Infantile amnesia reflects a developmental critical period for hippocampal learning

  • An Erratum to this article was published on 01 July 2017

Abstract

Episodic memories formed during the first postnatal period are rapidly forgotten, a phenomenon known as 'infantile amnesia'. In spite of this memory loss, early experiences influence adult behavior, raising the question of which mechanisms underlie infantile memories and amnesia. Here we show that in rats an experience learned during the infantile amnesia period is stored as a latent memory trace for a long time; indeed, a later reminder reinstates a robust, context-specific and long-lasting memory. The formation and storage of this latent memory requires the hippocampus, follows a sharp temporal boundary and occurs through mechanisms typical of developmental critical periods, including the expression switch of the NMDA receptor subunits from 2B to 2A, which is dependent on brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptor 5 (mGluR5). Activating BDNF or mGluR5 after training rescues the infantile amnesia. Thus, early episodic memories are not lost but remain stored long term. These data suggest that the hippocampus undergoes a developmental critical period to become functionally competent.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Latent infantile memories are rapidly forgotten but reinstate later in life with reminders.
Figure 2: The latent infantile memory trace is hippocampus dependent.
Figure 3: Training at PN17 increases pTrkB and switches the ratio of GluN2B/GluN2A levels in the dorsal hippocampus.
Figure 4: BDNF is required for the formation of the latent infantile memory and for the GluN2B/GluN2A switch.
Figure 5: GluN2B- and mGluR5-dependent switch of GluN2B/GluN2A is required to form the latent infantile memory.
Figure 6: BDNF closes the infantile amnesia period.

Change history

  • 29 August 2016

    In the version of this article initially published, y-axis labels in Figures 3a,b, 4c, 5d and 6c report the “GluN2B/GluN2A ratio”; this should be changed to “GluN2A/GluN2B ratio.” The error has been corrected in the HTML and PDF versions of the article.

  • 01 July 2017

    Nat. Neurosci. 19, 1225–1233 (2016); published online 18 July 2016; corrected after print 29 August 2016 In the version of this article initially published, y-axis labels in Figures 3a,b, 4c, 5d and 6c report the “GluN2B/GluN2A ratio”; this should be “GluN2A/GluN2B ratio.” The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Campbell, B.A. & Spear, N.E. Ontogeny of memory. Psychol. Rev. 79, 215–236 (1972).

    CAS  Article  Google Scholar 

  2. 2

    Hayne, H. Infant memory development: implications for childhood amnesia. Dev. Rev. 24, 33–73 (2004).

    Article  Google Scholar 

  3. 3

    Rovee-Collier, C. The development of infant memory. Curr. Dir. Psychol. Sci. 8, 80–85 (1999).

    Article  Google Scholar 

  4. 4

    Heim, C. & Nemeroff, C.B. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol. Psychiatry 49, 1023–1039 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Dumas, T.C. & Rudy, J.W. Development of the hippocampal memory system: creating networks and modifiable synapses. in Oxford Handbook of Developmental Behavioral Neuroscience (eds. Blumberg, M.S., Freeman, J.H. & Robinson, S.R.) (Oxford, 2010).

  6. 6

    Nelson, C.A. Neural plasticity in human development: the role of early experience in sculpting memory systems. Dev. Sci. 3, 115–136 (2000).

    Article  Google Scholar 

  7. 7

    Akers, K.G. et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 344, 598–602 (2014).

    CAS  Article  Google Scholar 

  8. 8

    Callaghan, B.L., Li, S. & Richardson, R. The elusive engram: what can infantile amnesia tell us about memory? Trends Neurosci. 37, 47–53 (2014).

    CAS  Article  Google Scholar 

  9. 9

    Kim, J.H., McNally, G. & Richardson, R. Recovery of fear memories in rats: role of gamma-amino butyric acid (GABA) in infantile amnesia. Behav. Neurosci. 120, 40–48 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Campbell, B.A. & Jaynes, J. Reinstatement. Psychol. Rev. 73, 478–480 (1966).

    CAS  Article  Google Scholar 

  11. 11

    Spear, N.E. & Parsons, P.J. Analysis of a reactivation treatment: ontogenetic determinants of alleviated forgetting. in Processes in Animal Memory (eds. Medin, D.L., Roberts, W.A. & Davis, R.T.) 135–165 (Lawrence Erlbaum Associates, 1976).

  12. 12

    Haroutunian, V. & Riccio, D.C. Effect of arousal conditions during reinstatement treatment upon learned fear in young rats. Dev. Psychobiol. 10, 25–32 (1977).

    CAS  Article  Google Scholar 

  13. 13

    Davis, J.M. & Rovee-Collier, C.K. Alleviated forgetting of a learned contingency in 8-week-old infants. Dev. Psychol. 19, 353–365 (1983).

