The brain has an extraordinary capacity for memory storage, but how it stores new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex. These task-related, branch-specific Ca2+ spikes cause long-lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca2+ spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca2+ spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca2+ spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences.
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This work was supported by National Institutes of Health R01 NS047325 and P01 NS074972 to W.-B.G. We thank L. Looger, G. Chen and members of the Gan laboratory for their comments on the manuscript. We thank the Genetically-Encoded Neuronal Indicator and Effector (GENIE) Project and the Janelia Farm Research Campus of the Howard Hughes Medical Institute for sharing GCaMP6 constructs.
The authors declare no competing financial interests.
Extended data figures and tables
Extended Data Figure 1 The forelimb motor cortex is important for treadmill running and performance improvement.
a, Representative forelimb gait traces from wild-type mice running forward on the treadmill during the first few minutes of training. Several gait patterns (drag, sweep, wobble and steady run) were observed. b, Average width between forelimbs in steady run decreased during forward treadmill running. c, Backward running elicited changes in gait patterning over two 20-min training sessions. Initially, the mice exhibited mostly steady run (34%) and drag (55%) gait patterns without sweep. With continued training, mice refined their gait from drag to steady run (75%) over 40 min. d, Average stride length in steady run increased during backward treadmill training. e, Bilateral injections of muscimol, a GABA receptor agonist, into the forelimb motor cortex acutely impaired treadmill running performance (n = 4). Muscimol injected mice displayed high percentages of untrained gait features (drag: 70% (0–5 min) and 80% (50–55 min)), whereas mice injected with saline to forelimb motor cortex did not (drag: 44% (0–5 min) and 13% (50–55 min)) (n = 5). Muscimol injections into barrel cortex did not impair treadmill running performance (drag: 34% (0–5 min) and 18% (50–55 min)) (n = 4). Data are presented as mean ± s.e.m. *P < 0.05, ***P < 0.001, paired t-test.
Extended Data Figure 2 Detection of motor learning-induced Ca2+ spikes by various GCaMPs in apical tuft dendrites of layer 5 neurons in the motor cortex.
a, b, Coronal sections of forelimb motor cortex from mice expressing AAV-GCaMP5G (a) or GCaMP2.2c (b). Boxed regions shows the expression of GCaMPs in L5. c, Two-photon images of GCaMP2.2c-, 3- and 5G-expressing dendrites during quiet resting state and forward running. Images of baseline Ca2+ signals under quiet resting state (top) and running-induced Ca2+ spikes (bottom; yellow arrowheads) are shown. d, e, Fast-scanning of apical tuft dendrites during forward running in mice expressing GCaMP2.2c (n = 18) and GCaMP5G (n = 14). Grey traces are individual Ca2+ transients and black trace represents the average. f, Average rise and decay times of apical tuft Ca2+ spikes during running for different GCaMPs (unpaired t-test). g, Measurements of Ca2+ fluorescence along long dendritic segments in the plane of imaging. Both GCaMP6s (n = 10) and GCaMP2.2c (n = 7) detected comparable fluorescent signals across entire dendritic segments. h, Number of Ca2+ spikes during quiet resting, running forward, running backward, and with local application of MK801(paired t-test). Ca2+ spikes were detected on L5 tuft branches in an image field (160 × 80 μm) over 2.5 min in Thy-1 GCaMP2.2c transgenic mice. i, The number of dendritic Ca2+ spikes generated in early running trials was not significantly different from that in later (30 min) running trials (P = 0.89, paired t-test). Scale bar, 50 μm (a, b) and 15 μm (c). *P < 0.05, *** P < 0.001.
