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• W2959094443 abstract "While many studies indicate that dendrites can perform a range of local computations on their inputs, work from the Harnett lab in this issue of Neuron suggests that the vast majority of active dendritic events are synchronized across the somato-dendritic axis of cortical pyramidal neurons. While many studies indicate that dendrites can perform a range of local computations on their inputs, work from the Harnett lab in this issue of Neuron suggests that the vast majority of active dendritic events are synchronized across the somato-dendritic axis of cortical pyramidal neurons. Theoretical and experimental work since the 1960s has established that the complex geometry of dendrites, together with their unique electrical properties, endows them with the capacity to perform a range of computations on their inputs (Stuart and Spruston, 2015Stuart G.J. Spruston N. Dendritic integration: 60 years of progress.Nat. Neurosci. 2015; 18: 1713-1721Crossref PubMed Scopus (253) Google Scholar). These dendritic computations range from local sub-linear interactions with other synaptic inputs, due to changes in electrochemical driving force, to active supra-linear responses (or dendritic spikes) due to recruitment of dendritic voltage-gated ion channels. Active dendritic spikes can remain local to the dendritic branch in which they are generated, but they can also trigger more global dendritic activity. While both local and global forms of dendritic integration have been observed in vitro, and more recently in vivo, it is less clear to what extent these different types of dendritic integration contribute to neuronal output in awake behaving animals (Figure 1). In this issue of Neuron, Beaulieu-Laroche and colleagues investigate how dendritic activity is correlated with activity at the soma of layer 5 pyramidal neurons by imaging calcium at distal apical dendritic and somatic compartments quasi-simultaneously (Beaulieu-Laroche et al., 2019Beaulieu-Laroche L. Toloza E.H.S. Brown N.J. Harnett M.T. Widespread and Highly Correlated Somato-dendritic Activity in Cortical Layer 5 Neurons.Neuron. 2019; 103 (this issue): 235-241Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Calcium influx was detected using 2-photon microscopy with the genetically encoded calcium indicator GCaMP (Chen et al., 2013Chen T.W. Wardill T.J. Sun Y. Pulver S.R. Renninger S.L. Baohan A. Schreiter E.R. Kerr R.A. Orger M.B. Jayaraman V. et al.Ultrasensitive fluorescent proteins for imaging neuronal activity.Nature. 2013; 499: 295-300Crossref PubMed Scopus (3645) Google Scholar), with recordings performed in visual cortex of awake mice. Consistent with earlier work in motor cortex (Peters et al., 2017Peters A.J. Lee J. Hedrick N.G. O’Neil K. Komiyama T. Reorganization of corticospinal output during motor learning.Nat. Neurosci. 2017; 20: 1133-1141Crossref PubMed Scopus (74) Google Scholar), Beaulieu-Laroche and colleagues find an almost perfect correlation in the timing of calcium transients at distal dendritic and somatic compartments of layer 5 pyramidal neurons. These “global” events were common and found in essentially all layer 5 pyramidal neurons. Isolated dendritic events occurring in the absence of a change in somatic calcium were rarely observed. These data suggest that somatic and dendritic electrical activity is strongly coupled. Further, they find that coupling between the soma and dendrites is unchanged by visual stimuli and locomotion, so it does not appear to depend on cortical state. Importantly, Beaulieu-Laroche and colleagues use dual somatic and dendritic whole-cell recording in vitro to determine the nature of the electrical events underlying the global calcium signals observed in vivo. These in vitro experiments indicated that dendritic spikes of sufficient duration to drive prolonged high-frequency action potential firing at the soma, or high-frequency (200 Hz) somatic action potential trains, were required to evoke global increases in calcium influx. The observation that detectable changes in dendritic calcium are only observed during stimuli sufficient to drive high-frequency action potential firing is similar to observations in earlier work in layer 5 pyramidal cells using dye-based indicators (Helmchen et al., 1999Helmchen F. Svoboda K. Denk W. Tank D.W. In vivo dendritic calcium dynamics in deep-layer cortical pyramidal neurons.Nat. Neurosci. 1999; 2: 989-996Crossref PubMed Scopus (309) Google Scholar). Surprisingly, Beaulieu-Laroche and colleagues find that changes in somatic calcium were only observed during high-frequency action potential firing, with essentially no detectable rise in somatic calcium during single spikes. This contrasts with observations in layer 2/3 pyramidal cells, where individual spikes at the soma are detectable using GCaMP (Chen et al., 2013Chen T.W. Wardill T.J. Sun Y. Pulver S.R. Renninger S.L. Baohan A. Schreiter E.R. Kerr R.A. Orger M.B. Jayaraman V. et al.Ultrasensitive fluorescent proteins for imaging neuronal activity.Nature. 