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A cortico-collicular circuit for orienting to shelter during escape

Nature volume 613, pages 111–119 (2023)Cite this article

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Abstract

When faced with predatory threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. Animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions1,2. Although previous work has identified neural mechanisms of escape initiation3,4, it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that the mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes the shelter-direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP–SC pathway disrupts the orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network because of higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter-direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically constrained spiking network model in which RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP–SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible.

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Fig. 1: RSP and SC neurons encode egocentric shelter direction.
Fig. 2: Shelter-direction tuning in SC and orientation to shelter during escape depend on RSP input.
Fig. 3: Orientation and navigation errors after RSP–SC inactivation are specific to escape behaviour.
Fig. 4: RSP synaptic input has a diverging effect on SC vGAT+ and vGluT2+ neurons.
Fig. 5: A feedforward lateral inhibition model for mapping shelter direction from RSP to SC.

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Data availability

The data and code that support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

This work was funded by a Wellcome Senior Research Fellowship (214352/Z/18/Z), by the Sainsbury Wellcome Centre Core Grant from the Gatsby Charitable Foundation and Wellcome (GAT3755 and 219627/Z/19/Z) and by a European Research Council grant (Consolidator no. 864912) (T.B.), MRC PhD Studentship (R.V.), Boehringer Ingelheim Fonds PhD fellowship (R.V.), Gatsby Unit/SWC Joint Research Fellowship in Neuroscience (D.C.), UCL Wellcome 4-year PhD Programme in Neuroscience (O.P.A.), A*STAR National Science Scholarship (PhD) (Y.L.T.), the SWC PhD Programme (Y.L.T.), Weizmann UK Making Connections Grant (R.S.P.) and BBSRC grant BB/V009680/1 (R.S.P.). We thank members of the Branco laboratory and T. Mrsic-Flogel for discussions; J. Rapela and P. Shamash for advice on statistical analysis; A. Murray, I. Duguid, C. Schmidt-Hieber, N. Burgess, M. Tripodi and the I. Bianco laboratory for comments on the manuscript; M. Strom, T. Okbinoglu, R. Campbell, the SWC Neurobiological Research Facility and FabLabs for technical support; K. Betsios for programming the data acquisition software; T. R. Stones for inspiration; and G. T. Gray for viral constructs. Source of mouse silhouettes: https://scidraw.io/.

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  1. These authors contributed equally: Dario Campagner, Ruben Vale

Authors and Affiliations

  1. UCL Sainsbury Wellcome Centre for Neural Circuits and Behaviour, London, UK

    Dario Campagner, Ruben Vale, Yu Lin Tan, Panagiota Iordanidou, Oriol Pavón Arocas, Federico Claudi, A. Vanessa Stempel, Sepiedeh Keshavarzi, Troy W. Margrie & Tiago Branco

  2. UCL Gatsby Computational Neuroscience Unit, London, UK

    Dario Campagner

  3. MRC Laboratory of Molecular Biology, Cambridge, UK

    Ruben Vale

  4. Division of Neuroscience, University of Manchester, Manchester, UK

    Rasmus S. Petersen

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Contributions

D.C. and R.V.: behavioural experiments. D.C., F.C. and Y. L.T.: theoretical modelling. D.C.: single-unit recordings. O.P.A., A.V.S. and Y.L.T.: in vitro electrophysiology. D.C., P. I., S.K. and R.V.: surgeries. D.C., O.P.A., R.S.P., Y.L.T. and R.V. data analysis. D.C., P. I., Y.L.T. and R.V.: histological preparations and imaging. T.B., D.C., Y.L.T. and R.V.: experimental design. T.B. and R.V. conceived the project. T.B. wrote the manuscript, with critical input from D.C., T.W.M., Y.L.T. and R.V.

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Correspondence to Tiago Branco.

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Extended data figures and tables

Extended Data Fig. 1 Single unit recordings of shelter-direction and head-direction cells.

(A) Left: Coronal image of post-recording histology showing the track of the neuropixels probe (red). Right: 3D rendering of probe tracks in all chronically implanted mice (B) Example tuning curves for a shelter-direction neuron in the RSP before and after shelter rotation. (C) Tuning curves for non-overlapping subsets of data generated by random sampling. For RSP and SC, the plot on the left is sorted by tuning peak, and the sorting indexes have been used to sort the plot on the right. (D) Summary plot of preferred tuning angle for RSP and SC shelter-direction neurons. (E) Example tuning curves for allocentric head-direction neurons in the SC and RSP. We recorded 2% head-direction cells in the SC, and 6% in the RSP. (F) Summary plot showing the occupancy of the arena during exploratory behaviour in the presence of a second, closed shelter.

Extended Data Fig. 2 Tuning entanglement decoupling analysis.

