Sensory experience in early postnatal life, during so-called critical periods, restructures neural circuitry to enhance information processing1. Why the cortex is susceptible to sensory instruction in early life and why this susceptibility wanes with age are unclear. Here we define a developmentally restricted engagement of inhibitory circuitry that shapes localized dendritic activity and is needed for vision to drive the emergence of binocular visual responses in the mouse primary visual cortex. We find that at the peak of the critical period for binocular plasticity, acetylcholine released from the basal forebrain during periods of heightened arousal directly excites somatostatin (SST)-expressing interneurons. Their inhibition of pyramidal cell dendrites and of fast-spiking, parvalbumin-expressing interneurons enhances branch-specific dendritic responses and somatic spike rates within pyramidal cells. By adulthood, this cholinergic sensitivity is lost, and compartmentalized dendritic responses are absent but can be re-instated by optogenetic activation of SST cells. Conversely, suppressing SST cell activity during the critical period prevents the normal development of binocular receptive fields by impairing the maturation of ipsilateral eye inputs. This transient cholinergic modulation of SST cells, therefore, seems to orchestrate two features of neural plasticity—somatic disinhibition and compartmentalized dendritic spiking. Loss of this modulation may contribute to critical period closure.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
White, E. J., Hutka, S. A., Williams, L. J. & Moreno, S. Learning, neural plasticity and sensitive periods: implications for language acquisition, music training and transfer across the lifespan. Front. Syst. Neurosci. 7, 90 (2013)
Hübener, M. & Bonhoeffer, T. Neuronal plasticity: beyond the critical period. Cell 159, 727–737 (2014).
Froemke, R. C., Merzenich, M. M. & Schreiner, C. E. A synaptic memory trace for cortical receptive field plasticity. Nature 450, 425–429 (2007).
Letzkus, J. J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480, 331–335 (2011).
Cichon, J. & Gan, W.-B. Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity. Nature 520, 180–185 (2015).
Kerlin, A. et al. Functional clustering of dendritic activity during decision-making. Preprint at https://www.bioRxiv.org/content/10.1101/440396v1 (2018).
Spruston, N. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci. 9, 206–221 (2008).
Bear, M. F. & Singer, W. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320, 172–176 (1986).
Kuhlman, S. J. et al. A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex. Nature 501, 543–546 (2013).
Levelt, C. N. & Hübener, M. Critical-period plasticity in the visual cortex. Annu. Rev. Neurosci. 35, 309–330 (2012).
Crair, M. C., Gillespie, D. C. & Stryker, M. P. The role of visual experience in the development of columns in cat visual cortex. Science 279, 566–570 (1998).
Faguet, J., Maranhao, B., Smith, S. L. & Trachtenberg, J. T. Ipsilateral eye cortical maps are uniquely sensitive to binocular plasticity. J. Neurophysiol. 101, 855–861 (2009).
Wang, B.-S., Sarnaik, R. & Cang, J. Critical period plasticity matches binocular orientation preference in the visual cortex. Neuron 65, 246–256 (2010).
Wilson, D. E., Whitney, D. E., Scholl, B. & Fitzpatrick, D. Orientation selectivity and the functional clustering of synaptic inputs in primary visual cortex. Nat. Neurosci. 19, 1003–1009 (2016).
Iacaruso, M. F., Gasler, I. T. & Hofer, S. B. Synaptic organization of visual space in primary visual cortex. Nature 547, 449–452 (2017).
Weber, J. P. et al. Location-dependent synaptic plasticity rules by dendritic spine cooperativity. Nat. Commun. 7, 11380 (2016).
Losonczy, A., Makara, J. K. & Magee, J. C. Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452, 436–441 (2008).
Makara, J. K., Losonczy, A., Wen, Q. & Magee, J. C. Experience-dependent compartmentalized dendritic plasticity in rat hippocampal CA1 pyramidal neurons. Nat. Neurosci. 12, 1485–1487 (2009).
Tremblay, R., Lee, S. & Rudy, B. GABAergic interneurons in the neocortex: from cellular properties to circuits. Neuron 91, 260–292 (2016).
Gordon, J. A. & Stryker, M. P. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J. Neurosci. 16, 3274–3286 (1996).
Lee, A. M. et al. Identification of a brainstem circuit regulating visual cortical state in parallel with locomotion. Neuron 83, 455–466 (2014).
Reimer, J. et al. Pupil fluctuations track fast switching of cortical states during quiet wakefulness. Neuron 84, 355–362 (2014).
Chen, N., Sugihara, H. & Sur, M. An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity. Nat. Neurosci. 18, 892–902 (2015).
Fanselow, E. E., Richardson, K. A. & Connors, B. W. Selective, state-dependent activation of somatostatin-expressing inhibitory interneurons in mouse neocortex. J. Neurophysiol. 100, 2640–2652 (2008).
