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The hippocampus is crucial for forming non-hippocampal long-term memory during sleep

Abstract

There is a long-standing division in memory research between hippocampus-dependent memory and non-hippocampus-dependent memory, as only the latter can be acquired and retrieved in the absence of normal hippocampal function1,2. Consolidation of hippocampus-dependent memory, in particular, is strongly supported by sleep3,4,5. Here we show that the formation of long-term representations in a rat model of non-hippocampus-dependent memory depends not only on sleep but also on activation of a hippocampus-dependent mechanism during sleep. Rats encoded non-hippocampus-dependent (novel-object recognition6,7,8) and hippocampus-dependent (object–place recognition) memories before a two-hour period of sleep or wakefulness. Memory was tested either immediately thereafter or remotely (after one or three weeks). Whereas object–place recognition memory was stronger for rats that had slept after encoding (rather than being awake) at both immediate and remote testing, novel-object recognition memory profited from sleep only three weeks after encoding, at which point it was preserved in rats that had slept after encoding but not in those that had been awake. Notably, inactivation of the hippocampus during post-encoding sleep by intrahippocampal injection of muscimol abolished the sleep-induced enhancement of remote novel-object recognition memory. By contrast, muscimol injection before remote retrieval or memory encoding had no effect on test performance, confirming that the encoding and retrieval of novel-object recognition memory are hippocampus-independent. Remote novel-object recognition memory was associated with spindle activity during post-encoding slow-wave sleep, consistent with the view that neuronal memory replay during slow-wave sleep contributes to long-term memory formation. Our results indicate that the hippocampus has an important role in long-term consolidation during sleep even for memories that have previously been considered hippocampus-independent.

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Fig. 1: Effects of post-encoding sleep versus wakefulness on memory in the NOR and OPR tasks.
Fig. 2: Effects of reversibly inactivating the hippocampus on NOR memory.
Fig. 3: Contribution of post-encoding slow wave sleep to remote NOR memory.

References

  1. 1.

    Squire, L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).

    CAS  Article  Google Scholar 

  2. 2.

    Moscovitch, M., Cabeza, R., Winocur, G. & Nadel, L. Episodic memory and beyond: the hippocampus and neocortex in transformation. Annu. Rev. Psychol. 67, 105–134 (2016).

    Article  Google Scholar 

  3. 3.

    Stickgold, R. Sleep-dependent memory consolidation. Nature 437, 1272–1278 (2005).

    ADS  CAS  Article  Google Scholar 

  4. 4.

    Rasch, B. & Born, J. About sleep’s role in memory. Physiol. Rev. 93, 681–766 (2013).

    CAS  Article  Google Scholar 

  5. 5.

    Tononi, G. & Cirelli, C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81, 12–34 (2014).

    CAS  Article  Google Scholar 

  6. 6.

    Winters, B. D., Forwood, S. E., Cowell, R. A., Saksida, L. M. & Bussey, T. J. Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe. J. Neurosci. 24, 5901–5908 (2004).

    CAS  Article  Google Scholar 

  7. 7.

    Winters, B. D., Saksida, L. M. & Bussey, T. J. Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci. Biobehav. Rev. 32, 1055–1070 (2008).

    Article  Google Scholar 

  8. 8.

    Oliveira, A. M., Hawk, J. D., Abel, T. & Havekes, R. Post-training reversible inactivation of the hippocampus enhances novel object recognition memory. Learn. Mem. 17, 155–160 (2010).

    Article  Google Scholar 

  9. 9.

    Eichenbaum, H. A cortical-hippocampal system for declarative memory. Nat. Rev. Neurosci. 1, 41–50 (2000).

    CAS  Article  Google Scholar 

  10. 10.

    McClelland, J. L., McNaughton, B. L. & O’Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995).

    Article  Google Scholar 

  11. 11.

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

    CAS  Article  Google Scholar 

  12. 12.

    King, B. R., Hoedlmoser, K., Hirschauer, F., Dolfen, N. & Albouy, G. Sleeping on the motor engram: the multifaceted nature of sleep-related motor memory consolidation. Neurosci. Biobehav. Rev. 80, 1–22 (2017).

    Article  Google Scholar 

  13. 13.