(A) Left, plot illustrating a driver variable (v1) and a correlated passenger variable (v2; Pearson’s correlation coefficient = 0.45). v1 samples are drawn from a normal distribution of mean 0 and standard deviation 1. The jth sample of v2 is computed as v2, j = 0.5× v1,j+εj, where each εj is drawn from a second normal distribution with mean 0 and standard deviation 1. Right, v1 is used to simulate the spiking of a neuron such that the probability of firing is equal to 0.1 × v1 if v1 > 1 and 0 if v1 ≤ 1. TunED analysis was then applied to v1, v2 and simulated spiking data as described in Methods to compute observed and expected tuning curves to v1 and v2. The method correctly identifies v1 as the driver variable. The observed tuning curve to the passenger variable v2 (dark yellow) can be fully explained by the tuning to the driver variable (brown). In contrast, the observed tuning to driver variable (dark blue), cannot be explained by the tuning to the passenger variable (light blue). (B) Left, schematic of head–shelter angle and head direction variables during the experiment. Right, correlation between head–shelter angle and head direction in our experimental setting plotted for eight values of head direction for each grid location. (C) Left, tuning curves of neurons for which the driver variable was head direction (top) or head–shelter angle (bottom). Right, illustration of the statistical method used to determine whether the driver variable of the neuron was head shelter offset, head direction or none of them (see Methods for details). Briefly, the distribution of dHSA - dHD (dark grey histogram) indicates whether the expected and observed tuning curves are more similar for head–shelter angle or for head direction. If the dHSA - dHD distribution is significantly smaller than zero (both 2.5th and 97.5th percentile <0, vertical dotted lines) the cell is classified as a head direction cell; if the distribution of dHSA - dHD is significantly larger than zero (both 2.5th and 97.5th percentile > 0) the cell is classified as a head-shelter angle cell; otherwise the cell is not considered a shelter-direction nor head direction cell.

Extended Data Fig. 3 Histology for loss-of-function of SC-projecting RSP neurons.

3D rendering of the location of SC-projecting RSP neurons expressing hM4Di for the mice in the following datasets: escape behaviour assay, orientation to sound assay, food-seeking assay, single unit recordings during chemogenetic inactivation. For an example coronal section see Fig. 2a.

Extended Data Fig. 4 RSP loss-of-function does not affect average SC firing rates.

(A) Population histograms for firing rate of SC single units after saline and CNO i.p. injection in animals expressing hM4Di in SC-projecting RSP neurons (P = 0.75 one-tailed Kolmogorov-Smirnov test; N = 264 units, 2 mice).

Extended Data Fig. 5 Shelter orientation error does not depend on the environment luminance level.

Shelter orientation error increases both during light and dark conditions upon inactivation of SC-projecting RSP neurons, in comparison to saline control (Dark: P = 0.0302 permutation test; saline: 5 mice, 24 trials; CNO: 11 mice, 58 trials. Light: P = 0.038 permutation test; saline: 6 mice, 27 trials; CNO: 9 mice, 47 trials). No significant differences were observed between saline in light and dark condition (P = 0.46 permutation test) or CNO in light and dark condition (P = 0.26 permutation test).

Extended Data Fig. 6 Additional analysis of the effect of RSP-SC loss-of-function on behaviour.

(A–F) Navigation during exploratory behaviour is not affected by inactivation of SC-projecting RSP neurons. Panels show quantification of exploratory behaviour during the time period preceding the presentation of the first threatening stimulus for saline control (black, N = 6) and CNO (blue, N = 11) mice, expressing hM4Di in SC-projecting RSP neurons. None of the metrics differs between the two groups (P > 0.15 for all metrics, 2-tailed Mann-Whitney test). (A) Latency between the beginning of the experiment and the first time the mouse entered the shelter. (B) Number of times the mouse entered the shelter. (C) Percentage of time the mouse spent outside the shelter. (D) Total length of the path travelled while outside the shelter. (E) Percentage of the arena surface explored while outside the shelter. (F) Average and 95th percentile of mouse locomotion speed while outside the shelter. The duration of the time period preceding the presentation of the first threatening stimulus did not differ between saline control and CNO groups (P = 0.51, 2 tailed Mann-Whitney test). (G) Average change in speed after threat presentation for saline control (black) and CNO (blue) showing that both groups of mice initiate escape with similar vigour. (H) Summary data for time to reach the shelter after escape initiation. (I) Length of flight after escape initiation as a function of orientation error, showing that larger errors are associated with shorter flights. (Fitted function: Boltzmann sigmoidal equation; slope −5.5, P = 0.02; F-statistic goodness of fit test against constant model, P < 0.0001). Shaded area: 95% confidence interval. Distance is normalized to the distance to shelter at escape onset.

Extended Data Fig. 7 Histology for cortical loss-of-function.

