Organization of complex memories in the mammalian brain - testing basic assumptions of systems consolidation theories
Final Report Abstract
The project set out to study the organization of recent and remote long-term memories in order to test opposing predications of the standard model of consolidation and multiple trace theory, two prevalent theoretical accounts on long-term memory. However, this objective had to be abandoned after the discovery that rats relatively quickly forget hippocampus-dependent long-term object location memories; thus, the behavioural task on which the planned experiment were based, turned out to be unsuitable and the lack of appropriate alternative paradigms afforded a redirection of the research project. Our discovery that fully consolidated long-term object location memories are forgotten over time shifted the focus on questions about the neurobiology of memory persistence and forgetting, about which very little is known to date. In summary, these research activities led to the following discoveries: 1) Fully consolidated long-term object location memories are forgotten over time. For as long as these memories persist, they are actively maintained by kinases of the PKC family, most likely by PKMζ. PKMζ maintains these memories by sustaining the post-synaptic expression of GluA2-containing AMPA receptors (GluA2/AMPAR). 2) Forgetting is an active process that involves the activity-dependent removal of GluA2/AMPARs because the suppression of GluA2-dependent synaptic removal of AMPARs in the hippocampus with the peptide GluA23Y prevents forgetting of location memories. 3) Active forgetting involves glutamate signaling and the activation of GluN2B-containing NMDA receptors because blocking these receptors with the highly GluN2B-selective antagonist Ro25-6981 preserves object location memories. 4) This active forgetting of object location memories over time does not reflect interference from newly acquired memories because suppressing synaptic removal of GluA2/AMPARs with GluA23Y not only permits new learning in naïve rats, but also potentiates learning in previously trained animals. Therefore, application of GluA23Y during the retention interval prevented forgetting because it attenuated a decay process that actively removes established memories. These findings have widespread implications: It is likely that the default process in memory is not memory retention, but memory removal and forgetting. Thus, in order to persist, memories have to actively counteract a constitutive decay process. It is likely that constitutive decay processes bear functional significance for memory, and that deregulated forgetting processes are involved in pathologies of memory, such as accelerated memory loss in senescence and dementias, like Alzheimer’s Disease.
Publications
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(2009, Juni). PKMζ maintains object location knowledge in dorsal hippocampus. Talk presented at the Spring Hippocampal Research Conference, June 14-19, Verona, Italy
Hardt, O.
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(2009, October). Memory for object location, but not object identity, depends on PKMζ activity in the dorsal hippocampus at remote and recent time points. Annual meeting of the Society for Neuroscience, October, Chicago, IL
Hardt, O., Hastings, M.H., Wong, J., Migues, P.V., & Nader, K.
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(2009, October). Neural substrates of objectlocation memory change with extensive training. Annual meeting of the Society for Neuroscience, October, Chicago, IL
Hastings, M.H., Wong, J., Litwin, L., Nader, K., & Hardt, O.
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(2009, October). PKMζ maintains memories through GluR2-dependent AMPA receptor trafficking. Annual meeting of the Society for Neuroscience, October, Chicago, IL
Migues, P.V., Hardt, O., Wu, D., Gamache, K., Sacktor, T., Wang, Y., & Nader, K
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(2010). A bridge over troubled water: reconsolidation as a link between cognitive and neuroscientific memory research traditions. Annual Review of Psychology, 61, 141– 167
Hardt, O., Einarsson, E. Ö., & Nader, K.
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(2010). Object location memory becomes independent of the dorsal hippocampus with extensive training: hippocampal involvement in restabilization, but not retrieval, of these extra-hippocampal memories. FENS Abstr. vol 5, 057.30.
Hardt, O., Pors, J., Wong, J., & Nader, K.
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(2010). PKMzeta maintains 1-day- and 6-day-old long-term object location but not object identity memory in dorsal hippocampus. Hippocampus, 20(6), 691–695
Hardt, O., Migues, P. V., Hastings, M., Wong, J., & Nader, K.
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(2010). PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nature Neuroscience, 13(5), 630–634
Migues, P. V., Hardt, O., Wu, D. C., Gamache, K., Sacktor, T. C., Wang, Y. T., & Nader, K.
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(2010). PKMζ and long-term maintenance of object recognition memory: A double dissociation of perirhinal cortex and dorsal hippocampus. Annual meeting of the Society for Neuroscience, November, San Diego, CA
Hardt O., Migues, P.V., Augereau, K., Wong, J., & Nader, K.
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(2010). Stabilization of postsynaptic GluR2/AMPA receptors maintains long-term memories. FENS Abstr. vol 5, 057.50
Migues P.V., Hardt O., Wu D.C., Gamache K., Sacktor T.C., Wang Y.T., & Nader, K.
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(2010). Stabilization of postsynaptic GluR2/AMPA receptors maintains long-term memories. Talk presented at the Nanosymposium on Postsynaptic Signaling Mechanism at the annual meeting of the Society for Neuroscience, November, San Diego, CA
Migues P.V., Hardt O., Wu D.C., Gamache K., Sacktor T.C., Wang Y.T., & Nader, K.
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(2010, July). Persistence of object identity memory requires PKMzeta activation in perirhinal cortex. EMCCS-FENS 4th annual meeting, July 1 and 2, Amsterdam
Hardt, O., Bozzo, A., Augereau, K., Migues, P.V., & Nader, K.
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(2011). The biological basis of everyday forgetting. Talk presented at the annual meeting of the Memory Disorders Research Society, Barcelona, Spain
Hardt, O., Migues, P.V., Wong, J., & Nader, K.
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(2011). The interaction between GluR2 and N-ethylmaleimidesensitive factor is crucial for memory maintenance in the hippocampus. 43rd European Brain and Behaviour Society Meeting, September, Seville, Spain
Migues, P.V., Hardt, O., & Nader, K.
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(2011). The neurobiology of forgetting: Internalization of GluR2 containing AMPA receptors mediates decay of long-term memory in hippocampus. 43rd European Brain and Behaviour Society Meeting, September, Seville, Spain
Hardt, O., Migues, P.V., Wong, J., & Nader, K.
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(2011). Update on memory systems and processes. Neuropsychopharmacology, 36(1), 251–273
Nadel, L., & Hardt, O.
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(2013). Decay happens: the role of active forgetting in memory. Trends in Cognitive Sciences, 17(3), 111–120
Hardt, O., Nader, K., & Nadel, L.
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(2014). GluA2-dependent AMPA receptor endocytosis and the decay of early and late long-term potentiation: possible mechanisms for forgetting of short- and long-term memories. Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1633), 20130141
Hardt, O., Nader, K., & Wang, Y. T.
