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Trajectory events across hippocampal place cells require previous experience

Nature Neuroscience volume 18, pages 1772–1779 (2015)Cite this article

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Abstract

Replay of hippocampal place cell sequences has been proposed as a fundamental mechanism of learning and memory. However, the standard interpretation of replay has been challenged by reports that similar activity is observed before experience ('preplay'). By the preplay account, pre-existing temporal sequences are mapped onto new experiences without learning sequential structure. Here we employed high density recording methods to monitor hundreds of place cells simultaneously while rats explored multiple novel environments. While we observed large numbers of synchronous spiking events before experience, they were not temporally correlated with subsequent experience. Multiple measures differentiated pre-experience and postexperience events that, taken together, defined the latter but not the former as trajectory-depicting. The formation of events with these properties was prevented by administration of an NMDA-receptor antagonist during experience. These results suggest that the sequential structure of behavioral episodes is encoded during experience and reexpressed as trajectory events.

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Figure 1: There are no sequentially structured events prior to experience.
Figure 2: Position depiction within candidate events during sleep 1 and run 1.
Figure 3: Trajectory events are found only after experience.
Figure 4: NMDA receptor antagonism spares place fields but abolishes replay.
Figure 5: Trajectory events under a degraded saline place field decoder.
Figure 6: NMDA receptor function is not required for replay retrieval.
Figure 7: Changes in drug efficacy were unlikely to account for preserved retrieval under d-CPPene.
Figure 8: Retrieved trajectory events over time.

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Acknowledgements

This work was supported by the Alfred P. Sloan Foundation (D.J.F.), the US National Institute for Mental Health (D.J.F.) and the US National Science Foundation (D.S.).

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Author notes

  1. Delia Silva and Ting Feng: These authors contributed equally to this work.

Authors and Affiliations

  1. Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Delia Silva, Ting Feng & David J Foster

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Contributions

D.S. and D.J.F. designed the experiment; D.S. collected the data; T.F. and D.S. developed the analyses; D.S., T.F. and D.J.F. wrote the paper. D.S. and T.F. contributed equally to this work.

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Correspondence to David J Foster.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Place field rate maps under saline

Example of 114 place fields from one saline session as they remap between three different tracks. The same 114 place cells are ordered by their peak firing positions on Track 1 (1st row), Track 2 (2nd row) and Track 3 (3rd row) respectively.

Supplementary Figure 2 Animals’ running speeds between different runs were not significantly different

Left, saline days, Kruskal-Wallis test: H(2)=1.87, p=0.39; right, D-CPPene days, Kruskal-Wallis test: H(2)=4.01, p=0.13. The edges of the box are the 25th (q1) and 75th (q3) percentiles of the data. The red line in the box shows the median. Red crosses mark individual outliers that are larger than q3 + 1.5*(q3 – q1) or smaller than q1 – 1.5*(q3 – q1). The black whiskers extend to the most extreme data points not considering outliers.

Supplementary Figure 3 Place field properties on saline days

Place cells remapped between different runs. Place cell firing rates, field sizes and sparsity were not significantly different between runs. Kruskal-Wallis test: H(2)=4.98, p=0.08 for place cell average firing rates; H(5)=53.4, p=2.79*10-10 for remapping index; H(2)=5.07, p=0.08 for place field size; H(2)=1.16, p=0.56 for place field sparsity. The edges of each box are the 25th (q1) and 75th (q3) percentiles of the data. The red line in each box shows the median. Red crosses mark the biggest or smallest outlier. Outliers were defined as values larger than q3 + 1.5*(q3 – q1) or smaller than q1 – 1.5*(q3 – q1). The black whiskers extend to the most extreme data points not considering outliers.