    Diekelmann, S. & Born, J. The memory function of sleep. Nat. Rev. Neurosci. 11, 114–126 (2010).

    CAS  Article  Google Scholar 

  14. 14.

    Lewis, P. A. & Durrant, S. J. Overlapping memory replay during sleep builds cognitive schemata. Trends Cogn. Sci. 15, 343–351 (2011).

    Article  Google Scholar 

  15. 15.

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

    ADS  CAS  Article  Google Scholar 

  16. 16.

    Rasch, B., Büchel, C., Gais, S. & Born, J. Odor cues during slow-wave sleep prompt declarative memory consolidation. Science 315, 1426–1429 (2007).

    ADS  CAS  Article  Google Scholar 

  17. 17.

    Latchoumane, C. V., Ngo, H. V., Born, J. & Shin, H. S. Thalamic spindles promote memory formation during sleep through triple phase-locking of cortical, thalamic, and hippocampal rhythms. Neuron 95, 424–435.e6 (2017).

    CAS  Article  Google Scholar 

  18. 18.

    Seibt, J. et al. Cortical dendritic activity correlates with spindle-rich oscillations during sleep in rodents. Nat. Commun. 8, 684 (2017).

    ADS  Article  Google Scholar 

  19. 19.

    Ramanathan, D. S., Gulati, T. & Ganguly, K. Sleep-dependent reactivation of ensembles in motor cortex promotes skill consolidation. PLoS Biol. 13, e1002263 (2015).

    Article  Google Scholar 

  20. 20.

    Li, W., Ma, L., Yang, G. & Gan, W. B. REM sleep selectively prunes and maintains new synapses in development and learning. Nat. Neurosci. 20, 427–437 (2017).

    CAS  Article  Google Scholar 

  21. 21.

    Brown, M. W. & Aggleton, J. P. Recognition memory: what are the roles of the perirhinal cortex and hippocampus? Nat. Rev. Neurosci. 2, 51–61 (2001).

    CAS  Article  Google Scholar 

  22. 22.

    Inostroza, M., Binder, S. & Born, J. Sleep-dependency of episodic-like memory consolidation in rats. Behav. Brain Res. 237, 15–22 (2013).

    Article  Google Scholar 

  23. 23.

    Oyanedel, C. N. et al. Role of slow oscillatory activity and slow wave sleep in consolidation of episodic-like memory in rats. Behav. Brain Res. 275, 126–130 (2014).

    Article  Google Scholar 

  24. 24.

    Broadbent, N. J., Gaskin, S., Squire, L. R. & Clark, R. E. Object recognition memory and the rodent hippocampus. Learn. Mem. 17, 5–11 (2009).

    Article  Google Scholar 

  25. 25.

    van de Ven, G. M., Trouche, S., McNamara, C. G., Allen, K. & Dupret, D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples. Neuron 92, 968–974 (2016).

    Article  Google Scholar 

  26. 26.

    Albouy, G. et al. Maintaining vs. enhancing motor sequence memories: respective roles of striatal and hippocampal systems. Neuroimage 108, 423–434 (2015).

    Article  Google Scholar 

  27. 27.

    de Lima, M. N., Luft, T., Roesler, R. & Schröder, N. Temporary inactivation reveals an essential role of the dorsal hippocampus in consolidation of object recognition memory. Neurosci. Lett. 405, 142–146 (2006).

    Article  Google Scholar 

  28. 28.

    Rossato, J. I. et al. On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory. Learn. Mem. 14, 36–46 (2007).

    Article  Google Scholar 

  29. 29.

    Kim, J. M., Kim, D. H., Lee, Y., Park, S. J. & Ryu, J. H. Distinct roles of the hippocampus and perirhinal cortex in GABAA receptor blockade-induced enhancement of object recognition memory. Brain Res. 1552, 17–25 (2014).

    CAS  Article  Google Scholar 

  30. 30.

    Cohen, S. J. & Stackman, R. W. Jr Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285, 105–117 (2015).

    Article  Google Scholar 

  31. 31.

    Squire, L. R., Wixted, J. T. & Clark, R. E. Recognition memory and the medial temporal lobe: a new perspective. Nat. Rev. Neurosci. 8, 872–883 (2007).

    CAS  Article  Google Scholar 

  32. 32.

