Hippocampo-cortical coupling mediates memory consolidation during sleep

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Abstract

Memory consolidation is thought to involve a hippocampo-cortical dialog during sleep to stabilize labile memory traces for long-term storage. However, direct evidence supporting this hypothesis is lacking. We dynamically manipulated the temporal coordination between the two structures during sleep following training on a spatial memory task specifically designed to trigger encoding, but not memory consolidation. Reinforcing the endogenous coordination between hippocampal sharp wave-ripples, cortical delta waves and spindles by timed electrical stimulation resulted in a reorganization of prefrontal cortical networks, along with subsequent increased prefrontal responsivity to the task and high recall performance on the next day, contrary to control rats, which performed at chance levels. Our results provide, to the best of our knowledge, the first direct evidence for a causal role of a hippocampo-cortical dialog during sleep in memory consolidation, and indicate that the underlying mechanism involves a fine-tuned coordination between sharp wave-ripples, delta waves and spindles.

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Figure 1: Increased hippocampo-cortical oscillatory coupling correlates with memory consolidation.
Figure 2: SPW-R–triggered stimulation of neocortical deep layers enhances the temporal coupling between hippocampal and cortical events.
Figure 3: Enhancing the fine-tuned coupling of hippocampal SPW-Rs and cortical delta waves and spindles boosts next day performance in a spatial memory task.
Figure 4: Changes in spatio-temporal spiking profiles of mPFC neurons parallel memory consolidation and recall improvements.

References

  1. 1

    Marr, D. Simple memory: a theory for archicortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 262, 23–81 (1971).

  2. 2

    Buzsáki, G. Two-stage model of memory trace formation: a role for “noisy” brain states. Neuroscience 31, 551–570 (1989).

  3. 3

    Ferino, F., Thierry, A.M. & Glowinski, J. Anatomical and electrophysiological evidence for a direct projection from Ammon's horn to the medial prefrontal cortex in the rat. Exp. Brain Res. 65, 421–426 (1987).

  4. 4

    Maviel, T., Durkin, T.P., Menzaghi, F. & Bontempi, B. Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96–99 (2004).

  5. 5

    Bontempi, B., Laurent-Demir, C., Destrade, C. & Jaffard, R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675 (1999).

  6. 6

    Wilson, M.A. & McNaughton, B.L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).

  7. 7

    Lee, A.K. & Wilson, M.A. Memory of sequential experience in the hippocampus during slow-wave sleep. Neuron 36, 1183–1194 (2002).

  8. 8

    Euston, D.R., Tatsuno, M. & McNaughton, B.L. Fast-forward playback of recent memory sequences in prefrontal cortex during sleep. Science 318, 1147–1150 (2007).

  9. 9

    Peyrache, A., Khamassi, M., Benchenane, K., Wiener, S.I. & Battaglia, F.P. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nat. Neurosci. 12, 919–926 (2009).

  10. 10

    Girardeau, G., Benchenane, K., Wiener, S.I., Buzsáki, G. & Zugaro, M.B. Selective suppression of hippocampal ripples impairs spatial memory. Nat. Neurosci. 12, 1222–1223 (2009).

  11. 11

    Ego-Stengel, V. & Wilson, M.A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 20, 1–10 (2010).

  12. 12

    Marshall, L., Helgadóttir, H., Mölle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006).

  13. 13

    Ngo, H.-V.V., Martinetz, T., Born, J. & Mölle, M. Auditory closed-loop stimulation of the sleep slow oscillation enhances memory. Neuron 78, 545–553 (2013).

  14. 14

    Johnson, L.A., Euston, D.R., Tatsuno, M. & McNaughton, B.L. Stored-trace reactivation in rat prefrontal cortex is correlated with down-to-up state fluctuation density. J. Neurosci. 30, 2650–2661 (2010).

  15. 15

    Mednick, S.C. et al. The critical role of sleep spindles in hippocampal-dependent memory: a pharmacology study. J. Neurosci. 33, 4494–4504 (2013).

  16. 16

    Sirota, A., Csicsvari, J., Buhl, D. & Buzsáki, G. Communication between neocortex and hippocampus during sleep in rodents. Proc. Natl. Acad. Sci. USA 100, 2065–2069 (2003).