Supplementary Figure 4 Structured events prior to experience are also absent with place cells randomly downsampled or downsampled by L-ratio

(a) Distribution of spike correlations of 8310 candidate events during Sleep 1 after down-sampling to 15 cells. 15% candidate events in Sleep 1 did not produce real number correlation after down-sampling cells thus were not included in the histogram. Open bars indicate spiking events versus the original place fields templates; filled bars indicate spiking events versus 5000 shuffled templates scaled down 5000 times. Left, both place fields templates in two running directions were included (absolute correlation medians: 0.35 versus 0.36, data versus shuffle; one-tailed Wilcoxon rank sum test: p=0.75; one-tailed Kolmogorov-Smirnov test: p=0.81; Monte-Carlo P-value>0.4 with criteria of absolute correlation >0.5 or 0.6 or 0.7, see Methods). Right, only the biggest absolute spike correlation resulting from the two templates for each candidate event and shuffle were included (absolute correlation medians: 0.44 versus 0.47, data versus shuffle; one-tailed Wilcoxon rank sum test: p=1; one-tailed Kolmogorov-Smirnov test: p=1; Monte-Carlo P-value=1 with criteria of absolute correlation >0.5 or 0.6 or 0.7, see Methods). (b) Histogram (bin size=0.001) of L-ratio for 442 manually clustered, putative excitatory units in Sleep 1. Red line indicates the median value. (c) Distribution of spike correlations of 8051 candidate events during Sleep 1 after sub-sampling cells that have an L-ratio equal to or lower than the median value. 18% candidate events in Sleep 1 did not produce real number correlation after sub-sampling cells thus were not included in the histogram. Open and filled bars are as described in (a). Left, same as in (a); absolute correlation medians: 0.36 versus 0.36, data versus shuffle; one-tailed Wilcoxon rank sum test: p=0.40; one-tailed Kolmogorov-Smirnov test: p=0.60; Monte-Carlo P-value>0.1 with criteria of absolute correlation >0.5 or 0.6 or 0.7. Right, same as in (a); absolute correlation medians: 0.48 versus 0.50, data versus shuffle; one-tailed Wilcoxon rank sum test: p=1; one-tailed Kolmogorov-Smirnov test: p=1; Monte-Carlo P-value=1 with criteria of absolute correlation >0.5 or 0.6 or 0.7.

Supplementary Figure 5 Significance matrices for all runs and conditions

Running epochs are denoted as e1 (Run 1), e2 (Run 2), e3 (Run 3); sleep epochs are denoted as s1 (Sleep 1), s2 (Sleep 2), s3 (Sleep 3); saline and D-CPPene days are denoted as sal and cpp respectively. Sleep 1 is the sleep epoch before any running experience, and the significance matrices for Sleep 1 (1st column) are denoted as e1s1, e2s1 and e3s1, using place fields from Track 1, Track 2 and Track 3 respectively. Significant matrices during current running experiences are denoted as e1e1, e2e2, e3e3 for three tracks respectively (2nd column). Significant matrix of retrieved Track 1 place fields during Sleep 2 is denoted as e1s2 (3nd column). Significant matrices during Sleep 3 are denoted as e1s3, e2s3, e3s3 respectively for three tracks (4th column). Red box denotes post-experience on D-CPPene days, where red dashed box denotes the D-CPPene epoch before drug administration (Run 1).

Supplementary Figure 6 Chemical structure of d-CPPene and activity profile

The first selective NMDAR antagonists AP5((2R)-amino-5-phosphonovaleric acid; (2R)-amino-5-phosphonopentanoate) and AP-7 had to be infused via mini-pumps directly into the brain due to poor penetration of the blood brain barrier. CPP,3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid, was synthesized as a rigid analog of AP-7 and is a potent, selective, and competitive antagonist of NMDA-type receptors that can be administered intra-peritoneally (Lehmann et al., 1987). D-CPPene, D-4-[(2E)-3-Phosphono-2-propenyl]-2-piperazinecarboxylic acid, is an analog of CPP, as seen above. D-CPPene is the most potent, enantiomerically pure, competitive NMDA antagonist (Lowe et al., 1990).The standard form of CPP used in previous place cell studies has been a racemic mixture including both enantiomers (D- and L-) (e.g. Ekstrom et al., 2001; Kentros et al., 1998). For both CPP and CPPene the D-enantiomer is 15-20 times more potent than the L-enantiomer. D-CPPene is 4.7 times more potent than DL-CPP and 2.2 times more potent than D-CPP (Lowe et al., 1990).

