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Active dendritic currents gate descending cortical outputs in perception

Abstract

The output of cortical columns is routed to different downstream targets via distinct pathways: cortico-cortical and cortico-subcortical. It is as yet unclear what roles these pathways play in perception, and which cellular and circuit mechanisms regulate their gating. We recently showed that activation of the apical dendrites of layer 5 (L5) pyramidal neurons correlates with the threshold for perception, but these neurons come in two classes that target either other cortical or subcortical areas. In the present study, we took advantage of transgenic mouse lines for these L5 subclasses to determine their relative contributions to the perceptual process. We found that the activation of apical dendrites in neurons of the somatosensory cortex, which project to subcortical regions, almost exclusively determined the detection of tactile stimuli in mice. Our results suggest that dendritic activation drives context-dependent interactions between cortex and subcortical regions, including the higher-order thalamus, superior colliculus and striatum, which are crucial for perception.

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Fig. 1: Genetic dissociation of L5 pyramidal neurons in mouse S1: axonal projection patterns and physiological properties.
Fig. 2: Apical dendritic Ca2+ activity in PT neurons during the perceptual detection task.
Fig. 3: Apical dendritic Ca2+ activity in IT neurons during the perceptual detection task.
Fig. 4: Cell-type-specific activation of apical dendrites during behavior.
Fig. 5: Manipulation of apical dendrites of PT neurons biases tactile detection.
Fig. 6: Descending outputs of PT neurons are critical in tactile detection.
Fig. 7: Context-dependent activation of apical dendrites.

Data availability

All data included in this publication are stored on servers of Charité – Universitätsmedizin Berlin and are available from one of the corresponding authors upon reasonable request.

Code availability

Customized MATLAB scripts for data analysis and Igor Pro software for data collection are available from one of the corresponding authors upon reasonable request.

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Acknowledgements

We thank C. Koch (Allen Institute for Brain Science, Seattle), M. Murayama (RIKEN CBS, Wako) and J. Aru (Humboldt University of Berlin) for comments on and discussions about the manuscript. The present study was supported by the Deutsche Forschungsgemeinschaft (Exc 257 NeuroCure, LA 3442/3-1, project no. 327654276 SFB1315 TP.A04), the European Union Horizon 2020 Research and Innovation Programme (72070/HBP SGA1, 670118/ERC ActiveCortex) and the Einstein Foundation Berlin (EVF-2017-363).

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Contributions

N.T. and M.E.L. conceived the project and designed the experiments. N.T. performed in vivo experiments and data analysis. C.E. performed in vitro experiments. J.S.G. and S.M. conducted the histology. S.N. helped with behavioral training. N.T. and M.E.L. wrote the manuscript with comments from all authors.

Corresponding authors

Correspondence to Naoya Takahashi or Matthew E. Larkum.

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Extended data

Extended Data Fig. 1 Cre-driver mouse lines provide genetic access to L5 subpopulations in S1.

a, tdTomato expression in S1 of Sim1-Cre/Ai9 mice (left) and Tlx3-Cre/Ai9 mice (right). A single barrel column is highlighted in magenta. For each transgenic line, similar results were obtained in all brain sections independently tested (n = 5 sections from 2 Sim1-Cre/Ai9 mice; n = 4 sections from 2 Tlx3-Cre/Ai9 mice). b, Images of Sim1-Cre+ neurons expressing GCaMP6f in a section immunostained with an anti-Ctip2 antibody.

Extended Data Fig. 2 Critical frequency for dendritic electrogenesis in L5 pyramidal subclasses.

a, Left, in vitro whole-cell recording from PT (Sim1-Cre+) neurons in S1. Middle, increase in the after-depolarizing potential (ADP) evoked by high-frequency trains of four APs – indicative of dendritic regenerative potentials7. The inset shows the magnified ADPs after the last AP. Right, the sizes of somatic ADP as a function of AP frequency, fitted with a sigmoidal curve. The critical frequency was estimated from the turning point of a sigmoidal fit. b, Same as a, for IT (Tlx3-Cre+) neurons in S1. c,d, Critical frequencies and the changes in ADP size of PT neurons (orange; n = 17 neurons) versus IT neurons (purple; n = 17 neurons) (P = 9.1 × 10−4 for critical frequency, Student’s t-test; P = 2.2 × 10−3 for the change in ADP size, Mann-Whitney U test).

Extended Data Fig. 3 Dendritic Ca2+ activity during whisking behavior.

a, Top, C2 whisker position monitored by a high-speed video camera (500 frames/s). Whisking amplitude is the Hilbert transform of the absolute value of the band-pass filtered (6–30Hz) whisker angle. Bottom, examples of simultaneously-recorded dendritic Ca2+ activity of PT neurons. b, Top, cross-correlograms between whisking amplitude and dendritic Ca2+, sorted according to their peak amplitudes. Bottom, averaged cross-correlogram with s.e.m. (n = 300 dendrites from 4 mice). c, d, Same as a and b, for IT neurons (n = 227 dendrites from 2 mice).