    O’Neill, J., Pleydell-Bouverie, B., Dupret, D. & Csicsvari, J. Play it again: reactivation of waking experience and memory. Trends Neurosci. 33, 220–229 (2010).

    Article  Google Scholar 

  33. 33.

    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).

    CAS  Article  Google Scholar 

  34. 34.

    Chen, L., Tian, S. & Ke, J. Rapid eye movement sleep deprivation disrupts consolidation but not reconsolidation of novel object recognition memory in rats. Neurosci. Lett. 563, 12–16 (2014).

    CAS  Article  Google Scholar 

  35. 35.

    Brown, M. W., Barker, G. R., Aggleton, J. P. & Warburton, E. C. What pharmacological interventions indicate concerning the role of the perirhinal cortex in recognition memory. Neuropsychologia 50, 3122–3140 (2012).

    CAS  Article  Google Scholar 

  36. 36.

    Piterkin, P., Cole, E., Cossette, M. P., Gaskin, S. & Mumby, D. G. A limited role for the hippocampus in the modulation of novel-object preference by contextual cues. Learn. Mem. 15, 785–791 (2008).

    Article  Google Scholar 

  37. 37.

    Bergmann, T. O., Mölle, M., Diedrichs, J., Born, J. & Siebner, H. R. Sleep spindle-related reactivation of category-specific cortical regions after learning face-scene associations. Neuroimage 59, 2733–2742 (2012).

    Article  Google Scholar 

  38. 38.

    Chauvette, S., Seigneur, J. & Timofeev, I. Sleep oscillations in the thalamocortical system induce long-term neuronal plasticity. Neuron 75, 1105–1113 (2012).

    CAS  Article  Google Scholar 

  39. 39.

    Lisman, J. et al. Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat. Neurosci. 20, 1434–1447 (2017).

    CAS  Article  Google Scholar 

  40. 40.

    Miller, K. J., Botvinick, M. M. & Brody, C. D. Dorsal hippocampus contributes to model-based planning. Nat. Neurosci. 20, 1269–1276 (2017).

    CAS  Article  Google Scholar 

  41. 41.

    Pack, A. I. et al. Novel method for high-throughput phenotyping of sleep in mice. Physiol. Genomics 28, 232–238 (2007).

    CAS  Article  Google Scholar 

  42. 42.

    Neckelmann, D., Olsen, O. E., Fagerland, S. & Ursin, R. The reliability and functional validity of visual and semiautomatic sleep/wake scoring in the Møll-Wistar rat. Sleep 17, 120–131 (1994).

    CAS  Article  Google Scholar 

  43. 43.

    Dix, S. L. & Aggleton, J. P. Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition. Behav. Brain Res. 99, 191–200 (1999).

    CAS  Article  Google Scholar 

  44. 44.

    Chambon, C., Wegener, N., Gravius, A. & Danysz, W. A new automated method to assess the rat recognition memory: validation of the method. Behav. Brain Res. 222, 151–157 (2011).

    Article  Google Scholar 

  45. 45.

    Ozawa, T., Yamada, K. & Ichitani, Y. Long-term object location memory in rats: effects of sample phase and delay length in spontaneous place recognition test. Neurosci. Lett. 497, 37–41 (2011).

    CAS  Article  Google Scholar 

  46. 46.

    Goshen, I. et al. Dynamics of retrieval strategies for remote memories. Cell 147, 678–689 (2011).

    CAS  Article  Google Scholar 

  47. 47.

    Allen, T. A. et al. Imaging the spread of reversible brain inactivations using fluorescent muscimol. J. Neurosci. Methods 171, 30–38 (2008).

    CAS  Article  Google Scholar 

  48. 48.

    Bonnevie, T. et al. Grid cells require excitatory drive from the hippocampus. Nat. Neurosci. 16, 309–317 (2013).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank I. Sauter for technical support and E. Coffey and E. Bolinger for proof reading. This study was supported by a grant from the Deutsche Forschungsgemeinschaft (Tr-SFB 654). A.S. received a scholarship from the Development and Promotion of Science and Technology Talented Project (DPST), Thailand.

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Nature thanks J. Csicsvari, S. Ramirez and R. Stickgold for their contribution to the peer review of this work.