Kawaguchi, Y. Selective cholinergic modulation of cortical GABAergic cell subtypes. J. Neurophysiol. 78, 1743–1747 (1997).
Pfeffer, C. K., Xue, M., He, M., Huang, Z. J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat. Neurosci. 16, 1068–1076 (2013).
Lee, S., Kruglikov, I., Huang, Z. J., Fishell, G. & Rudy, B. A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat. Neurosci. 16, 1662–1670 (2013).
Alitto, H. J. & Dan, Y. Cell-type-specific modulation of neocortical activity by basal forebrain input. Front. Syst. Neurosci. 6, 79 (2013).
Cottam, J. C. H., Smith, S. L. & Häusser, M. Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing. J. Neurosci. 33, 19567–19578 (2013).
Berens, P. et al. Community-based benchmarking improves spike inference from two-photon calcium imaging data. PLoS Comput. Biol. 14, e1006157 (2017).
Smith, S. L., Smith, I. T., Branco, T. & Häusser, M. Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo. Nature 503, 115–120 (2013).
Do, J. P. et al. Cell type-specific long-range connections of basal forebrain circuit. eLife 5, e13214 (2016).
Gonchar, Y., Wang, Q. & Burkhalter, A. Multiple distinct subtypes of GABAergic neurons in mouse visual cortex identified by triple immunostaining. Front. Neuroanat. 1, 3 (2008).
We thank D. Buonomano, P. Golshani and L. Zipursky for their comments and suggestions. Funding: NIH R01 EY023871 (J.T.T.), NIH R01 EY018322 and NIH EB022915 (D.L.R.), and NIH F31 EY027196 (C.E.Y.).
Nature thanks Jeffrey C. Magee and the other anonymous reviewer(s) for their contribution to the peer review of this work.
J.T.T. is a co-owner of Neurolabware LLC.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Example GCaMP6s responses of a P28 SST cell during natural scenes with variable running activity. Treadmill motion and corresponding GCaMP6s signal are shown (15.5 fps), with grey bars denoting periods of visual stimulation. The z-score of the GCaMP signal is denoted by the colour map, and the trace denotes ΔF/F. Each presentation of the visual stimulus is classified as either a run (green) or still (black) trial. ΔF/F of GCaMP6s from all run (left) or still (right) trials are plotted. The median (red) of the median (black) ΔF/F response is taken to give an average value for still or run trials.
Extended Data Fig. 2 Current injection responses for SST, parvalbumin and VIP cells before and after carbachol application.
a, Example current injection responses showing distinct waveform from a SST cell. b, Change in voltage with 20 pA current steps for each cell type at P28 or P56. No significant change in excitability was found between age groups (P28: n = 11; P56: n = 9). P > 0.00625, two-way repeated-measures ANOVA followed by Mann–Whitney U-test, Bonferroni-corrected alpha. c, Evoked spiking for all cells before CCh application (open boxes) and after washout (yellow boxes), for respective cell types (n = 19). No significant change in response to current injection was found after CCh application; P > 0.0055, repeated-measures ANOVA followed by Wilcoxon signed-rank test, Bonferroni-corrected alpha. d, Example parvalbumin cell waveform. e, As in b, but for parvalbumin cells (P28: n = 8; P56: n = 9). No significant change in excitability was found between age groups; P > 0.0071, two-way repeated-measures ANOVA followed by Mann–Whitney U-test, Bonferroni-corrected alpha. f, As in c, but for parvalbumin cell responses before and after CCh washout (n = 17). No significant change was found; P > 0.0062, repeated-measures ANOVA followed by Wilcoxon signed-rank test, Bonferroni-corrected alpha. g, Example VIP cell waveform. h, As in b, but for VIP cells (P28: n = 10; P56: n = 8). No significant change in excitability was found between age groups; P > 0.0083, two-way repeated-measures ANOVA followed by Mann–Whitney U-test, Bonferroni-corrected alpha. i, As in c, but for VIP cell responses before and after carbachol washout (n = 18). No significant change was found; P > 0.0083, repeated-measures ANOVA followed by Wilcoxon signed-rank test, Bonferroni-corrected alpha. Box plot parameters as in Fig. 1.
a, As in Fig. 1, example VIP cell populations from P28 and P56. b, Plot of the visually evoked median ΔF/F of each cell as a function of behavioural state, for all recorded cells (P28: n = 220; P56: n = 305). Still to run, P = 1.63 × 10−64 (P28), P = 1.75 × 10−60 (P56), Wilcoxon signed-rank test. c, Example traces of VIP cell response to CCh application at P28 (left) and P56 (right). Recordings were made under current clamp and in the presence of synaptic blockers. Coloured box denotes time of CCh application. Insets show evoked VIP cell waveform. Scale bars, 0.25 s and 10 mV. d, Box plot of VIP cell firing rates evoked by CCh as a function of age (P28: n = 10; P56: n = 8). P = 0.9804, Mann–Whitney U-test. Box plot parameters as in Fig. 1.
a, Example whole-cell recordings of SST cell responses to CCh in voltage-clamp mode at P28 (left) or P56 (right). b, Median IPSC amplitudes evoked by CCh application for all recorded SST cells at P28 and P56 (P28, n = 6; P56, n = 8). P = 0.4136, Mann–Whitney U-test. Box plot parameters as in Fig. 1.