    Article  Google Scholar 

  14. 14

    Campbell, B.A. & Campbell, E.H. Retention and extinction of learned fear in infant and adult rats. J. Comp. Physiol. Psychol. 55, 1–8 (1962).

    CAS  Article  Google Scholar 

  15. 15

    Rudy, J.W. & Morledge, P. Ontogeny of contextual fear conditioning in rats: implications for consolidation, infantile amnesia, and hippocampal system function. Behav. Neurosci. 108, 227–234 (1994).

    CAS  Article  Google Scholar 

  16. 16

    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 

  17. 17

    Chen, D.Y., Bambah-Mukku, D., Pollonini, G. & Alberini, C.M. Glucocorticoid receptors recruit the CaMKIIα-BDNF-CREB pathways to mediate memory consolidation. Nat. Neurosci. 15, 1707–1714 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Raineki, C. et al. Functional emergence of the hippocampus in context fear learning in infant rats. Hippocampus 20, 1037–1046 (2010).

    Article  Google Scholar 

  19. 19

    Foster, J.A. & Burman, M.A. Evidence for hippocampus-dependent contextual learning at postnatal day 17 in the rat. Learn. Mem. 17, 259–266 (2010).

    Article  Google Scholar 

  20. 20

    Robinson-Drummer, P.A. & Stanton, M.E. Using the context preexposure facilitation effect to study long-term context memory in preweanling, juvenile, adolescent, and adult rats. Physiol. Behav. 148, 22–28 (2015).

    CAS  Article  Google Scholar 

  21. 21

    Minichiello, L. TrkB signaling pathways in LTP and learning. Nat. Rev. Neurosci. 10, 850–860 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Morris, R.G., Anderson, E., Lynch, G.S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).

    CAS  Article  Google Scholar 

  23. 23

    Tsien, J.Z., Huerta, P.T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996).

    CAS  Article  Google Scholar 

  24. 24

    Constantine-Paton, M., Cline, H.T. & Debski, E. Patterned activity, synaptic convergence, and the NMDA receptor in developing visual pathways. Annu. Rev. Neurosci. 13, 129–154 (1990).

    CAS  Article  Google Scholar 

  25. 25

    Sans, N. et al. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383–400 (2013).

    CAS  Article  Google Scholar 

  27. 27

    Hensch, T.K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Bellone, C. & Nicoll, R.A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55, 779–785 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992).

    CAS  Article  Google Scholar 

  30. 30

    Quinlan, E.M., Philpot, B.D., Huganir, R.L. & Bear, M.F. Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nat. Neurosci. 2, 352–357 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Philpot, B.D., Sekhar, A.K., Shouval, H.Z. & Bear, M.F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Caldeira, M.V. et al. BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Mol. Cell. Neurosci. 35, 208–219 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Yashiro, K. & Philpot, B.D. Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55, 1081–1094 (2008).

    CAS  Article  Google Scholar 

  35. 35

    Matta, J.A., Ashby, M.C., Sanz-Clemente, A., Roche, K.W. & Isaac, J.T. mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch. Neuron 70, 339–351 (2011).

    CAS  Article  Google Scholar 

  36. 36

    Huang, Z.J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Gianfranceschi, L. et al. Visual cortex is rescued from the effects of dark rearing by overexpression of BDNF. Proc. Natl. Acad. Sci. USA 100, 12486–12491 (2003).

    CAS  Article  Google Scholar 

  38. 38

    Schulenburg, C.J., Riccio, D.C. & Stikes, E.R. Acquisition and retention of a passive-avoidance response as a function of age in rats. J. Comp. Physiol. Psychol. 74, 75–83 (1971).

    CAS  Article  Google Scholar 

  39. 39

    Balsam, P.D., Drew, M.R. & Gallistel, C.R. Time and associative learning. Comp. Cogn. Behav. Rev. 5, 1–22 (2010).

    Article  Google Scholar 

  40. 40

    Cull-Candy, S., Brickley, S. & Farrant, M. NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11, 327–335 (2001).

    CAS  Article  Google Scholar 

  41. 41

    Gambrill, A.C. & Barria, A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc. Natl. Acad. Sci. USA 108, 5855–5860 (2011).

    CAS  Article  Google Scholar 

  42. 42

    Dumas, T.C. Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning. Prog. Neurobiol. 76, 189–211 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138–145 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Castrén, M.L. & Castrén, E. BDNF in fragile X syndrome. Neuropharmacology 76, 729–736 (2014).

    Article  Google Scholar 

  45. 45

    Greenough, W.T., Black, J.E. & Wallace, C.S. Experience and brain development. Child Dev. 58, 539–559 (1987).

