Activity in motor cortex predicts specific movements seconds before they occur, but how this preparatory activity relates to upcoming movements is obscure. We dissected the conversion of preparatory activity to movement within a structured motor cortex circuit. An anterior lateral region of the mouse cortex (a possible homologue of premotor cortex in primates) contains equal proportions of intermingled neurons predicting ipsi- or contralateral movements, yet unilateral inactivation of this cortical region during movement planning disrupts contralateral movements. Using cell-type-specific electrophysiology, cellular imaging and optogenetic perturbation, we show that layer 5 neurons projecting within the cortex have unbiased laterality. Activity with a contralateral population bias arises specifically in layer 5 neurons projecting to the brainstem, and only late during movement planning. These results reveal the transformation of distributed preparatory activity into movement commands within hierarchically organized cortical circuits.
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We thank B. Dickson, S. Druckmann, J. Dudman, D. Gutnisky, H. Inagaki, V. Jayaraman, D. O’Connor, S. Peron, T. Sato and G. Shepherd for comments on the manuscript and discussion, L. Walendy and E. Ophir for animal training, S. Michael and A. Hu for histology, T. Harris and B. Barbarits for the silicon probe recording system. This work was funded by the Howard Hughes Medical Institute. N.L. is a Helen Hay Whitney Foundation postdoctoral fellow.
The authors declare no competing financial interests.
Extended data figures and tables
a, Single-unit classification. Left, overlaid mean spike waveforms for putative fast-spiking (FS) interneurons (grey, n = 124) and putative pyramidal neurons (black, n = 1245). A small subset of single units with intermediate spike durations were not classified (brown, n = 39). Right, histogram of spike durations (Methods). b, Fast-spiking neurons population response (mean ± s.e.m.) during the lick right trials (contralateral, blue) and lick left trials (ipsilateral, red). Neurons are sorted by their preferred trial type using spike counts from 10 trials and the remaining data was used to compute the selectivity. Left, contra-preferring neurons. Right, ipsi-preferring neurons. c, Left, proportion of neurons in b with preparatory and peri-movement activity. Right, contra-preferring versus ipsi-preferring selectivity. Error bars, s.e.m. across animals, bootstrap. d, e, Same as (b) and (c) but for putative pyramidal neurons. f, Number of significantly selective putative pyramidal neurons as a function of time. Significant selectivity was based on spike counts in 200-ms time windows, P < 0.05, two-tailed t-test. Dashed lines, behavioural epochs.
Extended Data Figure 2 ALM neurons exhibit temporally complex responses and choice-specific selectivity.
a, Twenty example ALM neurons responding during different epochs of the object location discrimination. Correct lick right (blue) and lick left (red) trials only. Dashed lines, behavioural epochs. Averaging window, 200 ms. b, Six example ALM neurons during object location discrimination. Top, peri-stimulus time histogram for correct lick right and lick left trials. Bottom, peri-stimulus time histogram for error trials (transparent colour). c, ALM neurons show choice-specific preparatory activity. Selectivity is the firing rate difference between lick right and lick left trials during sample, delay or response epochs ((firing rate lick right)–(firing rate lick left)). Circles, individual neurons (n = 912). Filled circles, neurons with significant selectivity (P < 0.05, two-tailed t-test). On error trials, when mice licked in the opposite direction to the instruction provided by object location (Fig. 1a), a majority of ALM neurons switched their trial type preference to predict the licking direction, as indicated by the negative correlations (r, Pearson’s correlation).
a, Axonal projections of intratelencephalic neurons (top, Tlx_PL56 mice) and pyramidal tract neurons (bottom, Sim1_KJ18 mice). b, Top, retrogradely labelled pyramidal tract neurons in contralateral ALM. Bottom, intermediate nucleus of the reticular formation (IRt) axonal projections in the hypoglossal nucleus, 12N. c, Top, retrogradely labelled IRt neurons. Bottom, hypoglossal nerves. d, Retrograde labelling of pyramidal tract neurons (green) and intratelencephalic neurons (magenta). The ALM coronal slice shows intermingled labelling of pyramidal tract neurons and intratelencephalic neurons without overlap. e, Unilateral stimulation of ALM pyramidal tract or intratelencephalic neurons triggered contralateral licking during behaviour (blue, contralateral licking; red, ipsilateral licking). Top, average lick rate during ALM (left) and left vibrissal motor cortex (vM1) (right) photostimulation, n = 8 mice. Dashed lines, behavioural epochs. Cyan region, photostimulation. Bottom, fraction of trials in which photostimulation caused ‘early lick’ as a function of laser power. Sample and delay epoch photostimulation data were combined. IT, intratelencephalic; PT, pyramidal tract. f, Unilateral stimulation of ALM pyramidal tract or intratelencephalic neurons triggered contralateral licking in untrained mice (n = 6 mice). Fraction of trials in which photostimulation caused licking as a function of laser power. g, Unilateral stimulation of left vM1 pyramidal tract or intratelencephalic neurons triggered whisker movements in untrained mice. Left, whisker azimuthal angle traces, individual trials. Right, average whisker angle 500 ms before photostimulation (baseline) and during vM1 photostimulation (n = 6 mice).