Extended Data Fig. 5 Deconvolution and ΔF/F comparisons produce analogous findings in sister dendrites.
a, Top, time series showing ΔF/F and concurrent deconvolution for still and run epochs in a sister dendrite from a P28 mouse. Note the deconvolution is based on significant changes in slope. Spearman’s correlation coefficients (rs values) are shown. ΔF/F has been filtered for clarity. Bottom, as in the top panel for sister dendrites from a P56 mouse. Scale bar, ΔF/F = 1 and 1 s. Event probability = 1 AU. b, Median percentage change in ΔF/F from still to running, for all P28 and P56 branches (P28: n = 36 branches; P56: n = 96 branches). P = 0.6608, Mann–Whitney U-test. c, Correlation of ΔF/F between sister dendrites to movement at P28 or P56 (P28: n = 18 branch pairs; P56: n = 48 branch pairs). Still to run, ***P = 5.36 × 10−4 (P28), P = 0.043 (P56), Wilcoxon signed-rank test. N.S., not significant. Box plot parameters as in Fig. 1.
Examples of temporally deconvolved GCaMP6f traces showing event probability in sister dendrites from a P28 and P56 mouse. Grey bars mark periods of locomotion across traces. Left, P28 sister dendrites show decorrelated activity during movement. Right, P56 sister dendrites maintain synchronized activity across run and still epochs. Scale bar indicates event probability = 1 AU.
Extended Data Fig. 7 P28 and P56 modulation of pyramidal cell somas and dendrites during spontaneous activity.
a, Plot of the visually evoked median ΔF/F of each cell as a function of behavioural state, for all recorded cells, at P28 and P56, in the absence of visual stimulation, measured at the soma (P28: n = 563 cells; P56: n = 723 cells). Still to run, P = 4.31 × 10−60 (P28), P = 1.94 × 10−89 (P56), Wilcoxon signed-rank test. b, Plot of cumulative distributions of the correlation coefficients of GCaMP6f signals to running for all recorded pyramidal neurons while viewing a grey screen (P28: n = 860 cells; P56: n = 513 cells). P = 0.993, Mann–Whitney U-test. c, Box plots of temporally deconvolved event probabilities of dendrites during grey screen viewing at P28 and P58 during in running and still conditions (P28: n = 36 branches; P56: n = 96 branches). Still to run, **P = 0.0044 (P28), ***P = 4.36 × 10−6 (P56), Wilcoxon signed-rank test. d, Box plots of the fold change between sister branches as a function of age and behavioural state (P28: n = 18 branch pairs; P56: n = 56 branch pairs). Still to run, P = 0.987 (P28), P = 0.02 (P56), Wilcoxon signed-rank test. e, Box plots of the correlation coefficients between event probability time series of sister branches as a function of age and behavioural state (P28: n = 18 branch pairs; P56: n = 56 branch pairs). Still to run, P = 0.2914 (P28), **P = 0.0042 (P56), Wilcoxon signed-rank test. Box plot parameters as in Fig. 1.
a, SST cells expressing both ChR2-tdTomato and GCaMP6s. b, Representative time series heat map of SST cell GCaMP6s responses to optogenetic stimulation. The z-scores from individual cells are plotted per frame (15.5 fps); colour scale is −1 to 5 z-scores. Top, blue bars denote LED light pulses. Bottom, inset showing z-scored traces and significant increase in GCaMP6s signal for 14 cells.
a, Top, example evoked responses of a SST cell expressing DREADD receptors. Bottom, evoked responses from the same SST cell 4 h after intraperitoneal administration of CNO (2.5 mg kg−1). Scale bar, 10% ΔF/F and 30 s. b, Measurement of change in median evoked ΔF/F in SST cells after CNO administration over an 8 h period, in mice with or without DREADD expression (DREADD−/CNO+: n = 25 cells; DREADD+/CNO+: n = 21 cells). 2 h, DREADD− to DREADD+: ***P = 1.41 × 10−4; 4 h, DREADD− to DREADD+: ***P = 7.98 × 10−5, Wilcoxon signed-rank test. Error bars denote s.e.m.
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Yaeger, C.E., Ringach, D.L. & Trachtenberg, J.T. Neuromodulatory control of localized dendritic spiking in critical period cortex. Nature 567, 100–104 (2019). https://doi.org/10.1038/s41586-019-0963-3
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