  17. 17

    Battaglia, F.P., Sutherland, G.R. & McNaughton, B.L. Hippocampal sharp wave bursts coincide with neocortical “up-state” transitions. Learn. Mem. 11, 697–704 (2004).

  18. 18

    Peyrache, A., Battaglia, F.P. & Destexhe, A. Inhibition recruitment in prefrontal cortex during sleep spindles and gating of hippocampal inputs. Proc. Natl. Acad. Sci. USA 108, 17207–17212 (2011).

  19. 19

    Phillips, K.G. et al. Decoupling of sleep-dependent cortical and hippocampal interactions in a neurodevelopmental model of schizophrenia. Neuron 76, 526–533 (2012).

  20. 20

    Staresina, B.P. et al. Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep. Nat. Neurosci. 18, 1679–1686 (2015).

  21. 21

    Steriade, M., Nuñez, A. & Amzica, F. A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J. Neurosci. 13, 3252–3265 (1993).

  22. 22

    Sirota, A. & Buzsáki, G. Interaction between neocortical and hippocampal networks via slow oscillations. Thalamus Relat. Syst. 3, 245–259 (2005).

  23. 23

    Amzica, F. & Steriade, M. Cellular substrates and laminar profile of sleep K-complex. Neuroscience 82, 671–686 (1998).

  24. 24

    Barker, G.R.I. & Warburton, E.C. When is the hippocampus involved in recognition memory? J. Neurosci. 31, 10721–10731 (2011).

  25. 25

    Ballarini, F., Moncada, D., Martinez, M.C., Alen, N. & Viola, H. Behavioral tagging is a general mechanism of long-term memory formation. Proc. Natl. Acad. Sci. USA 106, 14599–14604 (2009).

  26. 26

    Vyazovskiy, V.V., Faraguna, U., Cirelli, C. & Tononi, G. Triggering slow waves during NREM sleep in the rat by intracortical electrical stimulation: effects of sleep/wake history and background activity. J. Neurophysiol. 101, 1921–1931 (2009).

  27. 27

    Kudrimoti, H.S., Barnes, C.A. & McNaughton, B.L. Reactivation of hippocampal cell assemblies: effects of behavioral state, experience, and EEG dynamics. J. Neurosci. 19, 4090–4101 (1999).

  28. 28

    Frankland, P.W. & Bontempi, B. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130 (2005).

  29. 29

    Luczak, A., Barthó, P., Marguet, S.L., Buzsáki, G. & Harris, K.D. Sequential structure of neocortical spontaneous activity in vivo. Proc. Natl. Acad. Sci. USA 104, 347–352 (2007).

  30. 30

    Womelsdorf, T. et al. Modulation of neuronal interactions through neuronal synchronization. Science 316, 1609–1612 (2007).

  31. 31

    Rosanova, M. & Ulrich, D. Pattern-specific associative long-term potentiation induced by a sleep spindle–related spike train. J. Neurosci. 25, 9398–9405 (2005).

  32. 32

    Girardeau, G., Cei, A. & Zugaro, M. Learning-induced plasticity regulates hippocampal sharp wave-ripple drive. J. Neurosci. 34, 5176–5183 (2014).

  33. 33

    Hazan, L., Zugaro, M. & Buzsáki, G. Klusters, NeuroScope, NDManager: a free software suite for neurophysiological data processing and visualization. J. Neurosci. Methods 155, 207–216 (2006).

  34. 34

    Barthó, P. et al. Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J. Neurophysiol. 92, 600–608 (2004).

  35. 35

    Hartigan, J. & Hartigan, P. The dip test of unimodality. Ann. Stat. 13, 70–84 (1985).

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Acknowledgements

We thank C. Drieu, V. Oberto, H.-Y. Gao, A. Cei, S. Sara, S.I. Wiener and K. Benchenane for advice and comments on the manuscript, and S. Doutremer, M.A. Thomas and Y. Dupraz for technical support. This work was supported by the French Ministry of Research (N.M.), a grant from the Fondation pour la Recherche Médicale (grant no. FDT20150532568) (N.M.), and a joint grant from École des Neurosciences de Paris Île-de-France and LabEx MemoLife (ANR-10-LABX-54 MEMO LIFE, ANR-10-IDEX-0001-02 PSL*) (R.T.).