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A.S., J.B. and M.I. planned and designed the experiments and wrote the manuscript. A.S. and C.S. performed the experiments and the histology. A.S., C.N.O. and N.N. analysed the data. All authors approved the final version of the paper.

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Correspondence to Jan Born or Marion Inostroza.

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Extended data figures and tables

Extended Data Fig. 1 Control measures for NOR and OPR task performance.

Total object exploration (s), total distance travelled (m) and average speed (m s−1) at retrieval testing. Mean values (± s.e.m., dot plots overlaid) for the first 1 and 3 min and for the entire 5 min of the retrieval phase are shown. a, Results from main experiments of NOR and OPR memory as illustrated in Fig. 1. Retrieval was tested either immediately after the 2-h retention interval (recent) or 1 week or (for the NOR task only) 3 weeks later (remote). In a supplementary experiment, NOR was tested 2 weeks after encoding (offset downwards). Red, sleep; grey, wake; n = 12, 8, 8 and 11 rats for NOR testing after 2 h and 1, 2 and 3 weeks, and n = 11 and 9 rats for OPR testing after 2 h and 1 week, respectively. b, Results from experiments after bilateral intrahippocampal infusion of muscimol as in Fig. 2. Top, muscimol (versus vehicle, grey bars, n = 8 rats) was infused either during the 2-h post-encoding interval (upon first occurrence of SWS, red bars, n = 8 rats) or 15 min before retrieval (blue bars, n = 9 rats) with the retrieval phase taking place 3 weeks after encoding. Bottom, control studies. Left, muscimol (purple, n = 7 rats) was infused shortly after encoding while the rats remained awake during the 2-h post-encoding interval, compared with untreated wake control rats (n = 8 rats, empty bars). Retrieval was tested 1 week after encoding (corresponding to Fig. 2b). Right, muscimol (blue bars, versus vehicle, grey bars) was infused either 15 min before retrieval testing (n = 12 rats) or 15 min before encoding (n = 6 rats) with the retrieval phase taking place 30 min after encoding (corresponding to Fig. 2c). There were no significant differences between sleep and wake or between muscimol and vehicle conditions (P > 0.194, for all comparisons based on ANOVA and two-sided post hoc t-tests, see Methods and Figs. 1, 2 for further details).

Source Data

Extended Data Fig. 2 Performance in recent and remote tests for NOR and OPR tasks.

Memory is indicated by mean ± s.e.m. discrimination ratios during the first 1 min, first 3 min, and entire 5 min of the retrieval phase on the NOR and OPR tasks (dot plots overlaid). a, NOR was tested with 2-h (recent) and with 1-week and 3-week (remote) retrieval tests. b, OPR was tested with 2-h (recent) and 1-week retrieval tests. Whereas OPR memory benefited from sleep (red bars; compared to wake, grey) at both recent and remote (1 week) retrieval tests, NOR benefited from sleep only at the 3-week retrieval test, when NOR memory had decayed in the wake condition. c, A supplementary experiment with NOR retrieval tested 2 weeks after post-encoding sleep and wake intervals showed that NOR memory in the wake condition had already faded at this 2-week point, whereas it was preserved in the sleep condition (F1,7 = 14.997, P = 0.006, for sleep/wake main effect; F1,14 = 18.151, P = 0.01 and F1,14 = 0.82, P = 0.382, for 1 versus 2-week comparisons in the wake and sleep conditions, respectively, F1,14 = 12.073, P = 0.005, for 1/2 weeks × sleep/wake interaction; P > 0.222 for all comparisons between 2- and 3-week retrieval). In all experiments, recognition memory was assessed by the discrimination ratios during the first 1 and first 3 min of the retrieval period, which typically cover exploration of novelty most sensitively on both the NOR and OPR tasks6,43,44,45. With extended exploration periods, the novelty response often decreases and is thought to become more noisy. Hence, here, the 5-min values were not used for the assessment of recognition memory. n = 12, 8, 11 and 8 rats for NOR testing at 2 h, 1 week, 3 weeks and 2 weeks; n = 11 and 9 rats for OPR testing at 2 h and 1 week, respectively. +++P < 0.001, ++P < 0.01, +P < 0.05 for one-sample t-test against chance level; ***P < 0.001, *P < 0.05 for pairwise t-tests (two-sided) between sleep and wake conditions.

