Dendritic integration: 60 years of progress

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.

[1]  Michael London,et al.  Local and Global Effects of Ih Distribution in Dendrites of Mammalian Neurons , 2007, The Journal of Neuroscience.

[2]  M. Stryker,et al.  Modulation of Visual Responses by Behavioral State in Mouse Visual Cortex , 2010, Neuron.

[3]  Christoph Schmidt-Hieber,et al.  Action potential initiation and propagation in hippocampal mossy fibre axons , 2008, The Journal of physiology.

[4]  M. Carandini,et al.  Inhibition dominates sensory responses in awake cortex , 2012, Nature.

[5]  Lin Tian,et al.  Activity in motor-sensory projections reveals distributed coding in somatosensation , 2012, Nature.

[6]  J. Magee,et al.  Dendritic voltage-gated ion channels regulate the action potential firing mode of hippocampal CA1 pyramidal neurons. , 1999, Journal of neurophysiology.

[7]  N. Spruston,et al.  Conditional dendritic spike propagation following distal synaptic activation of hippocampal CA1 pyramidal neurons , 2005, Nature Neuroscience.

[8]  Yuguo Yu,et al.  Properties of action-potential initiation in neocortical pyramidal cells: evidence from whole cell axon recordings. , 2007, Journal of neurophysiology.

[9]  Ad Aertsen,et al.  Synaptic integration in rat frontal cortex shaped by network activity. , 2005, Journal of neurophysiology.

[10]  J. Schiller,et al.  Active properties of neocortical pyramidal neuron dendrites. , 2013, Annual review of neuroscience.

[11]  H. Swadlow,et al.  Dendritic Backpropagation and the State of the Awake Neocortex , 2007, The Journal of Neuroscience.

[12]  J. Magee,et al.  Structured Synaptic Connectivity between Hippocampal Regions , 2014, Neuron.

[13]  A. Polsky,et al.  Properties of basal dendrites of layer 5 pyramidal neurons: a direct patch-clamp recording study , 2007, Nature Neuroscience.

[14]  Masanori Murayama,et al.  Fiberoptic system for recording dendritic calcium signals in layer 5 neocortical pyramidal cells in freely moving rats. , 2007, Journal of neurophysiology.

[15]  H. Dodt,et al.  Visualizing unstained neurons in living brain slices by infrared DIC-videomicroscopy , 1990, Brain Research.

[16]  R. Llinás,et al.  Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. , 1980, The Journal of physiology.

[17]  R. Masland,et al.  Action potentials in the dendrites of retinal ganglion cells. , 1999, Journal of neurophysiology.

[18]  B. Sakmann,et al.  A new cellular mechanism for coupling inputs arriving at different cortical layers , 1999, Nature.

[19]  Matthew E. Larkum,et al.  Enhanced dendritic activity in awake rats , 2009, Proceedings of the National Academy of Sciences.

[20]  D. Contreras,et al.  Nonlinear Integration of Sensory Responses in the Rat Barrel Cortex: An Intracellular Study In Vivo , 2003, The Journal of Neuroscience.

[21]  Nathalie L Rochefort,et al.  Dendritic organization of sensory input to cortical neurons in vivo , 2010, Nature.

[22]  B. Connors,et al.  Regenerative activity in apical dendrites of pyramidal cells in neocortex. , 1993, Cerebral cortex.

[23]  N. Spruston,et al.  Synapse Distribution Suggests a Two-Stage Model of Dendritic Integration in CA1 Pyramidal Neurons , 2009, Neuron.

[24]  Spencer L. Smith,et al.  Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo , 2013, Nature.

[25]  D. Johnston,et al.  K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons , 1997, Nature.

[26]  T. Poggio,et al.  Nonlinear interactions in a dendritic tree: localization, timing, and role in information processing. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Bartlett W. Mel,et al.  Pyramidal Neuron as Two-Layer Neural Network , 2003, Neuron.

[28]  Roberto Malinow,et al.  Compartmentalized versus Global Synaptic Plasticity on Dendrites Controlled by Experience , 2011, Neuron.

[29]  F. Helmchen,et al.  Boosting of Action Potential Backpropagation by Neocortical Network Activity In Vivo , 2004, The Journal of Neuroscience.

[30]  M. Larkum,et al.  High I(h) channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. , 2001, Journal of neurophysiology.

