Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Dendritic integration: 60 years of progress

Nature Neuroscience volume 18, pages 1713–1721 (2015)Cite this article

Subjects

Abstract

Understanding how individual neurons integrate the thousands of synaptic inputs they receive is critical to understanding how the brain works. Modeling studies in silico and experimental work in vitro, dating back more than half a century, have revealed that neurons can perform a variety of different passive and active forms of synaptic integration on their inputs. But how are synaptic inputs integrated in the intact brain? With the development of new techniques, this question has recently received substantial attention, with new findings suggesting that many of the forms of synaptic integration observed in vitro also occur in vivo, including in awake animals. Here we review six decades of progress, which collectively highlights the complex ways that single neurons integrate their inputs, emphasizing the critical role of dendrites in information processing in the brain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AP initiation, dendritic spikes and backpropagation.
Figure 2: Location dependence of dendritic spike generation.
Figure 3: Examples of dendritic integration during behavior.
Figure 4: Distribution and timing of synaptic input.

Similar content being viewed by others

References

  1. Coombs, J.S., Curtis, D.R. & Eccles, J.C. The interpretation of spike potentials of motoneurones. J. Physiol. (Lond.) 139, 198–231 (1957).

    Article  CAS  Google Scholar 

  2. Fuortes, M.G.F., Frank, K. & Becker, M.C. Steps in the production of motoneuron spikes. J. Gen. Physiol. 40, 735–752 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Palmer, L.M. et al. Initiation of simple and complex spikes in cerebellar Purkinje cells. J. Physiol. (Lond.) 588, 1709–1717 (2010).

    Article  CAS  Google Scholar 

  4. Palmer, L.M. & Stuart, G.J. Site of action potential initiation in layer 5 pyramidal neurons. J. Neurosci. 26, 1854–1863 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Action potential initiation and propagation in hippocampal mossy fibre axons. J. Physiol. (Lond.) 586, 1849–1857 (2008).

    Article  CAS  Google Scholar 

  6. Shu, Y., Duque, A., Yu, Y., Haider, B. & Mccormick, D.A. Properties of action-potential initiation in neocortical pyramidal cells: evidence from whole cell axon recordings. J. Neurophysiol. 97, 746–760 (2007).

    Article  PubMed  Google Scholar 

  7. Stuart, G. & Häusser, M. Initiation and spread of sodium action potentials in cerebellar Purkinje cells. Neuron 13, 703–712 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Stuart, G., Schiller, J. & Sakmann, B. Action potential initiation and propagation in rat neocortical pyramidal neurons. J. Physiol. (Lond.) 505, 617–632 (1997).

    Article  CAS  Google Scholar 

  9. Stuart, G.J. & Sakmann, B. Active propagation of somatic action potentials into neocortical pyramidal cell dendrites. Nature 367, 69–72 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Rall, W. Theoretical significance of dendritic trees for neuronal input-output relations. in Neural Theory and Modeling (ed. Reiss, R.F.) (Stanford University Press, Palo Alto, 1964).

  11. Koch, C., Poggio, T. & Torre, V. Nonlinear interactions in a dendritic tree: localization, timing, and role in information processing. Proc. Natl. Acad. Sci. USA 80, 2799–2802 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fatt, P. Electric potentials occurring around a neurone during its antidromic activation. J. Neurophysiol. 20, 27–60 (1957).

    Article  CAS  PubMed  Google Scholar 

  13. Rall, W. & Shepherd, G.M. Theoretical reconstruction of field potentials and dendrodendritic synaptic interactions in olfactory bulb. J. Neurophysiol. 31, 884–915 (1968).

    Article  CAS  PubMed  Google Scholar 

  14. Spencer, W.A. & Kandel, E.R. Electrophysiology of hippocampal neurons. IV. Fast prepotentials. J. Neurophysiol. 24, 272–285 (1961).

    Article  CAS  PubMed  Google Scholar 

  15. Llinás, R., Nicholson, C., Freeman, J.A. & Hillman, D.E. Dendritic spikes and their inhibition in alligator Purkinje cells. Science 160, 1132–1135 (1968).

