Recovery of learning and memory is associated with chromatin remodelling

Abstract

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.

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Figure 1: Environmental enrichment reinstates learning in CK-p25 Tg mice after neurodegeneration.
Figure 2: Environmental enrichment re-establishes access to long-term memories.
Figure 3: Environmental enrichment induces chromatin modifications, and histone-deacetylase inhibitors facilitate learning behaviour.
Figure 4: Sodium butyrate facilitates learning and re-establishes the access to long-term memories in CK-p25 Tg mice.

References

  1. 1

    Andorfer, C. et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J. Neurosci. 25, 5446–5454 (2005)

    CAS  Article  Google Scholar 

  2. 2

    Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B. & Tsai, L. H. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825–838 (2005)

    CAS  Article  Google Scholar 

  4. 4

    Cruz, J. C. & Tsai, L. H. Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr. Opin. Neurobiol. 14, 390–394 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H. & Tsai, L. H. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483 (2003)

    CAS  Article  Google Scholar 

  6. 6

    Nithianantharajah, J. & Hannan, A. J. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nature Rev. Neurosci. 7, 697–709 (2006)

    CAS  Article  Google Scholar 

  7. 7

    Kim, J. J. & Fanselow, M. S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. Neuropsychiatry Clin. Neurosci. 2000 1, 103–113 (1957)

    Google Scholar 

  9. 9

    Bradshaw, J., Saling, M., Hopwood, M., Anderson, V. & Brodtmann, A. Fluctuating cognition in dementia with Lewy bodies and Alzheimer's disease is qualitatively distinct. J. Neurol. Neurosurg. Psychiatry 75, 382–387 (2004)

    CAS  Article  Google Scholar 

  10. 10

    Palop, J. J., Chin, J. & Mucke, L. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773 (2006)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Frankland, P. W., Bontempi, B., Talton, L. E., Kaczmarek, L. & Silva, A. J. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883 (2004)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Need, A. C. & Giese, K. P. Handling and environmental enrichment do not rescue learning and memory impairments in αCamKIIT286A mutant mice. Genes Brain Behav. 2, 132–139 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Tang, Y. P., Wang, H. S., Feng, M., Kyin, Y. Z. & Tsien, J. Z. Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology 41, 779–790 (2001)

    CAS  Article  Google Scholar 

  14. 14

    Rampon, C. et al. Effects of environmental enrichment on gene expression in the brain. Proc. Natl Acad. Sci. USA 97, 12880–12884 (2000)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Levenson, J. M. et al. Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 279, 40545–40559 (2004)

    CAS  Article  Google Scholar 

  16. 16

    Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005)

    CAS  Article  Google Scholar 

  17. 17

    Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004)

    CAS  Article  Google Scholar 

  18. 18

    Korzus, E., Rosenfeld, M. G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004)

    CAS  Article  Google Scholar 

  19. 19

    Li, R. W. & Li, C. Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells. BMC Genomics 14, 1–14 (2006)

    Google Scholar 

  20. 20

    Iacomino, G., Tecce, M. F., Grimaldi, C., Tosto, M. & Russo, G. L. Transcriptional response of a human colon adenocarcinoma cell line to sodium butyrate. Biochem. Biophys. Res. Commun. 285, 1280–1289 (2001)

    CAS  Article  Google Scholar 

  21. 21

    Tabuchi, Y. et al. Genetic networks responsive to sodium butyrate in colonic epithelial cells. FEBS Lett. 580, 3035–3041 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 217–218 (2005)

    Article  Google Scholar 

  23. 23

    Tsankova, N. M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neurosci. 9, 519–525 (2006)

    CAS  Article  Google Scholar 

  24. 24

    Voss, H. U. et al. Possible axonal regrowth in late recovery from the minimally conscious state. J. Clin. Invest. 116, 2005–2011 (2006)

    CAS  Article  Google Scholar 

  25. 25

    van Praag, H., Kempermann, G. & Gage, F. H. Neuronal consequences of environmental enrichment. Nature Rev. Neurosci. 1, 191–198 (2000)

    CAS  Article  Google Scholar 

  26. 26

    Horn, D., Ruppin, E., Usher, M. & Hermann, M. Neural network modeling of Alzheimer's Disease. Neural Comput. 5, 736–749 (1993)

    Article  Google Scholar 

  27. 27

    Ruppin, E., Reggia, J. A. & Horn, D. Pathogenesis of schizophrenic delusions and hallucinations: a neural model. Schizophr. Bull. 22, 105–123 (1996)

    CAS  Article  Google Scholar 

  28. 28

    Horn, D., Levy, N. & Ruppin, E. Neuronal-based synaptic compensation: a computational study in Alzheimer's disease. Neural Comput. 8, 1227–1243 (1996)

    CAS  Article  Google Scholar 

  29. 29

    Fischer, A., Sananbenesi, F., Schrick, C., Spiess, J. & Radulovic, J. Cyclin-dependent kinase 5 is required for associative learning. J. Neurosci. 22, 3700–3707 (2002)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank B. Samuels, M. Bear, M. Wilson, W. Fischle and A. Schwienhorst for reading the manuscript and critical discussion, and all members of the Tsai laboratory for advice. We also thank S. Eimer and K. Schwarze for technical help. L-H.T. is an investigator of Howard Hughes Medical Institute. This work is partially supported by an NIH grant to L-H.T. This work was also partially supported by a Humboldt fellowship to A.F. and a German research foundation (DFG) fellowship to F.S., and by funds from the ENI Goettingen to A.F. The ENI is jointly funded by the Medical School University Goettingen and the Max Planck Society.

Author Contributions The studies were conceived and designed by A.F. and L.-H.T. A.F., F.S., X.W. and M.D. contributed to the experiments in this work. The paper was written by A.F. and L.-H.T.

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Correspondence to Andre Fischer or Li-Huei Tsai.

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Fischer, A., Sananbenesi, F., Wang, X. et al. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007). https://doi.org/10.1038/nature05772

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