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The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation

An Author Correction to this article was published on 01 October 2020

Abstract

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze1,2,3, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.

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Figure 1: The honeycomb maze.
Figure 2: Learning to navigate the honeycomb maze.
Figure 3: Factors that affect maze performance in controls.
Figure 4: Performance of rats with hippocampal lesions on the honeycomb maze.

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Acknowledgements

We thank M. Bertelli, A. Hastings, D. Howett, N. Khan, P. Mumford, A. O’Leary, B. Potter, S. Richards and R. Wu for their contribution to this work, and D. Farquharson and D. Halpin for their input to the design, building and testing of maze prototypes. This work was supported by grants from the Wellcome Trust and the Gatsby Charitable Foundation to J.O. R.A.W. is an MRC Clinical Research Training Fellow, J.K. is a Wellcome Trust/Royal Society Sir Henry Dale Fellow and is supported by the Kavli Foundation Dream Team project and the Isaac Newton Trust. D.C. is funded by the Cambridge NIHR Biomedical Research Centre and by the Wellcome Trust.

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Contributions

J.O. conceived the maze and the study. J.O., M.B., J.K. and S.B. were instrumental in designing, building and testing prototypes of the maze. J.K. and M.B. designed the custom-made software used to operate the maze. R.A.W. designed testing schedule 1 for the control experiment, and A.D. and J.O. designed testing schedule 2 for the lesion experiment. A.D. and S.B. performed the hippocampal lesion and sham lesion surgeries. R.A.W. acquired the behavioural data. R.A.W. and A.D. performed the histology for the lesion experiment, and R.A.W. measured hippocampal lesion volumes. R.A.W. conducted the data management and performed the statistical analyses. J.K., S.B. and J.O. collected the single-unit data and J.K. and J.O. analysed these data. J.O. and R.A.W. wrote the manuscript, with contributions to later drafts from all other authors.

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Correspondence to John O’Keefe.

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Extended data figures and tables

Extended Data Figure 1 Place cell recorded on the honeycomb maze.

A single place cell recorded during navigation on the honeycomb maze. a, Behaviour (black line) from a single trial (trial i) in which the rat was offered two consecutive choices (left, 0–73 s) to go from the start platform (second left, 0–25 s), to an intermediate platform (third left, 25–50 s) to the goal (right, 50–73 s). The program detained the rat on each platform for 20 s before the two choice platforms were raised or, in goal, the food presented. Non-chosen platforms not shown. As the rat waited on each platform, it sampled the immediate environment by circling the perimeter of the platform. b, The firing of a place cell during this trial (trial i); maximum rate in red shown top left. c, Rate map for the same cell on a separate trial (trial g) from a different start platform. d, Composite rate map from ten trials (trials cl), each from a different starting location in which the rat took a different path to the goal. e, Firing rate map of the same cell when all platforms were raised and the rat foraged for food over a period of 20 min (trial m). In this cell, the firing fields during navigation trials (d) and during the foraging condition (e) were similar (spatial correlation = 0.77). Not all place cells displayed this profile, and others (not shown) fired in a different location(s) during the navigation trials from that seen in the foraging condition (that is, remapped).

Extended Data Figure 2 Protocols used on the honeycomb maze.

a, Schedule 1 trial protocols for Aβ60 (left), Aβ120 (middle) and Aβ180 (right) trials. b, Schedule 2 protocol. For a and b: goal platform, black; start platforms, blue; orange vectors, correct choices; grey vectors, incorrect choices; green vectors, ‘forced’ choices. See Methods for more detail.

Extended Data Figure 3 Histology of brains from rats with hippocampal lesions.

Representative sections from brains of rats with hippocampal lesions, and one operated control with a sham hippocampal lesion (R2322), alongside mean performance scores on the honeycomb maze. Subjects are arranged in order of increasing lesion size. Horizontal sections (40 μm) stained with cresyl violet.

Extended Data Figure 4 Correlation between hippocampal volume and performance.

Correlation between remaining hippocampal volume and performance on the spatial navigation task on the honeycomb maze in eight rats with hippocampal lesions (n = 8 rats, ρ6 = 0.452, P = 0.260; Spearman’s correlation).

Source data

Extended Data Figure 5 Rats with hippocampal lesions have longer latencies.

Rats with hippocampal lesions (red, n = 8) have longer latencies than operated controls with sham hippocampal lesions (blue, n = 8) (F1,14 = 11.103, P = 0.005). Latencies also changed as a function of experience (day) (F16,224 = 5.612, P < 0.001) with a significant day × lesion interaction (F16,224 = 2.464, P = 0.002, two-way mixed ANOVA). **P < 0.005. Error bars indicate s.e.m.

Source data

Extended Data Figure 6 Vector-based navigation schema.

Left, The hippocampus represents a goal-direction vector pointing from the rat to the goal (A), which decreases as the rat is farther from the goal (right). The navigation system computes the projection of each choice platform vector (B, C) onto the goal-direction vector (inner product, Bgd, Cgd) and selects the larger of the two. This choice is easier with increased angle between choices (angle β) and consequent increased difference in the magnitudes of their projection vectors. The projection vector of the preferred platform, Bgd, is the output of the system that competes with other potential solutions to the problem (for example, choose between the leftmost or northmost platform).

Extended Data Table 1 Summary of multiple regression analysis
Extended Data Table 2 Coordinates of the sites of hippocampal lesions, and the volume of ibotenic acid used in rats with lesions
Extended Data Table 3 Coordinates of the sites of the sham medial entorhinal lesions

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Supplementary information

Supplementary Information

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Control rat navigating the Honeycomb Maze

A control rat making a series of choices as it navigates to the goal on the Honeycomb Maze. (MP4 5684 kb)

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Wood, R., Bauza, M., Krupic, J. et al. The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation. Nature 554, 102–105 (2018). https://doi.org/10.1038/nature25433

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