    Article  PubMed  Google Scholar 

  16. Yamamoto, C. & McIlwain, H. Potentials evoked in vitro in preparations from the mammalian brain. Nature 210, 1055–1056 (1966).

    Article  CAS  PubMed  Google Scholar 

  17. Llinás, R. & Sugimori, M. Electrophysiological properties of in vivo Purkinje cell somata in mammalian cerebellar slices. J. Physiol. (Lond.) 305, 171–195 (1980).

    Article  Google Scholar 

  18. Benardo, L.S., Masukawa, L.M. & Prince, D.A. Electrophysiology of isolated hippocampal pyramidal dendrites. J. Neurosci. 2, 1614–1622 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wong, R.K., Prince, D.A. & Basbaum, A.I. Intradendritic recordings from hippocampal neurons. Proc. Natl. Acad. Sci. USA 76, 986–990 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Herreras, O. Propagating dendritic action potential mediates synaptic transmission in CA1 pyramidal cells in situ. J. Neurophysiol. 64, 1429–1441 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Turner, R.W., Meyers, D.E. & Barker, J.L. Localization of tetrodotoxin-sensitive field potentials of CA1 pyramidal cells in the rat hippocampus. J. Neurophysiol. 62, 1375–1387 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Tank, D.W., Sugimori, M., Connor, J.A. & Llinas, R.R. Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice. Science 242, 773–777 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Jaffe, D.B. et al. The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons. Nature 357, 244–246 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Lasser-Ross, N. & Ross, W.N. Imaging voltage and synaptically activated sodium transients in cerebellar Purkinje cells. Proc. Biol. Sci. 247, 35–39 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Yuste, R. & Denk, W. Dendritic spines as basic functional units of neuronal integration. Nature 375, 682–684 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Koch, C., Zador, A. & Brown, T.H. Dendritic spines: convergence of theory and experiment. Science 256, 973–974 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Bloodgood, B.L., Giessel, A.J. & Sabatini, B.L. Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines. PLoS Biol. 7, e1000190 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Harnett, M.T., Makara, J.K., Spruston, N., Kath, W.L. & Magee, J.C. Synaptic amplification by dendritic spines enhances input cooperativity. Nature 491, 599–602 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Palmer, L.M. & Stuart, G.J. Membrane potential changes in dendritic spines during action potentials and synaptic input. J. Neurosci. 29, 6897–6903 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Helmchen, F., Svoboda, K., Denk, W. & Tank, D.W. In vivo dendritic calcium dynamics in deep-layer cortical pyramidal neurons. Nat. Neurosci. 2, 989–996 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Svoboda, K., Helmchen, F., Denk, W. & Tank, D.W. Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo. Nat. Neurosci. 2, 65–73 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Dodt, H.U. & Zieglgansberger, W. Visualizing unstained neurons in living brain slices by infrared DIC-videomicroscopy. Brain Res. 537, 333–336 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Stuart, G.J., Dodt, H.U. & Sakmann, B. Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy. Pflugers Arch. 423, 511–518 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Nevian, T., Larkum, M.E., Polsky, A. & Schiller, J. Properties of basal dendrites of layer 5 pyramidal neurons: a direct patch-clamp recording study. Nat. Neurosci. 10, 206–214 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Larkum, M.E., Nevian, T., Sandler, M., Polsky, A. & Schiller, J. Synaptic integration in tuft dendrites of layer 5 pyramidal neurons: a new unifying principle. Science 325, 756–760 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Häusser, M., Spruston, N. & Stuart, G.J. Diversity and dynamics of dendritic signaling. Science 290, 739–744 (2000).

