lamination of retinal axons generates multiple parallel input pathways in the tectum. J. Neurosci. 33:5027–39 [Google Scholar]
  78. Rubinov M, Sporns O. 2010. Complex network measures of brain connectivity: uses and interpretations. NeuroImage 52:1059–69 [Google Scholar]
  79. Shepherd GM. 1991. Foundations of the Neuron Doctrine New York: Oxford Univ. Press [Google Scholar]
  80. Shepherd GM. 2010. Creating Modern Neuroscience: The Revolutionary 1950s Oxford, UK: Oxford Univ. Press [Google Scholar]
  81. Shepherd GM. 2014. Diversity and complexity in the pyramidal tract projectome. Nat. Rev. Neurosci. 15:63 [Google Scholar]
  82. Sherrington CS. 1897. A Text Book of Physiology, Part III: The Central Nervous System M Foster 915–1252 London: Macmillan, 7th ed.. [Google Scholar]
  83. Shih C-T, Sporns O, Yuan S-L, Su T-A, Lin Y-J. et al. 2015. Connectomics-based analysis of information flow in the Drosophila brain. Curr. Biol. 25:1249–58 [Google Scholar]
  84. Shimosako N, Hadjieconomou D, Salecker I. 2014. Flybow to dissect circuit assembly in the Drosophila brain. Methods Mol. Biol. 1082:57–69 [Google Scholar]
  85. Simpson GG. 1961. Principles of Taxonomy New York: Columbia Univ. Press [Google Scholar]
  86. Sporns O. 2011. Networks of the Brain Cambridge, MA: MIT Press [Google Scholar]
  87. Sporns O, Tononi G, Kötter R. 2005. The human connectome: a structural description of the human brain. PLOS Comput. Biol. 1:4e42 [Google Scholar]
  88. Swanson LW. 1992. Brain Maps: Structure of the Rat Brain Amsterdam: Elsevier [Google Scholar]
  89. Swanson LW. 2000. A history of neuroanatomical mapping. Brain Mapping: The Systems AW Toga, JC Mazziota 77–109 San Diego, CA: Academic [Google Scholar]
  90. Swanson LW. 2004. Brain Maps: Structure of the Rat Brain. A Laboratory Guide with Printed and Electronic Templates for Data, Models and Schematics. Amsterdam: Elsevier, 3rd ed.. [Google Scholar]
  91. Swanson LW. 2012. Brain Architecture: Understanding the Basic Plan New York: Oxford Univ. Press, 2nd ed.. [Google Scholar]
  92. Swanson LW. 2014. Neuroanatomical Terminology: A Lexicon of Classical Origins and Historical Foundations New York: Oxford Univ. Press [Google Scholar]
  93. Swanson LW, Bota M. 2010. Foundational model of nervous system structural connectivity with a schema for wiring diagrams, connectome, and basic plan architecture. PNAS 107:20610–17 [Google Scholar]
  94. Thomas C, Ye FQ, Irfanoglu MO, Modi P, Saleem KS. et al. 2014. Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited. PNAS 111:16574–79 [Google Scholar]
  95. Tsuriel S, Gudes S, Draft RW, Binshtok AM, Lichtman JW. 2015. Multispectral labeling technique to map many neighboring axonal projections in the same tissue. Nat. Methods 12:547–52 [Google Scholar]
  96. van den Heuvel MP, Sporns O. 2011. Rich-club organization of the human connectome. J. Neurosci. 31:15775–86 [Google Scholar]
  97. Varshney LR, Chen BL, Paniagua E, Hall DH, Chklovskii DB. 2011. Structural properties of the Caenorhabditis elegans neuronal network. PLOS Comput. Biol. 7:2e1001066 [Google Scholar]
  98. Ward S, Thomson N, White JG, Brenner S. 1975. Electron microscopical reconstruction of the anterior sensory anatomy of the nematode Caenorhabditis elegans.. J. Comp. Neurol. 160:313–38 [Google Scholar]
  99. Weissman TA, Pan YA. 2015. Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis. Genetics 199:293–306 [Google Scholar]
  100. White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos. Trans. R. Soc. B 314:1–340 [Google Scholar]
  101. Wickersham IR, Lyon DC, Barnard RJ, Mori T, Finke S. et al. 2007. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53:639–47 [Google Scholar]
  102. Willis T. 1664. Cerebri Anatome: Cui Accessit Nervorum Descriptio et Usus London: Flesher, Martyn and Allestry [Google Scholar]
  103. Wolff T, Iyer NA, Rubin GM. 2015. Neuroarchitecture and neuroanatomy of the Drosophila central complex: a GAL4-based dissection of protocerebral bridge neurons and circuits. J. Comp Neurol. 523:997–1037 [Google Scholar]
  104. Xiong F, Obholzer ND, Noche RR, Megason SG. 2015. Multibow: digital spectral barcodes for cell tracing. PLOS ONE 10:5e0127822 [Google Scholar]
  105. Zador AM, Dubnau J, Oyibo HK, Zhan H, Cao G, Peikon ID. 2012. Sequencing the connectome. PLOS Biol. 10:10e1001411 [Google Scholar]
  106. Zhang GR, Zhao H, Abdul-Muneer PM, Cao H, Li X, Geller A. 2015. Neurons can be labeled with unique hues by helper virus-free HSV-1 vectors expressing Brainbow. J. Neurosci. Methods 240:77–88 [Google Scholar]
  107. Zingg B, Hintiryan H, Gou L, Song MY, Bay M. et al. 2014. Neural networks of the mouse neocortex. Cell 156:1096–111 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error