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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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.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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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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