    Article  PubMed  Google Scholar 

  37. Magee, J.C. Dendritic integration of excitatory synaptic input. Nat. Rev. Neurosci. 1, 181–190 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Major, G., Larkum, M.E. & Schiller, J. Active properties of neocortical pyramidal neuron dendrites. Annu. Rev. Neurosci. 36, 1–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Berger, T., Larkum, M.E. & Luscher, H.R. High I(h) channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. J. Neurophysiol. 85, 855–868 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci. 18, 7613–7624 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stuart, G. & Spruston, N. Determinants of voltage attenuation in neocortical pyramidal neuron dendrites. J. Neurosci. 18, 3501–3510 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Harnett, M.T., Magee, J.C. & Williams, S.R. Distribution and function of HCN channels in the apical dendritic tuft of neocortical pyramidal neurons. J. Neurosci. 35, 1024–1037 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Harnett, M.T., Xu, N.L., Magee, J.C. & Williams, S.R. Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons. Neuron 79, 516–529 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Williams, S.R. & Stuart, G.J. Dependence of EPSP efficacy on synapse location in neocortical pyramidal neurons. Science 295, 1907–1910 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Migliore, M. & Shepherd, G.M. Emerging rules for the distributions of active dendritic conductances. Nat. Rev. Neurosci. 3, 362–370 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Magee, J.C. & Johnston, D. Characterization of single voltage-gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J. Physiol. (Lond.) 487, 67–90 (1995).

    Article  CAS  Google Scholar 

  47. Hoffman, D.A., Magee, J.C., Colbert, C.M. & Johnston, D. K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 387, 869–875 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Angelo, K., London, M., Christensen, S.R. & Hausser, M. Local and global effects of I(h) distribution in dendrites of mammalian neurons. J. Neurosci. 27, 8643–8653 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Spruston, N., Schiller, Y., Stuart, G. & Sakmann, B. Activity-dependent action potential invasion and calcium influx into hippocampal CA1 dendrites. Science 268, 297–300 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Häusser, M., Stuart, G., Racca, C. & Sakmann, B. Axonal initiation and active dendritic propagation of action potentials in substantia nigra neurons. Neuron 15, 637–647 (1995).

    Article  PubMed  Google Scholar 

  51. Stuart, G., Spruston, N., Sakmann, B. & Häusser, M. Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci. 20, 125–131 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Vetter, P., Roth, A. & Häusser, M. Propagation of action potentials in dendrites depends on dendritic morphology. J. Neurophysiol. 85, 926–937 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Colbert, C.M., Magee, J.C., Hoffman, D.A. & Johnston, D. Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons. J. Neurosci. 17, 6512–6521 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jung, H.Y., Mickus, T. & Spruston, N. Prolonged sodium channel inactivation contributes to dendritic action potential attenuation in hippocampal pyramidal neurons. J. Neurosci. 17, 6639–6646 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Golding, N.L. & Spruston, N. Dendritic sodium spikes are variable triggers of axonal action potentials in hippocampal CA1 pyramidal neurons. Neuron 21, 1189–1200 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Losonczy, A. & Magee, J.C. Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Neuron 50, 291–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Sun, Q., Srinivas, K.V., Sotayo, A. & Siegelbaum, S.A. Dendritic Na spikes enable cortical input to drive action potential output from hippocampal CA2 pyramidal neurons. eLife 3 (2014).

  58. Llinás, R. & Hess, R. Tetrodotoxin-resistant dendritic spikes in avian Purkinje cells. Proc. Natl. Acad. Sci. USA 73, 2520–2523 (1976).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Pockberger, H. Electrophysiological and morphological properties of rat motor cortex neurons in vivo. Brain Res. 539, 181–190 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Amitai, Y., Friedman, A., Connors, B.W. & Gutnick, M.J. Regenerative activity in apical dendrites of pyramidal cells in neocortex. Cereb. Cortex 3, 26–38 (1993).

    Article  CAS  PubMed  Google Scholar 

  61. Golding, N.L., Jung, H.Y., Mickus, T. & Spruston, N. Dendritic calcium spike initiation and repolarization are controlled by distinct potassium channel subtypes in CA1 pyramidal neurons. J. Neurosci. 19, 8789–8798 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schiller, J., Schiller, Y., Stuart, G. & Sakmann, B. Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons. J. Physiol. (Lond.) 505, 605–616 (1997).