Extended Data Figure 3 The overlap of Ca2+ activity in apical dendritic trunk, somata, and apical tuft branches of L5 pyramidal neurons in the motor cortex in response to treadmill running.
a, Frequency distribution of the number of Ca2+ transients detected over 2.5 min in individual apical trunks in mice running forward and backward. b, Ca2+ imaging of layer 5 somata during forward and backward running. c, Frequency distribution of the number of Ca2+ transients in individual L5 somata detected over 2.5 min in mice running forward and backward (n = 504 cells from 10 mice). d, Layer 5 somata responded to multiple tasks when running in four directions (n = 242 cells from 4 mice). e, Summary of the overlap of Ca2+ activity in response to forward and backward running across different cortical layers in the motor cortex. f, Two-dimensional projection of six apical tuft branches from the same L5 neuron expressing GCaMP6s. Six ROIs corresponding to different branches were analysed over 2.5 min forward or backward running. Green arrowhead marks the location of the trunk (∼200 μm below the pia). Note that there is little or no overlap between forward spikes and backward spikes in these branches. g, Two-dimensional two-photon image of four apical tuft branches expressing GCaMP2.2c from an individual L5 neuron. Green arrowhead marks the trunk. Four ROIs corresponding to different branches were analysed over four trials of forward and backward running. ROI 2 and 3 generated Ca2+ transients in response to backward running. h, Distribution of forward and backward running-induced Ca2+ spikes on 33 sibling branches located 0–100 μm below the pia. Data were analysed over five 30-s trials of forward and backward running. i, j, Distribution of forward and backward running-induced Ca2+ spikes on 80 sibling branches located 100–200 μm below the pia (22 cells). Approximately 43% branches at this cortical depth exhibited spikes in response to both forward and backward running. Each of these branches was connected to higher order branches that were either inactive or exhibited spikes in response to forward, backward or both running modes (dotted boxes in i). k, Percentage of local or global Ca2+ spikes observed on sibling branches located at two different depths below the pia. **P < 0.01, ***P < 0.001, unpaired t-test.
Extended Data Figure 4 In vivo two-photon laser cutting of one apical tuft branch reduces calcium activity at the apical trunk.
a–c, Example of an individual neuron with three apical tuft branches (at 150 μm) and the apical trunk (at 300 μm; a) showed Ca2+ spikes during forward running. Laser cutting one tuft branch (b) induced a significant reduction in average peak ΔF/F0 of the trunk during forward running (c). d, Summary of average peak ΔF/F0 of the trunk before and after parking the laser beam in a region 30 μm away from the active dendrite (control cut; n = 7, P = 0.22, paired t-test). There was no significant change in the activity of the trunk in this control experiment. e, Summary of average peak ΔF/F0 of the trunk before and after cutting an active dendrite during forward (n = 7, P < 0.001, paired t-test) and backward running (P = 0.25; n = 5). ***P < 0.001. As expected, cutting a dendritic branch exhibiting forward running-induced Ca2+ spikes reduced the activity of the trunk when animals ran in the forward direction (left). When the branch with forward Ca2+ spikes was cut, the average activity of the trunk was also reduced for the backward direction (right), even though the uncut branch still exhibited Ca2+ spikes in response to backward running. This is probably related to the fact that apical tufted branches possess spines that are active during both forward and backward running (data not shown). Cutting a branch eliminated the contribution of not only dendritic Ca2+ spikes but also synaptic inputs to the depolarization at the trunk.
Extended Data Figure 5 Ca2+ spikes cause long-lasting potentiation of task-related dendritic spines.
