Remote Memory

Many events in our lives, whether they are personal or public, become etched in our memories. A fundamental question in memory research is how our brains are able to form these enduring memories—memories that can potentially last a lifetime. In humans, memories for facts, ideas and events (i.e., ‘declarative’ memories) initially depend on the temporal lobe system, including a brain region known as the hippocampus. Multidisciplinary approaches have helped us to elucidate many of the molecular and cellular mechanisms underlying the formation of these memories in hippocampal networks. However, as these memories mature they eventually become independent of the hippocampus, and are thought to become dependent on other brain regions such as the cortex. Our lab focuses on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.

Normal cortical plasticity is required for the formation of remote memories

During consolidation, the strengthening of cortico-cortical connections is thought to be crucial for cortical memories to gain independence from the hippocampus. Therefore, disrupting cortical plasticity should hinder the establishment of remote hippocampal-independent memories, and result in premature forgetting at extended retention delays. We tested this prediction using mice that are heterozygous for a null mutation of alpha-calcium/calmodulin kinase II (alpha-CaMKII +/- mice). These mice have global deficits in cortical plasticity, but normal hippocampal plasticity. Accordingly, they have normal memory at short retention delays (1-3 days), but pronounced forgetting at longer delays (10-50 days). These findings suggest that normal cortical plasticity is essential for the development of remote (hippocampal-independent) memories.

Activation of the anterior cingulate cortex following recall of remote contextual fear memory

To begin to identify which cortical regions support remote memory, we combined brain mapping, genetic and pharmacological approaches in mice. We examined the expression of activity-dependent genes (Zif268 , c-fos) following the recall of recent (1 day-old) or remote (36 day-old) contextual fear memories. The expression of these genes is tightly correlated with levels of neuronal activity and therefore can be used to track changes in the organization of memories at different times after learning. We found that patterns of brain activation were dramatically different at the two time points: The hippocampus was strongly activated only following recall of the recent (1 day-old) fear memory. In contrast, a number of different cortical regions (including the anterior cingulate cortex; ACC) were strongly activated only following recall of the remote (36 day-old) fear memory. Furthermore, activation of the ACC was absent in alpha-CaMKII +/- mice that are unable to form remote memories, and localized inactivation of the ACC specifically blocked remote memory. These data suggest that, as memories mature, there is a progressive recruitment of the ACC (as well as some other cortical regions), coupled with a gradual disengagement of the hippocampus.

The network properties of remote memory

Our studies show that recall of remote memories activates multiple cortical brain regions, suggesting that these memories are supported by a broad, distributed network of cortical regions. Currently we are using graph theoretical approaches to understand how the topology of this memory network affects its function.

Role of the ACC in expression of remote spatial memory

Our most recent studies have begun to explore whether the ACC plays a similar role in the expression of remote spatial memories. To address this question we have used the Morris water maze. Our experiments indicate that the ACC is activated following recall of remote spatial information, and that inactivation of the ACC specifically disrupts remote (but not recent) water maze memory. These data suggest that the ACC may play a conserved role in recall of remotely-learned material, regardless of content.

Publications on this topic:

  1. Santoro, A., Frankland, P.W.* and Richards, B.A.* (2016). Dual episodic and semantic control enhances reinforcement learning in dynamic environments. Journal of Neuroscience, 36, 12228-12242. *co-corresponding authors

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  2. Epp, J.R., Niibori, Y., Hsiang. H.-L., Mercaldo, V., Deisseroth, K., Josselyn, S.A. and Frankland, P.W. (2015). Optimization of CLARITY for clearing whole brain and other intact organs. eNeuro, 2(3) e0022-15.2015 1–15.

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  3. Josselyn, S.A., Kohler, S. and Frankland, P.W. (2015). Finding the engram. Nature Reviews Neuroscience, 16, 521-534.

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  4. Santoro, A. and Frankland, P.W. (2014). Chasing the trace. Neuron, 84, 243-245.

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  5. Richards, B.A., Xia, F., Husse, J., Santoro, A., Woodin, M.A., Josselyn, S.A. and Frankland, P.W. (2014). Patterns across multiple memories are identified over time. Nature Neuroscience, 17, 981-6.

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  6. Vousden, D., Epp, J., Okuno, H., Nieman, B.J., van Eede, M., Duzai, J., Ragan, J., Bito, H., Frankland, P.W., Lerch, J.P. and Henkelman, R.M. (2014). Whole brain mapping of behaviorally-induced neural activation in mice. Brain Structure and Function, 220, 2043-57.

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  7. Richards, B.A. and Frankland, P.W. (2013). The conjunctive trace. Hippocampus, 23, 207-212.

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  8. Wheeler, A.L., Lerch, J.P., Chakravarty, M.M., Friedel, M., Sled, J.G., Fletcher, P.J., Josselyn, S.A. and Frankland, P.W. (2013). Adolescent cocaine exposure causes enduring macroscale changes in brain structure. Journal of Neuroscience, 33, 1797-1803.