    Article  CAS  Google Scholar 

  63. Pérez-Garci, E., Larkum, M.E. & Nevian, T. Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o-β-subunit interaction with Cav1 channels. J. Physiol. (Lond.) 591, 1599–1612 (2013).

    Article  CAS  Google Scholar 

  64. Schiller, J., Major, G., Koester, H.J. & Schiller, Y. NMDA spikes in basal dendrites of cortical pyramidal neurons. Nature 404, 285–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Katz, Y. et al. Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons. Neuron 63, 171–177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rapp, M., Yarom, Y. & Segev, I. Modeling back propagating action potential in weakly excitable dendrites of neocortical pyramidal cells. Proc. Natl. Acad. Sci. USA 93, 11985–11990 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Larkum, M.E., Kaiser, K.M. & Sakmann, B. Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a critical frequency of back-propagating action potentials. Proc. Natl. Acad. Sci. USA 96, 14600–14604 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Magee, J.C. & Carruth, M. Dendritic voltage-gated ion channels regulate the action potential firing mode of hippocampal CA1 pyramidal neurons. J. Neurophysiol. 82, 1895–1901 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Williams, S.R. & Stuart, G.J. Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons. J. Physiol. (Lond.) 521, 467–482 (1999).

    Article  CAS  Google Scholar 

  70. Stuart, G.J. & Häusser, M. Dendritic coincidence detection of EPSPs and action potentials. Nat. Neurosci. 4, 63–71 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Mayer, M.L., Westbrook, G.L. & Guthrie, P.B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309, 261–263 (1984).

    Article  CAS  PubMed  Google Scholar 

  72. Palmer, L.M. et al. NMDA spikes enhance action potential generation during sensory input. Nat. Neurosci. 17, 383–390 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Lavzin, M., Rapoport, S., Polsky, A., Garion, L. & Schiller, J. Nonlinear dendritic processing determines angular tuning of barrel cortex neurons in vivo. Nature 490, 397–401 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Gambino, F. et al. Sensory-evoked LTP driven by dendritic plateau potentials in vivo. Nature 515, 116–119 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Bittner, K.C. et al. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat. Neurosci. 18, 1133–1142 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Larkum, M.E., Zhu, J.J. & Sakmann, B. A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature 398, 338–341 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Remy, S., Csicsvari, J. & Beck, H. Activity-dependent control of neuronal output by local and global dendritic spike attenuation. Neuron 61, 906–916 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Polsky, A., Mel, B.W. & Schiller, J. Computational subunits in thin dendrites of pyramidal cells. Nat. Neurosci. 7, 621–627 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Jarsky, T., Roxin, A., Kath, W.L. & Spruston, N. Conditional dendritic spike propagation following distal synaptic activation of hippocampal CA1 pyramidal neurons. Nat. Neurosci. 8, 1667–1676 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Larkum, M.E., Zhu, J.J. & Sakmann, B. Dendritic mechanisms underlying the coupling of the dendritic with the axonal action potential initiation zone of adult rat layer 5 pyramidal neurons. J. Physiol. (Lond.) 533, 447–466 (2001).

    Article  CAS  Google Scholar 

  81. Poirazi, P., Brannon, T. & Mel, B.W. Pyramidal neuron as two-layer neural network. Neuron 37, 989–999 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Gidon, A. & Segev, I. Principles governing the operation of synaptic inhibition in dendrites. Neuron 75, 330–341 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Petreanu, L., Mao, T., Sternson, S.M. & Svoboda, K. The subcellular organization of neocortical excitatory connections. Nature 457, 1142–1145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee, S.H. & Dan, Y. Neuromodulation of brain states. Neuron 76, 209–222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Waters, J., Larkum, M., Sakmann, B. & Helmchen, F. Supralinear Ca2+ Influx into Dendritic Tufts of Layer 2/3 Neocortical Pyramidal Neurons In Vitro and In Vivo. J. Neurosci. 23, 8558–8567 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bereshpolova, Y., Amitai, Y., Gusev, A.G., Stoelzel, C.R. & Swadlow, H.A. Dendritic backpropagation and the state of the awake neocortex. J. Neurosci. 27, 9392–9399 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Buzsáki, G. & Kandel, A. Somadendritic backpropagation of action potentials in cortical pyramidal cells of the awake rat. J. Neurophysiol. 79, 1587–1591 (1998).