Coronal sections and 3D renderings showing neurons targeted with hM4Di expression in the entire RSP (A), posterior parietal cortex (B) and anterior motor areas (C). D shows fluorescently-labelled muscimol targeted to the RSP. White circles represent infusion cannulae location.

Extended Data Fig. 8 Additional cortical inputs onto SC neurons.

Coronal images of monosynaptic rabies tracing from starter SC cells in excitatory (vGluT2+) and inhibitory (vGAT+) neuron populations, showing prominent inputs from the posterior parietal cortex (A), M2 (B) and anterior cingulate cortex (C).

Extended Data Fig. 9 Histology for projection-specific RSP-SC loss-of-function.

Coronal sections and 3D renderings showing guides and internal cannulae locations (white dotted lines and white circles) implanted in the superior colliculus (SC; A) and anterior cingulate cortex (ACC; B). Insets and blue shades in the right panels show SC-projecting RSP neurons of the respective mouse, expressing hM4Di. Inset in B (top-right) shows the axon collaterals to ACC of SC-projecting RSP neurons.

Extended Data Fig. 10 Quantification of head-displacement prediction and orientation to sound performance.

(A) Cross validated confusion matrix for LDA population decoding of the angle of future head displacement (100 ms ahead) from SC firing rates (prediction accuracy: 0.78). (B) Summary data showing that mice orient accurately to sound (with no biases for left nor right speaker neither for left nor right turns; P = 0.27 and P = 0.33 respectively, permutation test; N = 36, 6 mice), with short latencies (C, left) and fast movements (C, right). (D) Summary data showing that mice are equally accurate when orienting to sound or to shelter (P = 0.82 permutation test; orientation to sound N = 36, 6 mice; orientation to shelter N = 32, 5 mice). (E) Orientation to sound accuracy does not depend on the distance at sound onset between the mouse and the speaker (slope = −0.012, P = 0.48, linear regression).

Extended Data Fig. 11 Principal components of SC population dynamics during RSP activation.

Principal component 1 and 2 of SC vGAT+ and SC vGluT2+ neurons during cortical activation (same data as Fig. 4b). The first two principal components are sufficient to explain most of the variance present in the data (84%) and closely resemble the temporal dynamics observed for SC vGAT+ and SC VGluT2+ neurons.

Extended Data Fig. 12 Biophysical properties of SC neurons receiving RSP input.

(A) Summary curves for action potential firing from somatic current injection. (B) Summary data for short-term plasticity of RSP inputs onto SC neurons.

Extended Data Fig. 13 Elements of the lateral feedforward inhibition and ring attractor models.

(A) Real and simulated synaptic currents or potentials for all synaptic connections in the model. (B) Additional circuit elements of the feedforward lateral inhibition model (c.f. Fig. 5d). (C) Left: Circuit elements of the standard ring attractor model. Right: predicted firing rate of vGluT2+ and vGAT+ SC populations following 20 Hz activation of RSP neurons in the model, compared to observed dynamics (dashed lines, see also in Fig. 4b).

Extended Data Fig. 14 3D reconstruction of viral injection and fiber placement of dual-opsin-assisted circuit mapping and optotagging.

3D rendering of the location of ChrimsonR-expressing neurons in the entire RSP (blue), ChR2-expressing SC vGluT2+ and vGAT+ neurons (yellow), and optic fibers (white cylinders) used in the freely moving and head-fixed dual-opsin and optotagging experiments. For an example coronal section see Fig. 4a.

Supplementary information

Supplementary Information

Supplementary Tables 1–4.

Reporting Summary

Supplementary Video 1

Example escape from auditory threat in a naïve mouse.

Supplementary Video 2

Example of a chronically implanted mouse during exploration.

Supplementary Video 3

Estimation of the head shelter angle variable.

Supplementary Video 4

Example escapes to shelter position 1 and shelter position 2.

Supplementary Video 5

Chemogenetic inactivation of SC-projecting RSP neurons during escape.

Supplementary Video 6

Chemogenetic inactivation of RSP neurons during escape.

Supplementary Video 7

Pharmacological inactivation of RSP neurons during escape.

Supplementary Video 8

Chemogenetic inactivation of SC-projecting RSP neurons axon terminals in superior colliculus during escape.

Supplementary Video 9

Chemogenetic inactivation of SC-projecting RSP neurons axon terminals in anterior cingulate cortex during escape.

Supplementary Video 10

Orientation to sound assay.

Supplementary Video 11

Chemogenetic inactivation of SC-projecting RSP neurons during orientation to sound assay.

Supplementary Video 12

Chemogenetic inactivation of SC-projecting RSP neurons during food–seeking assay.

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Campagner, D., Vale, R., Tan, Y.L. et al. A cortico-collicular circuit for orienting to shelter during escape. Nature 613, 111–119 (2023). https://doi.org/10.1038/s41586-022-05553-9

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