Aebischer, B., Frey, P., Haerter, H.P., Herrling, P.L., Mueller, W., Olverman, H.J., and Watkins, J.C. (1989). Synthesis and NMDA Antagonistic Properties of the Enantiomers of 4-(3-Phosphonopropyl)Piperazine-2-Carboxylic Acid (Cpp) and of the Unsaturated Analog (E)-4-(3-Phosphonoprop-2-Enyl)Piperazine-2-Carboxylic Acid (Cpp-Ene). Helv Chim Acta 72, 1043-1051.

Lehmann, J., Schneider, J., McPherson, S., Murphy, D.E., Bernard, P., Tsai, C., Bennett, D.A., Pastor, G., Steel, D.J., Boehm, C., et al. (1987). CPP, a selective N-methyl-D-aspartate (NMDA)-type receptor antagonist: characterization in vitro and in vivo. J Pharmacol Exp Ther 240, 737-746.

Lowe, D.A., Neijt, H.C., and Aebischer, B. (1990). D-CPP-ene (SDZ EAA 494), a potent and competitive N-methyl-D-aspartate (NMDA) antagonist: effect on spontaneous activity and NMDA-induced depolarizations in the rat neocortical slice preparation, compared with other CPP derivatives and MK-801. Neurosci Lett 113, 315-321.

Ekstrom, A.D., Meltzer, J., McNaughton, B.L., and Barnes, C.A. (2001). NMDA receptor antagonism blocks experience-dependent expansion of hippocampal "place fields". Neuron 31, 631-638.

Kentros, C., Hargreaves, E., Hawkins, R.D., Kandel, E.R., Shapiro, M., and Muller, R.V. (1998). Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science 280, 2121-2126.

Supplementary Figure 7 Place field properties on d-CPPene days

Place cells remapped between different runs. Place cell average firing rates, field sizes are not significantly different between runs. Place field sparsity increased after drug administration. Kruskal-Wallis test: H(2)=3.78, p=0.15 for place cell average firing rates; H(5)=50.75, p=9.73*10-10 for remapping index; H(2)=6.83, p=0.03 for place field size, however post-hoc Bonferroni correction did not identify any run experience that is significantly different to others; H(2)=155.24, p<10-10 for place field sparsity, post-hoc Bonferroni correction indicates all runs are significantly different to each other.

Supplementary Figure 8 Place field rate maps under d-CPPene

Example of 111 place fields from one saline session as they remap between three different tracks. The same 111 place cells are ordered by their peak firing positions on Track 1 (1st row), Track 2 (2nd row) and Track 3 (3rd row) respectively.

Supplementary Figure 9 Position reconstruction during run

Cumulative distribution of the construction error during run for saline (blue) and D-CPPene (red) sessions (group data). Black and dashed black lines are respectively the decoding qualities at chance level for saline and D-CPPene days. Median ± s.e.m of construction error, saline versus D-CPPene, Wilcoxon rank sum test: 4.34 ± 0.25 versus 4.86± 0.25, p=0.08 for Run 1; 10.14 ± 0.38 versus 13.23± 0.43, p<10-10 for Run 2; 10.43 ± 0.38 versus 16.94± 0.46, p<10-10 for Run 3. All the decoding are significantly better than chance (p<10-10).

Supplementary Figure 10 Run decoding and replay decoding with diffuse place fields

(a) Histograms of place field sparsity from saline days. (b) Position decoding for each Run using only the subset of place fields with sparsity value greater than 0.5. The decoding qualities of the degraded decoder (blue) are significantly better than chance (black) for all three runs (Wilcoxon rank sum test, p<10-10). (c) Top 6 correlated events expressed during saline Runs using only diffuse place fields. (d) Corresponding significance matrix for trajectory events.

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Silva, D., Feng, T. & Foster, D. Trajectory events across hippocampal place cells require previous experience. Nat Neurosci 18, 1772–1779 (2015). https://doi.org/10.1038/nn.4151

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