    Article  PubMed  Google Scholar 

  89. Buzsáki, G., Penttonen, M., Nadasdy, Z. & Bragin, A. Pattern and inhibition-dependent invasion of pyramidal cell dendrites by fast spikes in the hippocampus in vivo. Proc. Natl. Acad. Sci. USA 93, 9921–9925 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kamondi, A., Acsady, L. & Buzsaki, G. Dendritic spikes are enhanced by cooperative network activity in the intact hippocampus. J. Neurosci. 18, 3919–3928 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Larkum, M.E. & Zhu, J.J. Signaling of layer 1 and whisker-evoked Ca2+ and Na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vivo and in vivo. J. Neurosci. 22, 6991–7005 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Waters, J. & Helmchen, F. Boosting of action potential backpropagation by neocortical network activity in vivo. J. Neurosci. 24, 11127–11136 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Waters, J. & Helmchen, F. Background synaptic activity is sparse in neocortex. J. Neurosci. 26, 8267–8277 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Llinas, R. & Nicholson, C. Electrophysiological properties of dendrites and somata in alligator Purkinje cells. J. Neurophysiol. 34, 532–551 (1971).

    Article  CAS  PubMed  Google Scholar 

  95. Zhu, J.J. & Connors, B.W. Intrinsic firing patterns and whisker-evoked synaptic responses of neurons in the rat barrel cortex. J. Neurophysiol. 81, 1171–1183 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Xu, N.L. et al. Nonlinear dendritic integration of sensory and motor input during an active sensing task. Nature 492, 247–251 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Smith, S.L., Smith, I.T., Branco, T. & Hausser, M. Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo. Nature 503, 115–120 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Murayama, M. et al. Dendritic encoding of sensory stimuli controlled by deep cortical interneurons. Nature 457, 1137–1141 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Palmer, L.M. et al. The cellular basis of GABA(B)-mediated interhemispheric inhibition. Science 335, 989–993 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Grienberger, C., Chen, X. & Konnerth, A. NMDA receptor-dependent multidendrite Ca(2+) spikes required for hippocampal burst firing in vivo. Neuron 81, 1274–1281 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Sheffield, M.E. & Dombeck, D.A. Calcium transient prevalence across the dendritic arbour predicts place field properties. Nature 517, 200–204 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Cichon, J. & Gan, W.B. Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity. Nature 520, 180–185 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen, X., Leischner, U., Rochefort, N.L., Nelken, I. & Konnerth, A. Functional mapping of single spines in cortical neurons in vivo. Nature 475, 501–505 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Higley, M.J. & Contreras, D. Nonlinear integration of sensory responses in the rat barrel cortex: an intracellular study in vivo. J. Neurosci. 23, 10190–10200 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hill, D.N., Varga, Z., Jia, H., Sakmann, B. & Konnerth, A. Multibranch activity in basal and tuft dendrites during firing of layer 5 cortical neurons in vivo. Proc. Natl. Acad. Sci. USA 110, 13618–13623 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Jia, H., Rochefort, N.L., Chen, X. & Konnerth, A. Dendritic organization of sensory input to cortical neurons in vivo. Nature 464, 1307–1312 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Jia, H., Varga, Z., Sakmann, B. & Konnerth, A. Linear integration of spine Ca2+ signals in layer 4 cortical neurons in vivo. Proc. Natl. Acad. Sci. USA 111, 9277–9282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Léger, J.F., Stern, E.A., Aertsen, A. & Heck, D. Synaptic integration in rat frontal cortex shaped by network activity. J. Neurophysiol. 93, 281–293 (2005).