Extended Data Figure 4 Transgenic ChR2 expression in intratelencephalic and pyramidal tract neurons.
a, ChR2 expression in layer 5 intratelencephalic neurons. Tlx_PL56-Cre mouse crossed to a Rosa-ChR2-eYFP reporter mouse (Ai32). Top, ChR2 expression in ALM. Bottom, ChR2 expression in three coronal sections from anterior to posterior. b, Same as a for ChR2 expression in pyramidal tract neurons. Sim1_KJ18-Cre mouse crossed to Ai32.
a, Pyramidal tract neuron recordings. Top, left ALM neurons were infected with AAV2/5-FLEX-ChR2-tdTomato (Sim1_KJ18-Cre mice). An optical fibre was implanted into the left (ipsilateral) reticular formation to antidromically stimulate the pyramidal tract neuron axons. Pyramidal tract neurons were identified based on back-propagating antidromic spikes (tagging). Bottom, expression of ChR2-tdTomato in left ALM; injection site (left), axon terminals in the reticular formation (right). b, Recording traces for four example neurons activated by antidromic stimulation of pyramidal tract neurons (blue). Red ticks, individual spikes. Red traces, collision tests. Left, two pyramidal tract neurons that passed the collision test; antidromic spikes were absent when preceded by spontaneous spikes. These neurons were classified as pyramidal tract neurons. Right, two neurons that failed the collision test. The top neuron could not be tested for collision due to an absence of baseline firing. The bottom neuron failed the collision test because light-evoked spikes occurred even when preceded by spontaneous spikes. This neuron was classified as a pyramidal-tract-activated neuron. Scale bars, 200 µV, 5 ms. c, d, Same as a and b but for intratelencephalic neuron recordings. e, Antidromic spike latency versus jitter (SD) for pyramidal tract neurons, intratelencephalic neurons, pyramidal-tract-activated neurons, and intratelencephalic-activated neurons. f, Recording yield. ‘Activated’, neurons activated by antidromic stimulation; ‘Passed’, subsets of activated neurons that passed the collision test. These neurons were classified as pyramidal tract neurons or intratelencephalic neurons. ‘Failed’, subsets of activated neurons in which spontaneous spikes failed to block light-evoked spikes. ‘Could not test’, the subset of activated neurons without spontaneous activity. These neurons were excluded from analyses. ‘Suppressed’, neurons suppressed by antidromic stimulation. g, Top, light-evoked responses across all pyramidal tract neurons and intratelencephalic neurons. Middle, pyramidal-tract-activated neurons and intratelencephalic-activated neurons. Bottom, pyramidal-tract-suppressed neurons and intratelencephalic-suppressed neurons.
Extended Data Figure 6 Photostimulation of intratelencephalic and pyramidal tract neurons biases upcoming licking direction.
a, Performance change, pyramidal tract neurons activation. Re-plot of the data in Fig. 5b. Grey areas represent 95% confidence interval of expected behavioural variability. We estimated the behavioural variability by computing performance changes on re-sampled data sets in which we sampled with replacement from only the control trials (Methods, repeated 104 times). The number of trials in the re-sampled data sets was matched to the actual experiments. b, Dose response for individual mouse in a. Delay epoch photostimulation data only. c, d, Same as a and b but for intratelencephalic neurons activation.
Extended Data Figure 7 Photostimulation of pyramidal tract neurons during the sample epoch causes persistent changes in ALM activity and a directional bias.
a, Simultaneous recordings and photostimulation of left ALM pyramidal tract neurons during behaviour. Two mice, eight sessions, 91 neurons. b, Stimulation of left ALM pyramidal tract neurons during the sample epoch biased the upcoming licking to the contralateral direction. Top, sample epoch photostimulation. Bottom, performance change relative to the control trials. Thick lines, mean; thin lines, individual mice. c, Spike raster plots and peri-stimulus time histograms of six example neurons. Correct lick right (blue) and lick left (red) trials only. Dashed lines, behavioural epochs. For each neuron: top, control trials; bottom, photostimulation trials (solid colour). Control trials are overlaid in transparent colour. Averaging window, 200 ms. d, Average population selectivity (black line, ±s.e.m. across neurons). Left, control trials. Right, photostimulation trials. Neurons are sorted by their preferred trial type (top, contra-preferring neurons; bottom, ipsi-preferring neurons). Selectivity is the difference in spike rate between the preferred and non-preferred trial type.
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Li, N., Chen, T., Guo, Z. et al. A motor cortex circuit for motor planning and movement. Nature 519, 51–56 (2015). https://doi.org/10.1038/nature14178
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