[31]  Arnd Roth,et al.  Initiation of simple and complex spikes in cerebellar Purkinje cells , 2010, The Journal of physiology.

[32]  P. Detwiler,et al.  Directionally selective calcium signals in dendrites of starburst amacrine cells , 2002, Nature.

[33]  A. Gamal,et al.  Miniaturized integration of a fluorescence microscope , 2011, Nature Methods.

[34]  G. Buzsáki,et al.  Somadendritic backpropagation of action potentials in cortical pyramidal cells of the awake rat. , 1998, Journal of neurophysiology.

[35]  A. Holtmaat,et al.  Sensory-evoked LTP driven by dendritic plateau potentials in vivo , 2014, Nature.

[36]  D. Johnston,et al.  Characterization of single voltage‐gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. , 1995, The Journal of physiology.

[37]  M. Häusser,et al.  Dendritic coincidence detection of EPSPs and action potentials , 2001, Nature Neuroscience.

[38]  O Herreras,et al.  Propagating dendritic action potential mediates synaptic transmission in CA1 pyramidal cells in situ. , 1990, Journal of neurophysiology.

[39]  Padraig Gleeson,et al.  Glutamate-Bound NMDARs Arising from In Vivo-like Network Activity Extend Spatio-temporal Integration in a L5 Cortical Pyramidal Cell Model , 2014, PLoS Comput. Biol..

[40]  Bert Sakmann,et al.  Supralinear Ca2+ Influx into Dendritic Tufts of Layer 2/3 Neocortical Pyramidal Neurons In Vitro and In Vivo , 2003, The Journal of Neuroscience.

[41]  Nelson Spruston,et al.  Synaptic amplification by dendritic spines enhances input cooperativity , 2012, Nature.

[42]  G. Stuart,et al.  Site of Action Potential Initiation in Layer 5 Pyramidal Neurons , 2006, The Journal of Neuroscience.

[43]  John A. Freeman,et al.  Dendritic Spikes and Their Inhibition in Alligator Purkinje Cells , 1968, Science.

[44]  G. Shepherd,et al.  Theoretical reconstruction of field potentials and dendrodendritic synaptic interactions in olfactory bulb. , 1968, Journal of neurophysiology.

[45]  N. Spruston,et al.  Activity-dependent action potential invasion and calcium influx into hippocampal CA1 dendrites. , 1995, Science.

[46]  G. Stuart,et al.  Membrane Potential Changes in Dendritic Spines during Action Potentials and Synaptic Input , 2009, The Journal of Neuroscience.

[47]  Stephen R. Williams,et al.  Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons , 1999, The Journal of physiology.

[48]  Kaori Ikeda,et al.  Sublinear integration underlies binocular processing in primary visual cortex , 2013, Nature Neuroscience.

[49]  B. Sakmann,et al.  Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy , 1993, Pflügers Archiv.

[50]  F. Helmchen,et al.  Background Synaptic Activity Is Sparse in Neocortex , 2006, The Journal of Neuroscience.

[51]  N. Spruston,et al.  Dendritic spikes induce single-burst long-term potentiation , 2007, Proceedings of the National Academy of Sciences.

[52]  B. Connors,et al.  Intrinsic firing patterns and whisker-evoked synaptic responses of neurons in the rat barrel cortex. , 1999, Journal of neurophysiology.

[53]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[54]  N. Spruston,et al.  Action potential initiation and backpropagation in neurons of the mammalian CNS , 1997, Trends in Neurosciences.

[55]  G. Buzsáki,et al.  Dendritic Spikes Are Enhanced by Cooperative Network Activity in the Intact Hippocampus , 1998, The Journal of Neuroscience.

[56]  G. Stuart,et al.  Dependence of EPSP Efficacy on Synapse Location in Neocortical Pyramidal Neurons , 2002, Science.

[57]  J. Schiller,et al.  NMDA spikes in basal dendrites of cortical pyramidal neurons , 2000, Nature.

[58]  B. Sakmann,et al.  Dendritic mechanisms underlying the coupling of the dendritic with the axonal action potential initiation zone of adult rat layer 5 pyramidal neurons , 2001, The Journal of physiology.

[59]  Bernardo L. Sabatini,et al.  Biphasic Synaptic Ca Influx Arising from Compartmentalized Electrical Signals in Dendritic Spines , 2009, PLoS biology.

[60]  Idan Segev,et al.  Principles Governing the Operation of Synaptic Inhibition in Dendrites , 2012, Neuron.