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  9. Wheeler, A.L., Teixeira, C.M., Wang, A.H., Xiong, X., Kovacevic, N., Lerch, J.P., McIntosh, A.R., Parkinson, J. & Frankland, P.W. (2013). Identification of a functional connectome for long-term fear memory in mice. PLoS Computational Biology, 9(1): e1002853. doi:10.1371/journal.pcbi.1002853.

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  10. Sekeres, M., Mercado, V., Richards, B.A., Sargin, D., Mahadevan, V., Woodin, M.A., Frankland, P.W. and Josselyn, S.A. (2012). Increasing CRTC1 function in the dentate gyrus during memory formation or reactivation increases memory strength without compromising memory quality. Journal of Neuroscience, 32, 17857-17868.

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  11. Cole C.J.*, Mercaldo V.*, Restivo L., Yiu A.P., Sekeres M.J., Han J.H., Vetere G., Ross P.J., Pekar T., Neve R.L., Frankland P.W. & Josselyn S.A. (2012). MEF2 negatively regulates learning-induced structural plasticity and memory formation. Nature Neuroscience, 15, 1255-64. doi: 10.1038/nn.3189. *equal contribution

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  12. Vetere, G., Restivo, L., Cole, C.J., Ross, P.J., Ammassari-Teule, M., Josselyn, S.A. and Frankland, P.W. (2011). MEF2-regulated spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory. Proceedings of the National Academy of Sciences, 108, 8456-60.

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  13. Lerch, J.P., Yiu, A.P., Martinez-Canabal, A., Pekar, T., Bohbot, V., Frankland, P.W., Henkelman, R.M., Josselyn, S.A., Sled, J.G. (2011). Maze training in mice induces MRI detectable brain shape changes specific to the type of learning. Neuroimage, 54, 2086-95.

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  14. Sekeres M.J., Neve R.L., Frankland P.W., Josselyn S.A. (2010). Dorsal hippocampal CREB is both necessary and sufficient for spatial memory. Learning & Memory, 17(6), 280-3.

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  15. Winocur, G., Frankland, P.W., Sekeres, M., Fogel, S. and Moscovitch, M. (2009). Manipulating context-specificity in a memory reconsolidation paradigm: Selective effects of hippocampal lesions. Learning & Memory, 16, 722-729.

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  16. Akers, K.G. & Frankland, P.W. (2009). Gradients graded: Evidence for time-dependent memory reorganization in experimental animals. Journal of Experimental Neuroscience, 2, 13-22.

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  17. Wang, S.H., Teixeira, C.M., Wheeler, A.L. and Frankland, P.W. (2009). The precision of remote contextual memories does not require the hippocampus. Nature Neuroscience, 12, 253-255.

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  18. Mamiya, N., H, Fukushima, H., Suzuki, A., Matsuyama, Z., Homma, S., Frankland, P.W., and Kida, S. (2009). Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory. Journal of Neuroscience, 29, 402-413.

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  19. Ding, H.K., Teixeira, C.M. and Frankland, P.W. (2008). Inactivation of the anterior cingulate cortex blocks expression of remote, but not recent, conditioned taste aversion memory. Learning & Memory, 15, 290-293.

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  20. Frankland, P.W., Teixeira, C.M. and Wang, S.H. (2007). Grading the gradient: Evidence for time-dependent memory reorganization in experimental animals. Debates in Neuroscience, 1, 67-78

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  21. Frankland, P.W., Ding, H.K., Takahashi, E., Suzuki, A., Kida, S. and Silva, A.J. (2006). Stability of recent and remote contextual fear memory. Learning & Memory, 13, 451-457.

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  22. Teixeira, C.M., Pomedli, S., Maei, H.R., Kee, N. and Frankland, P.W. (2006). Involvement of the anterior cingulate cortex in the expression of remote spatial memory. The Journal of Neuroscience, 26, 7555-7564.

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  23. Frankland, P.W. and Bontempi, B. (2006). Fast track to the medial prefrontal cortex. Proceedings of the National Academy of Sciences, 103, 509-510.

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  24. Frankland, P.W. and Bontempi, B. (2005). The organization of recent and remote memory. Nature Reviews Neuroscience, 6, 119-130.

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  25. Frankland, P.W. (2005; online publication only). Networking to remember: The cortex and remote memory. Finalist essay for Eppendorf & Science Prize for Neurobiology, 2005. Published in Science Online (http://www.eppendorfscienceprize.org).

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  26. Frankland, P.W., Bontempi, B., Talton, L.E., Kaczmarek, L. and Silva, A.J. (2004). The involvement of the anterior cingulate cortex in remote contextual fear memory. Science, 304 (5671), 881-883.

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