a, Frequency distribution of the number of Ca2+ transients in individual spines detected by GCaMP6s over 2.5-min running (n = 199 spines from 14 dendritic branches). b, Frequency distribution of the peak amplitude (ΔF/F0) of spine Ca2+ transients on apical tuft branches expressing GCaMP6s during running. c, Frequency distribution of spine Ca2+ transient duration during running. d, Frequency distribution of the number of spine Ca2+ transients detected by GCaMP2.2c over 2.5-min running. e, Frequency distribution of the peak amplitude (ΔF/F0) of spine Ca2+ transients induced by forward running in tuft dendrites expressing GCaMP2.2c. As expected, spine Ca2+ transients detected with GCaMP6s were significantly higher than those detected by GCaMP2.2c in terms of amplitude (>200%) and frequency (>150%). f, Task-specific activation of dendritic spines detected by GCaMP2.2c during forward and backward running (n = 98 spines from 12 dendrites). g, Two-photon images of an apical tuft dendrite expressing GCaMP2.2c. An active spine (green) denoted by yellow arrowhead and a Ca2+ spike (red) are shown. h, i, Representative two-photon images and fluorescent traces of potentiated spines on L5 apical tuft dendritic segments expressing GCaMP2.2c and 5G. Ca2+ spikes occurred during trial 5 in h and i. j, Many spines were active before, during and after the generation of Ca2+ spikes. Horizontal lines indicate the start and end of spine Ca2+ transients. Variable Ca2+ spike duration indicated by red shaded bar. k, l, Comparison of spine head and shaft fluorescence for spines active at the time of spike generation versus neighbouring spines that are not active at the time of spike generation. ΔF/F0 of active spine heads are significantly larger (P < 0.001; 236.5% (GCaMP6s); 319.2% (GCaMP2.2c)) than that of neighbouring inactive spines during Ca2+ spike generation. m, Percentage change in average peak ΔF/F0 of spine Ca2+ transients before and after spikes detected by GCaMP6s (green) and GCaMP2.2c (red). The peaks of 3–4 spine Ca2+ transients (ΔF/F0) were averaged before and after the spike. There was no significant difference in the degree of spine Ca2+ transient potentiation detected by GCaMP6s (green) and GcaMP2.2c (red) (P = 0.22, unpaired t-test). n, Percentage change in the peak ΔF/F0 of individual spine Ca2+ transients (no average) immediately before and after spikes detected by GCaMP6s (green) and GCaMP2.2c (red) (P = 0.16, unpaired t-test). o, Comparison of spine size versus the percentage change in the peak amplitude of spine Ca2+ transients at 2 min and 40 min post spike. Data are mean ± s.e.m. Scale bars, 5 μm.
Extended Data Figure 6 CaMKII inhibitors block potentiation of task-related dendritic spines but not Ca2+ spike generation.
a, There is no correlation between the percentage change in the peak amplitude of spine Ca2+ transients and the peak amplitude of dendritic Ca2+ spike during forward running in the presence of CaMKII inhibitors (KN-62: P = 0.08; KN-93: P = 0.42, Pearson’s correlation). b, Two-photon images of apical tuft dendrites expressing GCaMP2.2c during quiet resting state and forward running in the presence of ACSF, KN-93 and KN-62. c, d, Local application of CaMKII inhibitors, KN-93 and KN-62, to layer 1 did not induce significant changes in Ca2+ spike frequency or peak amplitude as compared to ACSF controls (P > 0.05, unpaired t-test). Scale bar, 10 μm. Data are mean ± s.e.m.
a, b, In mice running forward, most spines (54%, red) exhibited activities at the time of the spike generation (near t = 0). Only a small fraction of spines were active <5 s before Ca2+ spike generation (17%, green). Thus, most spines active during forward running coincide with the spike generation. Of the spines that were active asynchronously relative to Ca2+ spikes, the average time interval between the two events was 12.2 ± 1.6 s. c, d, Changes in the peak amplitude of Ca2+ transients in forward running-activated spines versus the time interval between spine activity and the onset of task switching from forward to backward running. e, Spines active <5 s or >5 s before task switching (no backward spike) show no significant reduction in the peak amplitude of Ca2+ transients afterwards (<5 s: P = 0.31; n = 9; >5 s: P = 0.84; n = 22; unpaired t-test). f, There are no significant changes in the peak amplitude of spine Ca2+ transients (no backward spike) during the first and second half of a 30-s forward running trial, either before or after the task switching (paired t-test). Thus, spine transients do not gradually decrease during the initial forward running and recover to their highest values after the second forward running session is switched on. This suggests that the depotentation of spines active within 5 s before spikes in Fig. 3 is related to their interactions with local Ca2+ spikes.
Extended Data Figure 8 The effect of inactivating SST neurons on Ca2+ spikes and potentiation of task-related dendritic spines.