Author information

N.M., G.G. and M.Z. designed the study. N.M., G.G. and M.G. performed the experiments. N.M., R.T. and M.Z. designed the analyses. N.M. and R.T. performed the analyses. N.M. and M.Z. wrote the manuscript with input from all authors.

Correspondence to Michaël Zugaro.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Hippocampo-cortical oscillatory interactions during unperturbed SWS.

a. Temporal cross-correlation between SPW-Rs and delta waves at different timescales. The two peaks around SPW-R times indicate that SPW-Rs are both preceded and followed by delta waves. b. Temporal cross-correlation between delta waves and spindles. Note the increased spindle probability immediately following delta waves.

Supplementary Figure 2 Incidence of hippocampo-cortical rhythms is unchanged between coupled and delayed stimulation epochs.

a. A large fraction of the applied stimulations efficiently triggered delta waves (left) or delta-spindle sequences (right) in both delayed (purple bars) and coupled (green bars) conditions. Stimulation efficacy was identical across conditions (delta waves efficacy, coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 0.18, P = 0.859; delta-spindle efficacy, coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 0.06, P = 0.953). b. SPW-R, delta wave and spindle occurrence rates during Pre-sleep (black bars) and during stimulation epochs (purple and green bars). As expected, delta waves and spindles were more frequent during stimulation than Pre-sleep epochs, but their occurrence rates were identical between stimulation conditions. SPW-R incidence, Friedman test, χ2 = 2.57, n = 7, d.f. = 2, P = 0.277. Spindle incidence, Friedman test, χ2 = 10.57, n = 7, d.f. = 2, P = 0.005; Wilcoxon matched pairs test, n = 7, Pre-sleep vs. coupled: Z = 2.36, *P = 0.018; Pre-sleep vs. delayed: Z = 2.36, *P = 0.018; coupled vs. delayed: Z = 0.17, P = 0.866. Delta incidence, Friedman test, χ2 = 10.57, n = 7, d.f. = 2, P = 0.005; Wilcoxon matched pairs test, n = 7, Pre-sleep vs. coupled: Z = 2.36, *P = 0.018; Pre-sleep vs. delayed: Z = 2.36, *P = 0.018; coupled vs. delayed: Z = 0.34, P = 0.735. c. Delta power was similar between naturally occurring and induced events (black, Pre-sleep; green, coupled stimulation; purple; delayed stimulation) Friedman test, χ2 = 0.89, n = 9, d.f. = 2, P = 0.641. d. Same as in c for spindle peaks. Friedman test, χ2 = 0.67, n = 9, d.f. = 2, P = 0.716. e. Proportion of endogenous (black) and induced (gray) delta waves associated with a down state revealing a strong correlation between these events (Wilcoxon matched pairs test, n = 11 sessions with nPFC neurons> 7, Z = 0.27, P = 0.790). f. Mean HPC population activity during delta-down events identified in e, relative to the firing rate outside of these events during SWS (Wilcoxon matched pairs test, n = 11 sessions with nPFC neurons & nHPC neurons > 7, Z = 0.27, P = 0.790). Error bars represent s.e.m.

Supplementary Figure 3 Stimulation did not trigger direct, hyper-synchronous activation of mPFC neurons.

a. Average local field potential recorded in the mPFC (top trace, low-pass filtered) around stimulations (n = 1,000) in one example session. b. Top, Multiunit activity of mPFC pyramidal cells. Bottom, average population firing rate across stimulations. c. Same as in b for mPFC interneurons. While stimulation-induced delta waves are accompanied by neuronal silence characteristic of endogenous down states, neither pyramidal cells nor interneurons dramatically increase their firing rates at the time of stimulation.

Supplementary Figure 4 Stimulation conditions and global sleep architecture.

a. The duration of uninterrupted SWS epochs was similar during delayed (purple) and coupled (green) stimulation sessions (coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 0.56, P = 0.575). b. Same as in a, for REM epochs (coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 0.98, P = 0.327). c. Average REM/SWS ratios were similar across stimulation conditions (coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 0.70, P = 0.484). Error bars represent s.e.m.