[61]  J. Magee,et al.  Pathway Interactions and Synaptic Plasticity in the Dendritic Tuft Regions of CA1 Pyramidal Neurons , 2009, Neuron.

[62]  Susumu Tonegawa,et al.  Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons , 2015, Nature Neuroscience.

[63]  D. Prince,et al.  Intradendritic recordings from hippocampal neurons. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[64]  P. Fatt Electric potentials occurring around a neurone during its antidromic activation. , 1957, Journal of neurophysiology.

[65]  N. Spruston,et al.  Prolonged Sodium Channel Inactivation Contributes to Dendritic Action Potential Attenuation in Hippocampal Pyramidal Neurons , 1997, The Journal of Neuroscience.

[66]  K. Svoboda,et al.  The subcellular organization of neocortical excitatory connections , 2009, Nature.

[67]  M. Häusser,et al.  Propagation of action potentials in dendrites depends on dendritic morphology. , 2001, Journal of neurophysiology.

[68]  T. H. Brown,et al.  Dendritic spines: convergence of theory and experiment. , 1992, Science.

[69]  Bert Sakmann,et al.  Linear integration of spine Ca2+ signals in layer 4 cortical neurons in vivo , 2014, Proceedings of the National Academy of Sciences.

[70]  B. Sakmann,et al.  Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a critical frequency of back-propagating action potentials. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[71]  G. Shepherd,et al.  Emerging rules for the distributions of active dendritic conductances , 2002, Nature Reviews Neuroscience.

[72]  Nathalie L Rochefort,et al.  Functional mapping of single spines in cortical neurons in vivo , 2011, Nature.

[73]  D. Johnston,et al.  Slow Recovery from Inactivation of Na+ Channels Underlies the Activity-Dependent Attenuation of Dendritic Action Potentials in Hippocampal CA1 Pyramidal Neurons , 1997, The Journal of Neuroscience.

[74]  Matthew E Larkum,et al.  Effect of common anesthetics on dendritic properties in layer 5 neocortical pyramidal neurons. , 2008, Journal of neurophysiology.

[75]  C. Yamamoto,et al.  Potentials evoked in vitro in Preparations from the Mammalian Brain , 1966, Nature.

[76]  M. Häusser,et al.  Initiation and spread of sodium action potentials in cerebellar purkinje cells , 1994, Neuron.

[77]  Norio Matsuki,et al.  Locally Synchronized Synaptic Inputs , 2012, Science.

[78]  J. Magee Dendritic Hyperpolarization-Activated Currents Modify the Integrative Properties of Hippocampal CA1 Pyramidal Neurons , 1998, The Journal of Neuroscience.

[79]  Y. Dan,et al.  Neuromodulation of Brain States , 2012, Neuron.

[80]  Lin Tian,et al.  Functional imaging of hippocampal place cells at cellular resolution during virtual navigation , 2010, Nature Neuroscience.

[81]  Idan Segev,et al.  Modeling back propagating action potential in weakly excitable dendrites of neocortical pyramidal cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[82]  W. N. Ross,et al.  The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons , 1992, Nature.

[83]  A. Polsky,et al.  Synaptic Integration in Tuft Dendrites of Layer 5 Pyramidal Neurons: A New Unifying Principle , 2009, Science.

[84]  M. Larkum,et al.  The Cellular Basis of GABAB-Mediated Interhemispheric Inhibition , 2012, Science.

[85]  Nace L. Golding,et al.  Dendritic Calcium Spike Initiation and Repolarization Are Controlled by Distinct Potassium Channel Subtypes in CA1 Pyramidal Neurons , 1999, The Journal of Neuroscience.

[86]  Jianhua Cang,et al.  Sublinear Binocular Integration Preserves Orientation Selectivity in Mouse Visual Cortex , 2013, Nature Communications.

[87]  Nace L. Golding,et al.  Dendritic Sodium Spikes Are Variable Triggers of Axonal Action Potentials in Hippocampal CA1 Pyramidal Neurons , 1998, Neuron.

[88]  N. Spruston,et al.  Diversity and dynamics of dendritic signaling. , 2000, Science.

[89]  S. Siegelbaum,et al.  Dendritic Na+ spikes enable cortical input to drive action potential output from hippocampal CA2 pyramidal neurons , 2014, eLife.