Source Data

Extended Data Fig. 3 Performance on NOR task for hippocampal inactivation studies.

Memory is indicated by mean ± s.e.m. discrimination ratios during the first 1 min, first 3 min, and entire 5 min of the retrieval phase on the NOR task in experiments involving reversible inactivation of the hippocampus (dot plots overlaid). a, Muscimol (red bars, n = 8 rats, versus vehicle, grey bars, n = 8 rats) was infused into the hippocampus in the post-encoding interval upon the first occurrence of continuous SWS, or 15 min before retrieval testing (blue bars, n = 9 rats). Retrieval was tested 3 weeks after encoding. b, Control study in which muscimol (purple bars, n = 7 rats) was infused shortly after encoding while the rats remained awake during the 2-h post-encoding interval, compared with untreated wake control rats (n = 8 rats, empty bars). Retrieval was tested 1 week after encoding. Infusion of muscimol during post-encoding wakefulness tended to enhance NOR performance, which suggests that during wakefulness hippocampal activity normally interferes with NOR memory consolidation8. It might also reflect compensatory plasticity occurring in extrahippocampal regions upon hippocampal suppression46. c, Control studies in which muscimol (blue bars, versus vehicle, grey bars) was infused 15 min before retrieval testing of recent NOR memory (left, n = 12 rats for each substance condition) or 15 min before the encoding phase (right, n = 6 rats for each substance condition). Retrieval was tested 30 min after encoding, with the rats staying awake during this interval. +++P < 0.001, ++P < 0.01, +P < 0.05 for one-sample t-test against chance level; **P < 0.01, *P < 0.05 for pairwise t-tests (two-sided) between conditions. See Fig. 2 for further details.

Source Data

Extended Data Fig. 4 Remote 3-week OPR testing.

OPR memory was tested in n = 6 rats, 3 weeks after a 2-h post-encoding sleep interval. These supplementary experiments followed the same procedures as described for the 1-week sleep condition on the OPR task, but included sleep EEG recordings. a, OPR memory is indicated by the mean ± s.e.m. discrimination ratio during the first 1 min and 3 min of exploration. +P = 0.034, for one-sample t-test against chance level. Rats displayed significant OPR memory after 3 min (as well as for the whole 5-min exploration period). b, OPR performance (discrimination ratio at 1 min) at the 3-week retrieval test was correlated with sleep spindle duration during the first 30 min of post-encoding sleep (*P = 0.029, Pearson’s product–moment correlation). A similar correlation with NOR performance at the 3-week retrieval (Fig. 3a) points towards a similar mechanism underlying the formation of long-term NOR and OPR memory during sleep.

Source Data

Extended Data Fig. 5 Verification of cannula location and muscimol spreading.

a, Coronal brain section showing location of cannula in the dorsal hippocampus (black arrow) together with position of guide cannula in overlying cortex. b, Coronal brain section showing spread of muscimol (red) after infusion into the hippocampus. Experiments were repeated in n = 3 rats with similar results. The infusion protocol was the same as in the behavioural experiments. In brief, after implantation of the guide cannula in the dorsal hippocampus, animals were infused using the injection cannulae with 0.5 µl fluorophore-conjugated muscimol47,48. After infusion, animals were intracardially perfused and brains were post-fixed with PFA 4% for 24 h. Brains were cut on a vibratome to obtain 70-µm-thick sections and stained with DAPI (1:5,000 µl in PBS) for 15 min. Fluorescent images were acquired by epifluorescence microscopy (Axio imager Zeiss, Germany). Scale bars, 1 mm.

Extended Data Table 1 Sleep parameters
Extended Data Table 2 Correlations between NOR after 3 weeks and sleep parameters

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Sawangjit, A., Oyanedel, C.N., Niethard, N. et al. The hippocampus is crucial for forming non-hippocampal long-term memory during sleep. Nature 564, 109–113 (2018). https://doi.org/10.1038/s41586-018-0716-8

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Keywords

  • Object Place Recognition (OPR)
  • Muscimol
  • Hippocampus-dependent Memory
  • Remote Testing
  • Discrimination Ratio

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