Extended Data Fig. 4 No difference in behavioral performance between Sim1-Cre and Tlx3-Cre mice.

a, Perceptual threshold for detecting whisker stimuli in Sim1-Cre mice (0.61 ± 0.18, n = 12 mice) versus Tlx3-Cre mice (0.70 ± 0.30, n = 9 mice) (P = 0.50, Mann-Whitney U test). b, Reaction time, that is, delay between a whisker stimulus and the first lick, for near-threshold and salient stimuli in Sim1-Cre mice (261 ± 44 ms and 193 ± 40 ms for threshold and salient stimuli, respectively, n = 12 mice) versus Tlx3-Cre mice (252 ± 41 ms and 198 ± 35 ms for threshold and salient stimuli, respectively, n = 9 mice) (P = 0.38, two-way repeated measures ANOVA).

Extended Data Fig. 5 Licking-associated sparse activation of apical dendrites of PT neurons.

a, Top, two-photon Ca2+ imaging from apical dendrites of GCaMP6f-expressing PT neurons in S1 in mice drinking a water reward. Bottom, averaged licking response to a water reward delivered through a spout with a random interval independent of whisker detection (n = 162 trials). b, Two examples of Ca2+ activities in apical dendrites of PT neurons, indicated in a, aligned by the timing of water deliveries. c, Histograms of dendritic Ca2+ responses in PT neurons to a free water reward (light blue; n = 293 dendrites from 3 mice) versus those to a reward upon detection of whisker stimuli, that is, hit trials (dark blue; n = 359 dendrites from 6 mice). Mann-Whitney U test. d, Top, Ca2+ response in reward-only trials versus hit trials aligned by the timing of first licks, averaged across dendrites that were significantly active in those trials compared with catch trials (mean ± s.e.m., n = 95 dendrites from 3 mice and 176 dendrites from 6 mice for reward-only and hit trials, respectively; ***P = 8.1 × 10−6). Bottom, histogram of the Ca2+ onset timings (P = 0.086). Mann-Whitney U test.

Extended Data Fig. 6 Functional characterization of dendrite-targeting ChR2 in vitro.

a, Left, whole-cell recording from ChR2-MBD-expressing PT neurons in S1. Right, somatic voltage response measured during dendritic photostimulation (illumination site is indicated in the right panel). b, Same as a, for ChR2-MBD-expressing IT neurons. c, Somatic voltage changes by dendritic photostimulation of PT neurons (orange; n = 6 neurons) versus IT neurons (purple; n = 6 neurons) (P = 0.39, Mann-Whitney U test).

Extended Data Fig. 7 Neither inactivation of PT outputs to the brainstem nor CNO alone changes animals’ perceptual performance in non-transgenic mice.

a, Subpopulation-unspecific expression of hM4Di-mCherry injected in S1 of wild-type mice. b, Detection probabilities before and after local CNO (10 µM) application in pons in wild-type mice expressing hM4Di in S1 (mean ± s.e.m., n = 3 sessions from 3 mice). c, Same as a, for local CNO application in medulla (n = 3 sessions from 3 mice). d, Detection probabilities before and after systemic CNO (5 mg/kg, i.p.) application in non hM4Di-expressing, wild-type mice (mean ± s.e.m., n = 6 sessions from 4 mice, P = 0.72, two-way repeated measures ANOVA). eg, Detection probabilities (mean ± s.e.m.) before and after local CNO (10 µM) application in näive mice, targeted in striatum (n = 6 sessions from 4 mice, P = 0.21, e), POm (n = 6 sessions from 4 mice, P = 0.62, f), and SC (n = 6 sessions from 4 mice, P = 0.16, g). Two-way repeated measures ANOVA.

Extended Data Fig. 8 Long-range projections to the superficial layers in S1.

Retrograde labeling of presynaptic neurons (cyan) in different brain regions that project to the superficial layers of S1. Top left, immersion site of Fast Blue (cyan) on S1, overlaid with nuclear staining (red). Similar results were obtained in three independent experiments (n = 3 mice).

Extended Data Fig. 9 Dendritic Ca2+ activity and behavioral context.

a, Standard deviations (SDs) of spontaneous dendritic Ca2+ activity of PT neurons at the baseline in the active versus the passive context (n = 229 dendrites from 4 mice, Wilcoxon signed-rank test). b, Same as a, for IT neurons (n = 367 dendrites from 4 mice). c, Histograms (left) and scatter plot (right) of dendritic Ca2+ responses to whisker deflections in IT neurons in the active (dark green) versus the passive context (light green) (n = 367 dendrites from 4 mice, P = 0.055, Wilcoxon signed-rank test).

Extended Data Fig. 10 Proposed cellular and circuit mechanisms for perceptual tactile detection.

Downstream targets of PT and IT neurons are shown in different brain structures. When a stimulus reaches the suprathreshold intensity, Ca2+ spikes are selectively activated in the apical dendrites of PT neurons in S1 (45.7% of PT dendrites versus 9.5% of IT dendrites). The activation of dendritic Ca2+ spikes is strongly dependent on inputs to the distal apical dendrites carrying contextual information. Ca2+ spikes trigger bursts of high-frequency somatic APs6,7. Boosted AP outputs of PT neurons are broadcasted to subcortical regions, with a critical involvement of higher-order thalamus, superior colliculus, and striatum, for the subsequent perceptual process or motor action (for example, licking). Thus, dendritic Ca2+ spikes drive context-dependent interactions between cortex and subcortical structures that are crucial for perceptual tactile detection.

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Takahashi, N., Ebner, C., Sigl-Glöckner, J. et al. Active dendritic currents gate descending cortical outputs in perception. Nat Neurosci 23, 1277–1285 (2020). https://doi.org/10.1038/s41593-020-0677-8

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