[90]  B. Sakmann,et al.  Active propagation of somatic action potentials into neocortical pyramidal cell dendrites , 1994, Nature.

[91]  R E Burke,et al.  Composite nature of the monosynaptic excitatory postsynaptic potential. , 1967, Journal of neurophysiology.

[92]  Jackie Schiller,et al.  Nonlinear dendritic processing determines angular tuning of barrel cortex neurons in vivo , 2012, Nature.

[93]  W. Denk,et al.  Dendritic spines as basic functional units of neuronal integration , 1995, Nature.

[94]  M. Mayer,et al.  Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones , 1984, Nature.

[95]  Winfried Denk,et al.  Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo , 1999, Nature Neuroscience.

[96]  Jozsef Csicsvari,et al.  Activity-Dependent Control of Neuronal Output by Local and Global Dendritic Spike Attenuation , 2009, Neuron.

[97]  J. Eccles,et al.  The interpretation of spike potentials of motoneurones , 1957, The Journal of physiology.

[98]  G. Bi,et al.  Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type , 1998, The Journal of Neuroscience.

[99]  R. Llinás,et al.  Electrophysiological properties of dendrites and somata in alligator Purkinje cells. , 1971, Journal of neurophysiology.

[100]  D. Tank,et al.  Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice. , 1988, Science.

[101]  P. J. Sjöström,et al.  A Cooperative Switch Determines the Sign of Synaptic Plasticity in Distal Dendrites of Neocortical Pyramidal Neurons , 2006, Neuron.

[102]  David S. Greenberg,et al.  Changing the responses of cortical neurons from sub- to suprathreshold using single spikes in vivo , 2013, eLife.

[103]  Daniel Johnston,et al.  LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites , 2004, Nature Neuroscience.

[104]  H. Markram,et al.  Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. , 1997, The Journal of physiology.

[105]  Johannes J. Letzkus,et al.  Learning Rules for Spike Timing-Dependent Plasticity Depend on Dendritic Synapse Location , 2006, The Journal of Neuroscience.

[106]  R. Llinás,et al.  Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. , 1980, The Journal of physiology.

[107]  D. Johnston,et al.  Plasticity of dendritic excitability. , 2005, Journal of neurobiology.

[108]  Daniel N Hill,et al.  Multibranch activity in basal and tuft dendrites during firing of layer 5 cortical neurons in vivo , 2013, Proceedings of the National Academy of Sciences.

[109]  Yasushi Miyashita,et al.  Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons , 2001, Nature Neuroscience.

[110]  Winfried Denk,et al.  Miniaturization of two-photon microscopy for imaging in freely moving animals. , 2013, Cold Spring Harbor protocols.

[111]  Nicholas J. Priebe,et al.  Neuroscience: Each synapse to its own , 2010, Nature.

[112]  B. Sakmann,et al.  Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons , 1997, The Journal of physiology.

[113]  D. Tank,et al.  In vivo dendritic calcium dynamics in deep-layer cortical pyramidal neurons , 1999, Nature Neuroscience.

[114]  Nicholas Oesch,et al.  Direction-Selective Dendritic Action Potentials in Rabbit Retina , 2005, Neuron.

[115]  N. Spruston,et al.  Determinants of Voltage Attenuation in Neocortical Pyramidal Neuron Dendrites , 1998, The Journal of Neuroscience.

[116]  D. Prince,et al.  Electrophysiology of isolated hippocampal pyramidal dendrites , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[117]  Rafael Yuste,et al.  Ca2+ accumulations in dendrites of neocortical pyramidal neurons: An apical band and evidence for two functional compartments , 1994, Neuron.

[118]  J. Magee,et al.  On the Initiation and Propagation of Dendritic Spikes in CA1 Pyramidal Neurons , 2004, The Journal of Neuroscience.

[119]  J. Magee Dendritic integration of excitatory synaptic input , 2000, Nature Reviews Neuroscience.

[120]  J. Barker,et al.  Localization of tetrodotoxin-sensitive field potentials of CA1 pyramidal cells in the rat hippocampus. , 1989, Journal of neurophysiology.

[121]  Bert Sakmann,et al.  Axonal initiation and active dendritic propagation of action potentials in substantia nigra neurons , 1995, Neuron.

[122]  D. Tank,et al.  Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice , 2007, Neuron.

[123]  Wilfrid Rall,et al.  Theoretical significance of dendritic trees for neuronal input-output relations , 1964 .