    Article  PubMed  Google Scholar 

  109. Longordo, F., To, M.S., Ikeda, K. & Stuart, G.J. Sublinear integration underlies binocular processing in primary visual cortex. Nat. Neurosci. 16, 714–723 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Varga, Z., Jia, H., Sakmann, B. & Konnerth, A. Dendritic coding of multiple sensory inputs in single cortical neurons in vivo. Proc. Natl. Acad. Sci. USA 108, 15420–15425 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhao, X., Liu, M. & Cang, J. Sublinear binocular integration preserves orientation selectivity in mouse visual cortex. Nat. Commun. 4, 2088 (2013).

    Article  PubMed  CAS  Google Scholar 

  112. Burke, R.E. Composite nature of the monosynaptic excitatory postsynaptic potential. J. Neurophysiol. 30, 1114–1137 (1967).

    Article  CAS  PubMed  Google Scholar 

  113. Murayama, M. & Larkum, M.E. Enhanced dendritic activity in awake rats. Proc. Natl. Acad. Sci. USA 106, 20482–20486 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sivyer, B. & Williams, S.R. Direction selectivity is computed by active dendritic integration in retinal ganglion cells. Nat. Neurosci. 16, 1848–1856 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Oesch, N., Euler, T. & Taylor, W.R. Direction-selective dendritic action potentials in rabbit retina. Neuron 47, 739–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Velte, T.J. & Masland, R.H. Action potentials in the dendrites of retinal ganglion cells. J. Neurophysiol. 81, 1412–1417 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Euler, T., Detwiler, P.B. & Denk, W. Directionally selective calcium signals in dendrites of starburst amacrine cells. Nature 418, 845–852 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Bliss, T.V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. (Lond.) 232, 331–356 (1973).

    Article  CAS  Google Scholar 

  119. Magee, J.C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).

    Article  CAS  PubMed  Google Scholar 

  120. Bi, G.-Q. & Poo, M.-M. Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J. Neurosci. 18, 10464–10472 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Markram, H., Lubke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Golding, N.L., Staff, N.P. & Spruston, N. Dendritic spikes as a mechanism for cooperative long-term potentiation. Nature 418, 326–331 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Letzkus, J.J., Kampa, B.M. & Stuart, G.J. Learning rules for spike timing-dependent plasticity depend on dendritic synapse location. J. Neurosci. 26, 10420–10429 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sjöström, P.J. & Hausser, M. A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons. Neuron 51, 227–238 (2006).

    Article  PubMed  CAS  Google Scholar 

  125. Remy, S. & Spruston, N. Dendritic spikes induce single-burst long-term potentiation. Proc. Natl. Acad. Sci. USA 104, 17192–17197 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Takahashi, H. & Magee, J.C. Pathway interactions and synaptic plasticity in the dendritic tuft regions of CA1 pyramidal neurons. Neuron 62, 102–111 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Pawlak, V., Greenberg, D.S., Sprekeler, H., Gerstner, W. & Kerr, J.N. Changing the responses of cortical neurons from sub- to suprathreshold using single spikes in vivo. eLife 2, e00012 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Frick, A., Magee, J. & Johnston, D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites. Nat. Neurosci. 7, 126–135 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Losonczy, A., Makara, J.K. & Magee, J.C. Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452, 436–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Gasparini, S., Migliore, M. & Magee, J.C. On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons. J. Neurosci. 24, 11046–11056 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Frick, A. & Johnston, D. Plasticity of dendritic excitability. J. Neurobiol. 64, 100–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Takahashi, N. et al. Locally Synchronized Synaptic Inputs. Science 335, 353–356 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Kleindienst, T., Winnubst, J., Roth-Alpermann, C., Bonhoeffer, T. & Lohmann, C. Activity-dependent clustering of functional synaptic inputs on developing hippocampal dendrites. Neuron 72, 1012–1024 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Fu, M., Yu, X., Lu, J. & Zuo, Y. Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature 483, 92–95 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Markram, H., Lubke, J., Frotscher, M., Roth, A. & Sakmann, B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. J. Physiol. (Lond.) 500, 409–440 (1997).