    CAS  Article  Google Scholar 

  46. 46

    Nelson, C.A. III et al. Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science 318, 1937–1940 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Anand, K.J., Coskun, V., Thrivikraman, K.V., Nemeroff, C.B. & Plotsky, P.M. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol. Behav. 66, 627–637 (1999).

    CAS  Article  Google Scholar 

  48. 48

    Zhao, M.G. et al. Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron 47, 859–872 (2005).

    CAS  Article  Google Scholar 

  49. 49

    Qi, C. et al. mGluR5 in the nucleus accumbens shell regulates morphine-associated contextual memory through reactive oxygen species signaling. Addict. Biol. 20, 927–940 (2015).

    CAS  Article  Google Scholar 

  50. 50

    Rudy, J.W. & Matus-Amat, P. DHPG activation of group 1 mGluRs in BLA enhances fear conditioning. Learn. Mem. 16, 421–425 (2009).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank G. Pollonini for technical assistance. We thank P. Magistretti, F. Ansermet, K. Weiss, P. Balsam, X. Ye, F. Fiumara and G. Philips for discussions or comments on the manuscript. This work was supported by R01-MH074736 and an Agalma Foundation grant to C.M.A. and R01 NS072359 to R.D.B. A.T. was supported by a fellowship from Agalma Foundation. R.B. was supported by a fellowship from the Swiss National Science Foundation.

Author information

Affiliations

Authors

Contributions

C.M.A. led the design and development of the study and the writing of the manuscript; R.D.B, designed the electrophysiology study; A.T., R.B., E.S.S., R.D.B. and C.M.A. designed experiments and analyzed data; A.T. carried out behavioral experiments and the majority of molecular and pharmacological experiments; R.B. carried out behavioral experiments and contributed to molecular and pharmacological experiments; E.S.S. carried out electrophysiology experiments; and A.T., E.S.S., R.D.B. and C.M.A. wrote the manuscript.

Corresponding author

Correspondence to Cristina M Alberini.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Short- and long-term memory retentions of adult rats.

Experimental schedule is shown above each panel. Acquisition (Acq.) and memory retention are expressed as mean latency ± s.e.m. (in seconds, s). (a) Mean latency ± s.e.m. of naïve and rats trained at PN80 (adults) and tested: (a) 30min (T1) and 1d after training (T2) [n= 11, 10, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(1,38)= 98.74, P< 0.0001. Testing F(1,38)= 3.718, P=0.0613, Interaction F(1,38)=3.894, P=0.0558; 3 independent experiments], and (b) 1d (T1) and 7d after training (T2) [n=5, 6, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(1,18)= 121.1, P< 0.0001,Testing F(1,18)= 0.2594, P= 0.6167, Interaction F(1,18)= 0.2921, P= 0.5955; 2 independent experiments]. ***P < 0.001. Latency score in Supplementary Table 10.

Supplementary Figure 2 Nociception of naive PN17 and PN24 rats.

Escape latency is expressed as mean ± s.e.m. (in seconds, s). Pain threshold in infant rats was measured by the escape latency to withdrawal from a 53 ± 1°C hotplate. The escape latency was averaged from four sessions, with an inter-session interval of 15-min. Student’s t-test revealed no significant difference between PN17 (10.1±0.8 seconds, n=6) and PN24 rats (8.2±0.9 seconds, n=6) (two-tailed t test, t =1.562, df=10, P=0.7028).

Supplementary Figure 3 Effect of training or shock-only on rat weight gain.

Gain weight compared to the weight taken immediately before training is expressed as mean ± s.e.m. (in grams, g). Training and shock-only at (a) PN17 [n= 8, 8, 8, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(2,42)= 1.332, P>0.05, Testing F(1,42)= 2515, P<0.0001, Interaction F(1,42)= 1.656, P>0.05; 3 independent experiments] or (b) PN24 [n= 8, 8, 8, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(2,42)= 0.4406, P>0.05, Testing F(1,42)= 801.7, P<0.0001, Interaction F(1,42)= 0.3349, P>0.05; 3 independent experiments] did not alter the average gain weight measured 1 d and 7 d later. Numeric values in Supplementary Table 11.

Supplementary Figure 4 The unpaired context–shock protocol failed to reinstate memory.

Experimental schedule is shown above the panel. Acquisition (Acq.) and memory retention are expressed as mean latency ± s.e.m. (in seconds, s). In the unpaired protocol, rats were exposed to the IA context similarly to the trained rats but did not receive a footshock in the dark chamber. They were returned to their home cage and, one hour later, were placed directly onto the grid floor of the dark chamber and immediately shocked (1.0 mA). The unpaired protocol failed to reinstate memory (n=8, 8, Two–way ANOVA followed by Bonferroni post hoc, Condition F(1.56,)=1.901, P=0.1735, Testing F(3,56)=4.720, P=0.0053, Interaction F(3,56)=1.245, P=0.3021; 3 independent experiments). Latency score in Supplementary Table 12.