[124]  Mark T. Harnett,et al.  Nonlinear dendritic integration of sensory and motor input during an active sensing task , 2012, Nature.

[125]  G. Buzsáki,et al.  Pattern and inhibition-dependent invasion of pyramidal cell dendrites by fast spikes in the hippocampus in vivo. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[126]  Attila Losonczy,et al.  Dendritic Inhibition in the Hippocampus Supports Fear Learning , 2014, Science.

[127]  M. Fuortes,et al.  STEPS IN THE PRODUCTION OF MOTONEURON SPIKES , 1957, The Journal of general physiology.

[128]  W. Gan,et al.  Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity , 2015, Nature.

[129]  B. Sakmann,et al.  Action potential initiation and propagation in rat neocortical pyramidal neurons , 1997, The Journal of physiology.

[130]  Judit K. Makara,et al.  Compartmentalized dendritic plasticity and input feature storage in neurons , 2008, Nature.

[131]  Christine Grienberger,et al.  NMDA Receptor-Dependent Multidendrite Ca2+ Spikes Required for Hippocampal Burst Firing In Vivo , 2014, Neuron.

[132]  E. Kandel,et al.  ELECTROPHYSIOLOGY OF HIPPOCAMPAL NEURONS: IV. FAST PREPOTENTIALS. , 1961, Journal of neurophysiology.

[133]  Mark T. Harnett,et al.  Potassium Channels Control the Interaction between Active Dendritic Integration Compartments in Layer 5 Cortical Pyramidal Neurons , 2013, Neuron.

[134]  Bert Sakmann,et al.  Dendritic coding of multiple sensory inputs in single cortical neurons in vivo , 2011, Proceedings of the National Academy of Sciences.

[135]  D. Johnston,et al.  A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons , 1997, Science.

[136]  Ju Lu,et al.  REPETITIVE MOTOR LEARNING INDUCES COORDINATED FORMATION OF CLUSTERED DENDRITIC SPINES IN VIVO , 2012, Nature.

[137]  W. N. Ross,et al.  Imaging voltage and synaptically activated sodium transients in cerebellar Purkinje cells , 1992, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[138]  Nace L. Golding,et al.  Dendritic spikes as a mechanism for cooperative long-term potentiation , 2002, Nature.

[139]  Daniel A. Dombeck,et al.  Calcium transient prevalence across the dendritic arbor predicts place field properties , 2014, Nature.

[140]  M. Larkum,et al.  NMDA spikes enhance action potential generation during sensory input , 2014, Nature Neuroscience.

[141]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[142]  Mark T. Harnett,et al.  Distribution and Function of HCN Channels in the Apical Dendritic Tuft of Neocortical Pyramidal Neurons , 2015, The Journal of Neuroscience.

[143]  P. Schwartzkroin,et al.  Electrophysiology of Hippocampal Neurons , 1987 .

[144]  Matthew E Larkum,et al.  Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o‐βγ‐subunit interaction with Cav1 channels , 2013, The Journal of physiology.

[145]  M. Larkum,et al.  Signaling of Layer 1 and Whisker-Evoked Ca2+ and Na+ Action Potentials in Distal and Terminal Dendrites of Rat Neocortical Pyramidal Neurons In Vitro and In Vivo , 2002, The Journal of Neuroscience.

[146]  J. Magee,et al.  Integrative Properties of Radial Oblique Dendrites in Hippocampal CA1 Pyramidal Neurons , 2006, Neuron.

[147]  H. Pockberger,et al.  Electrophysiological and morphological properties of rat motor cortex neurons in vivo , 1991, Brain Research.

[148]  Tobias Bonhoeffer,et al.  Activity-Dependent Clustering of Functional Synaptic Inputs on Developing Hippocampal Dendrites , 2011, Neuron.

[149]  Bartlett W. Mel,et al.  Computational subunits in thin dendrites of pyramidal cells , 2004, Nature Neuroscience.

[150]  W. Senn,et al.  Dendritic encoding of sensory stimuli controlled by deep cortical interneurons , 2009, Nature.

[151]  R. Llinás,et al.  Tetrodotoxin-resistant dendritic spikes in avian Purkinje cells. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[152]  Benjamin Sivyer,et al.  Direction selectivity is computed by active dendritic integration in retinal ganglion cells , 2013, Nature Neuroscience.