2013; 499: 295-300Crossref PubMed Scopus (3645) Google Scholar). While it is unclear what underlies the reduced sensitivity of GCaMP in layer 5 pyramidal neurons, this finding indicates that the results of Beaulieu-Laroche and colleagues cannot inform us about somato-dendritic coupling during low-frequency somatic action potential firing. A critical difficulty in clarifying the influence of dendritic spikes on neuronal output in vivo is the challenge of being able to confidently identify when dendritic spikes occur. One issue is that dendritic spikes are not the only electrical events that cause a significant rise in dendritic calcium. Active backpropagation of action potentials into the dendrites of many neuronal cell types also leads to increases in dendritic calcium, particularly during high-frequency action potential firing. It is therefore difficult to say whether global increases in calcium reflect the generation of dendritic spikes or instead are the result of active propagation of action potentials into dendrites during high-frequency somatic action potential firing (Figure 1, right). Distinguishing between these two scenarios is not trivial, as both would be expected to be associated with global rises in calcium at somatic and dendritic compartments. Alternative methods with higher temporal resolution, such as voltage imaging or electrical recording, will be required to differentiate between these two possibilities. This study by Beaulieu-Laroche and colleagues addresses the important issue of how active dendritic activity relates to neuronal output. The authors should be commended for investigating dendritic integration in awake behaving animals and for directly comparing florescence changes observed in vivo with electrical activity in vitro. This in vitro calibration of GCaMP signals is critical to an understanding of the electrical events that underlie changes in GCaMP fluorescence in vivo. These in vitro experiments, however, indicate that low-frequency events such as single action potentials are likely to have been missed in their in vivo experiments, in part due to cell-specific differences in GCaMP sensitivity. So while the conclusions of Beaulieu-Laroche and colleagues hold for GCaMP, whether similar observations will be found using methods with higher sensitivity, and ideally better temporal resolution, is yet to be determined. It is worth considering whether the observations by Beaulieu-Laroche and colleagues can be extrapolated to all parts of the dendritic tree or indeed to other layer 5 neurons. The recordings by Beaulieu-Laroche and colleagues were made primarily from the main apical dendrites of layer 5 pyramidal neurons. Previous work indicates that local branch-specific changes in calcium can be observed in the distal tuft dendrites of layer 5 pyramidal neurons in motor cortex in vivo (Hill et al., 2013Hill 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. 2013; 110: 13618-13623Crossref PubMed Scopus (56) Google Scholar), suggesting that electrical coupling is weaker at more distal dendritic locations. Other work suggests that branch-specific dendritic spikes in the distal tuft dendrites of these neurons may play a role in motor learning (Cichon and Gan, 2015Cichon J. Gan W.B. Branch-specific dendritic Ca(2+) spikes cause persistent synaptic plasticity.Nature. 2015; 520: 180-185Crossref PubMed Scopus (283) Google Scholar). In contrast, synchronized activation across the entire apical tuft of layer 5 pyramidal neurons is found in somatosensory cortex during active whisking (Xu et al., 2012Xu N.L. Harnett M.T. Williams S.R. Huber D. O’Connor D.H. Svoboda K. Magee J.C. Nonlinear dendritic integration of sensory and motor input during an active sensing task.Nature. 2012; 492: 247-251Crossref PubMed Scopus (321) Google Scholar). These data may indicate that local dendritic spikes play a more important role in synaptic plasticity than in neuronal output, with the summation of local dendritic spikes driving global somato-dendritic activity and in turn, high-frequency action potential firing. Finally, it is also important to note that not all layer 5 pyramidal neurons are alike, even within the same cortical area. Differences in electrical coupling between somatic and dendritic compartments of layer 5 pyramidal neurons have been observed across the rostro-caudal axis of rat visual cortex (Fletcher and Williams, 2019Fletcher L.N. Williams S.R. Neocortical Topology Governs the Dendritic Integrative Capacity of Layer 5 Pyramidal Neurons.Neuron. 2019; 101: 76-90.e4Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar), with weaker somato-dendritic coupling in layer 5 pyramidal neurons with longer apical dendrites. The idea that the extent of somato-dendritic coupling depends on the length of the apical dendrite may explain the strong somato-dendritic coupling observed in mouse visual cortex, as layer 5 pyramidal neurons in mice are smaller than those in rats. In contrast, recent work by the Harnett lab indicates that somato-dendritic coupling in human layer 5 pyramidal neurons, which have apical dendrites approximately twice as long as in rodents, is weak (Beaulieu-Laroche et al., 2018Beaulieu-Laroche L. Toloza E.H.S. van der Goes M.S. Lafourcade M. Barnagian D. Williams Z.M. Eskandar E.N. Frosch M.P. Cash S.S. Harnett M.T. Enhanced Dendritic Compartmentalization in Human Cortical Neurons.Cell. 2018; 175: 643-651 e614Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). Together, these data suggest that the extent of somato-dendritic coupling in layer 5 pyramidal neurons is directly related to their physical length, and thereby cortical thickness. In summary, the findings by Beaulieu-Laroche and colleagues show that powerful electrical coupling exists between the soma and dendrites of layer 5 pyramidal neurons in mouse visual cortex, indicating that active and widespread dendritic integration is common in these cells. To what extent these findings can be extrapolated to other neuronal cell types and brain regions remains to be determined. Widespread and Highly Correlated Somato-dendritic Activity in Cortical Layer 5 NeuronsBeaulieu-Laroche et al.NeuronJune 6, 2019In BriefBeaulieu-Laroche et al. perform near-simultaneous calcium imaging of somatic and dendritic activity to reveal that active dendritic integration is an integral feature of information processing in cortical pyramidal neurons. Full-Text PDF Open Archive" @default.
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• W2959094443 title "Local versus Global Dendritic Integration" @default.
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