a, Experimental design for perturbing branch-specific Ca2+ spikes by applying bicuculline (BIC) to L1. Local bicuculline administration did not have a significant effect (P > 0.05, paired t-test) on the number of Ca2+ spikes generated during forward running as compared to control mice. Before bicuculline: 60.2 ± 10.2 Ca2+ spikes over 2.5 min; after bicuculline application: 77.4 ± 13.7 Ca2+ spikes over 2.5 min. More than 200 Ca2+ spikes were measured under each condition from five mice. b, Local bicuculline administration increased the percentage of apical tuft branches exhibiting Ca2+ spikes during both forward and backward running (n = 5 mice, P = 0.007, paired t-test). c, Coronal sections of the motor cortex from control or SST-deleted mice stained for parvalbumin (PV) 2 days after diphtheria toxin administration. No significant effect on the number of parvalbumin cells was observed (P = 0.30, unpaired t-test). d, Coronal sections of motor cortex from control or SST-deleted mice stained for microglia (Iba1) 2 days after diphtheria toxin administration. No significant effect on the number of microglia was observed (P = 0.50, unpaired t-test). e, Two-photon images and quantification of SST cells expressing GCaMP6 and hM4Di-mCherry. f, Training protocol (left) to test the effect of inactivating SST cells after CNO treatment on branch-specific Ca2+ spike generation. Two-photon images (right) of apical tuft dendrites expressing GCaMP2.2c during forward and backward running before and after SST neuron silencing. Note that tuft dendrites after CNO exhibited Ca2+ spikes during both forward and backward running. g, The average peak amplitude of Ca2+ spikes during resting and running in SST-deleted and control mice expressing GCaMP2.2c. The peak ΔF/F0 of Ca2+ spikes during quiet resting and forward running in SST-deleted mice was significantly higher than in control mice (P < 0.001, unpaired t-test). h, In SST-deleted mice, spines active at the time of spike generation show enhanced Ca2+ signals after spike generation (n = 49. P < 0.001, paired t-test)), whereas spines not active at the spike generation (n = 27 spines) showed no significant increase in spine Ca2+ signals. In SST-deleted mice, the ratio of Ca2+ fluorescence intensity between spine heads and neighbouring shafts was 2.03 ± 0.23, significantly higher than that for neighbouring inactive spines (0.61 ± 0.03). Data are mean ± s.e.m. **P < 0.01, ***P < 0.001.
Extended Data Figure 9 CaMKII inhibitors block training-related potentiation of Ca2+ transients in L5 apical trunk nexus.
a, Texas Red dye injection in L5 or L1. b, Fluorescence signals spread to a region with a diameter ∼237 ± 19 μm in L5 and 188 ± 10 μm in L1 respectively. There is no overlap between the sites of injection in L5 and L1. c, Average ΔF/F0 of L5 soma detected by GCaMP6s over 2.5 min running under various conditions (no injection, L1 ACSF injection, L1 TTX injection) (P < 0.001, unpaired t-test). d, e, In control mice, local application of CaMKII inhibitors (KN-62 and KN-93) blocked the increase in Ca2+ transients at the apical trunk nexus after an initial and second training session of forward running.
Extended Data Figure 10 Deletion of somatostatin-expressing interneuron impairs performance improvement after motor learning.
a, Rotarod performance in control and SST-deleted mice subjected to forward–forward running or forward–backward running. When forward running on the accelerated rotarod was followed by backward running, SST-deleted mice displayed a reduction in their performance (the average speed animals achieved) as compared to control mice when tested again in forward running (P < 0.05, unpaired t-test). Data are mean ± s.e.m. b, A model showing the importance of BSDCS for inducing synaptic changes that affect L5 neuronal output during motor skill learning. Dendritic spines active (1, pink) at the time of spike generation (2) show enhanced Ca2+ activity and changes in synaptic strength (red) following the Ca2+ spike. Ca2+ spike-induced potentiation of synapses contributes to persistent synaptic changes, potentiated Ca2+ activity at the apical trunk and L5 soma, as well as improvements in performance over training sessions. In control mice, different motor tasks (that is, forward, backward running) induce Ca2+ spikes on different tuft branches of L5 neurons (not shown). Inactivation of SST interneurons results in individual dendritic branches generating Ca2+ spikes in response to both tasks (3). Loss of spatial segregation of Ca2+ spikes results in the depotentiation of synaptic changes-induced by previous learning in tuft dendritic branches and reduced Ca2+ activity in the apical trunk nexus and L5 soma when a different task is learned. SST interneuron inactivation induces a state of interference that impairs motor performance when several tasks are learned.
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Cichon, J., Gan, W. Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity. Nature 520, 180–185 (2015). https://doi.org/10.1038/nature14251
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