Supplementary Figure 5 Stimulation-induced delta waves did not alter subsequent SPW-R occurrence rates.

a. Proportion of delta waves preceded by SPW-Rs during Pre-sleep (black) and coupled (green bars) and delayed (purple bars) stimulation periods (only stimulation-evoked delta waves were counted in post-exploration sleep sessions). Friedman test, χ2 = 11.14, n = 7, d.f. = 2, P = 0.004; Wilcoxon matched pairs test, n = 7, Pre-sleep vs. coupled: Z = 2.36, *P = 0.018; Pre-sleep vs. delayed: Z = 1.18, P = 0.237; coupled vs. delayed: Z = 2.36, *P = 0.018. b. The proportion of delta waves followed by SPW-Rs was similar across conditions (only stimulation-evoked delta waves were counted in post-exploration sleep sessions). Friedman test, χ2 = 0.29, n = 7, d.f. = 2, P = 0.867. Error bars represent s.e.m.

Supplementary Figure 6 Coupling hippocampal and cortical oscillations enhances recall above chance level and induces preferential exploration of the displaced object.

Memory performance remained significantly above chance level in the coupled condition for the whole duration (5 minutes) of the recall phase, whereas in the delayed condition, performance did not differ from chance (2 min coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 2.66, **P = 0.008; 2 min coupled vs chance, Wilcoxon signed-rank test, n = 9, Z = 2.66, **P = 0.008; 2 min delayed vs chance, Wilcoxon signed-rank test, n = 9, Z = 1.48, P = 0.139. 3 min coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 2.66, **P = 0.008; 3 min coupled vs chance, Wilcoxon signed-rank test, n = 9, Z = 2.66, **P = 0.008; 3 min delayed vs chance, Wilcoxon signed-rank test, n = 9, Z = 0.65, P = 0.515. 5 min coupled vs delayed, Wilcoxon matched pairs test, n = 9, Z = 2.31, *P = 0.021; 5 min coupled vs chance, Wilcoxon signed-rank test, n = 9, Z = 2.66, **P = 0.008; 5 min delayed vs chance, Wilcoxon signed-rank test, n = 9, Z = 0.889, P = 0.374). Error bars represent s.e.m.

Supplementary Figure 7 Random, non SPW-R–triggered stimulation does not lead to memory consolidation on the spatial object recognition task.

a. Random stimulation protocol (top) and temporal cross-correlation between SPW-Rs and stimulation onset (bottom). b. Stimulation efficacy for the random stimulation protocol. c. Incidence of hippocampo-cortical events (left: SPW-R-delta, right: SPW-R-delta-spindle) during Pre-sleep (black) and random stimulation periods (blue). SPW-R-delta incidence, Wilcoxon matched pairs test, n = 6, Z = 1.57, P = 0.116; SPW-R-delta-spindle incidence, Wilcoxon matched pairs test, n = 6, Z = 1.36, P = 0.173. d. Performance did not differ from chance during recall following the random stimulation protocol (2 min random vs chance, Wilcoxon signed-rank test, n = 6, Z = 0.73, P = 0.463; 3 min random vs chance, Wilcoxon signed-rank test, n = 6, Z = 0.52, P = 0.600; 5 min random vs chance, Wilcoxon signed-rank test, n = 6, Z = 1.57, P = 0.116) Error bars represent s.e.m.

Supplementary Figure 8 Medial prefrontal cortical cells were not responsive to the objects during the encoding phase.

Cumulative distributions of mPFC responsivity indices to each object during the encoding phase of the task preceding each stimulation condition. mPFC cells were not responsive to any object in any condition (displaced object: coupled vs delayed, Wilcoxon rank-sum test, n = 77, n = 93, Z = 1.14, P = 0.255; coupled vs zero, Wilcoxon matched pairs test, n = 77, Z = 1.32, P = 0.188; delayed vs zero, Wilcoxon matched pairs test, n = 93, Z = 0.14, P = 0.890; stable object: coupled vs delayed, Wilcoxon rank-sum test, n = 77, n = 93, Z = 0.79, P = 0.432; coupled vs zero, Wilcoxon matched pairs test, n = 77, Z = 1.65, P = 0.099; delayed vs zero, Wilcoxon matched pairs test, n = 93, Z = 0.65, P = 0.516).

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Maingret, N., Girardeau, G., Todorova, R. et al. Hippocampo-cortical coupling mediates memory consolidation during sleep. Nat Neurosci 19, 959–964 (2016) doi:10.1038/nn.4304

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