Supplementary Figure 5 Memory reinstatement following different time intervals between test and reminder shock.

Experimental schedule is shown above the panel. Acquisition (Acq.) and memory retention are expressed as mean latency ± s.e.m. (in seconds, s). Mean latency ± s.e.m. of naïve, shock-only and rats trained at PN17, tested 7d later (T1) and given a reminder shock (RS) 4h, 1d or 7d after the test (T1). Memory retention was tested 1d (T2) and 7d (T3) after RS, and, 4d later, in a new context (NC) [n= 11, 13, 11, 11, 11, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(4,208)=18.27, P<0.0001, Testing F(3,208)=26.93, P<0.0001, Interaction F(12,208)=4.269, P<0.0001; 3 independent experiments]. Latency score in Supplementary Table 13.

Supplementary Figure 6 Hippocampal molecular changes either in untrained (naïve) conditions or following IA training at PN17 or PN24.

(a) Representative examples and densitometric western blot analyses of dorsal hippocampal total extracts from naïve rats euthanized at PN17, PN24 or PN80 (adult) (n=8, 8, 8). Data are expressed as mean percentage ± s.e.m. of adult naïve rats [One–way ANOVA followed by Newman-Keuls Multiple Comparison Test, TrkB F(2,21)= 0.6080, P=0.5537; GluN1 F(2,21)= 0.1954, P=0.8240, 3 independent experiments]. (b-c) Representative examples and densitometric western blot analyses of dHC total extracts from rats trained in IA at (b) PN17 or (c) PN24, and euthanized 30min, 9h, 24h or 48h after training (n=6-10/group). To account for developmental differences, two groups of naïve were used [(b) PN17 and PN19 or (c) PN24 and PN26]. Data are expressed as mean percentage ± s.e.m. of (b) PN17 [n= 8, 6, 10, 7, 6, 6, One–way ANOVA followed by Dunnett's Multiple Comparison Test, TrkB F(3,27)= 0.1618, P= 0.9211; GluN1 F(3,27)= 0.08967, P= 0.9650; 3 independent experiments] or (c) PN24 naïve rats [n=8, 6, 6, 7, 7, 8, One–way ANOVA followed by Dunnett's Multiple Comparison Test, TrkB F(3,23)= 0.06099, P= 0.9798; GluN1 F(3,23)= 0.2067, P= 0.8907; 3 independent experiments]. The numeric values are reported in Supplementary Table 3.

Supplementary Figure 7 Hippocampal molecular changes after shock- or context-only.

Densitometry of western blot analyses of dorsal hippocampal total extracts from rats euthanized 24 hours after (a) receiving a footshock immediately after being placed on a shock grid (shock-only) [n= 7, 7, Unpaired two-tailed Student’s t-test, pTrkB t=0.3263 df=12, P = 0.7498; GluN2A t=0.5967 df=12, P = 0.5618l; GluN2B t=0.1414 df=12, P = 0.8899; 2 independent experiments] or (b) exposed to the IA context without receiving the footshock (context-only) [n= 7, 7, Unpaired two-tailed Student’s t-test, pTrkB t=0.5199 df=12, P = 0.6126; GluN2A t=0.6308 df=12, P = 0.5400; GluN2B t=0.4679 df=12 P = 0.6482; 2 independent experiment]. Data are expressed as mean percentage ± s.e.m. of naive rats euthanized at the matched time point (i.e. PN18). The numeric values are reported in Supplementary Table 14.

Supplementary Figure 8 Hippocampal molecular changes after memory reinstatement.

Experimental schedule is shown above the panel. Densitometric western blot analyses of dorsal hippocampal total extracts obtained from rats trained (Tr) at PN17, 7 days later exposed to the reinstatement protocol [test (T1) and 2d later reminder shock (RS)] and euthanized 30min or 24 hours later. Data are expressed as mean percentage ± s.e.m. of rats trained at PN17, tested (T1) but not exposed to RS and euthanized at the matched time point [n=6/group, One–way ANOVA followed by Newman-Keuls Multiple Comparison Test, pTrkB F(2,17)= 0.27, P=0.77; GluN2A F(2,17)= 0.72, P=0.50; GluN2B F(2,17)= 0.08, P=0.82; 2 independent experiment). The numeric values are reported in Supplementary Table 15.

Supplementary Figure 9 Full-length pictures of the blots presented in the main figures.

Supplementary Figure 10 Full-length pictures of the blots presented in the main figures

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Travaglia, A., Bisaz, R., Sweet, E. et al. Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat Neurosci 19, 1225–1233 (2016). https://doi.org/10.1038/nn.4348

Download citation

Further reading