    Article  CAS  Google Scholar 

  136. Druckmann, S. et al. Structured synaptic connectivity between hippocampal regions. Neuron 81, 629–640 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Makino, H. & Malinow, R. Compartmentalized versus global synaptic plasticity on dendrites controlled by experience. Neuron 72, 1001–1011 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Niell, C.M. & Stryker, M.P. Modulation of visual responses by behavioral state in mouse visual cortex. Neuron 65, 472–479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Haider, B., Hausser, M. & Carandini, M. Inhibition dominates sensory responses in the awake cortex. Nature 493, 97–100 (2013).

    Article  PubMed  CAS  Google Scholar 

  140. Potez, S. & Larkum, M.E. Effect of common anesthetics on dendritic properties in layer 5 neocortical pyramidal neurons. J. Neurophysiol. 99, 1394–1407 (2008).

    Article  PubMed  Google Scholar 

  141. Farinella, M., Ruedt, D.T., Gleeson, P., Lanore, F. & Silver, R.A. Glutamate-bound NMDARs arising from in vivo-like network activity extend spatio-temporal integration in a L5 cortical pyramidal cell model. PLoS Comput. Biol. 10, e1003590 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Murayama, M., Perez-Garci, E., Luscher, H.R. & Larkum, M.E. Fiberoptic system for recording dendritic calcium signals in layer 5 neocortical pyramidal cells in freely moving rats. J. Neurophysiol. 98, 1791–1805 (2007).

    Article  PubMed  Google Scholar 

  143. Ghosh, K.K. et al. Miniaturized integration of a fluorescence microscope. Nat. Methods 8, 871–878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Helmchen, F., Denk, W. & Kerr, J.N. Miniaturization of two-photon microscopy for imaging in freely moving animals. Cold Spring Harb. Protoc. 2013, 904–913 (2013).

    Article  PubMed  Google Scholar 

  145. Dombeck, D.A., Khabbaz, A.N., Collman, F., Adelman, T.L. & Tank, D.W. Imaging large-scale neural activity with cellular resolution in awake, mobile mice. Neuron 56, 43–57 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Petreanu, L. et al. Activity in motor-sensory projections reveals distributed coding in somatosensation. Nature 489, 299–303 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lovett-Barron, M. et al. Dendritic inhibition in the hippocampus supports fear learning. Science 343, 857–863 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yuste, R., Gutnick, M.J., Saar, D., Delaney, K.R. & Tank, D.W. Ca2+ accumulations in dendrites of neocortical pyramidal neurons: an apical band and evidence for two functional compartments. Neuron 13, 23–43 (1994).

    Article  CAS  PubMed  Google Scholar 

  149. Dombeck, D.A., Harvey, C.D., Tian, L., Looger, L.L. & Tank, D.W. Functional imaging of hippocampal place cells at cellular resolution during virtual navigation. Nat. Neurosci. 13, 1433–1440 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Priebe, N.J. & Ferster, D. Neuroscience: Each synapse to its own. Nature 464, 1290–1291 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank the following funding sources: The John Curtin School of Medical Research (G.J.S.), the National Health and Medical Research Council of Australia (G.J.S.), the Australia Research Council (ARC) Centre of Excellence for Integrative Brain Function (G.J.S.) and the Howard Hughes Medical Institute (N.S.).

Author information

Authors and Affiliations

  1. Eccles Institute of Neuroscience and ARC Centre of Excellence for Integrative Brain Function, John Curtin School of Medical Research, Australian National University, Canberra, Australia

    Greg J Stuart

  2. Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, USA

    Nelson Spruston

Authors
  1. Greg J Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nelson Spruston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Greg J Stuart.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stuart, G., Spruston, N. Dendritic integration: 60 years of progress. Nat Neurosci 18, 1713–1721 (2015). https://doi.org/10.1038/nn.4157

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4157

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing