My lab uses genetic manipulation in mice to investigate the molecular events that are involved in learning and memory. We have primarily used the Tet system, which allows both anatomical and temporal control over the genetic changes. Our previous work has focused primarily on testing the role of molecular signaling pathways implicated in synaptic plasticity at the whole animal behavioral level. Recently we have developed mice that allow genetic manipulation of neurons that have been activated by specific environmental stimuli to allow us to focus molecular, structural, and genetic studies on those neurons that are most likely to participate in a given memory trace.
Calcium Signaling and Memory. We know relatively little at a molecular level about how the brain stores new information. One hypothesis, that we have tested, is that calcium regulated changes in the strength of synaptic connections between nerve cells can store information. The calcium calmodulin dependent protein kinase is abundant at synapses and when activated by calcium can strengthen synaptic connections. We used genetic manipulations to indiscriminately activate this kinase at all synapses in the entorhinal cortex, a part of the brain that is important for memory and is affected in the earliest stages of Alzheimer’s disease. We found that not only is the formation of new memories impaired, but also previously established memories could be erased. If memories are stored as precise patterns of synaptic weights, then the indiscriminant strengthening of synapses might be expected to erase memories in a manner similar to writing all ones in computer memory will erase previously stored information. We also examined where within the cell this protein functions. We found that the synthesis of this kinase from RNA located specifically at synapses is necessary for the stabilization of memories lasting several months.
Molecular Anatomy of Memory. When we learn new information we use only a tiny fraction of the neurons in our brain. One of the difficulties in studying memory is an inability to identify and specifically manipulate those neurons that participate in a particular memory trace. We have recently developed a genetic technique that allows us to specifically introduce genetic changes into neurons that are activated by behavioral stimuli. By introducing a visible marker protein we can permanently tag activated subsets of neurons creating a precise record of the activity pattern at a specific point in time. We used this approach to ask whether the same neurons that are activated during learning become reactivated during recall of a memory. Using fear conditioning we found that some of the same neurons activated during learning were reactivated when the animal recalled the fearful event. We went on to use this approach to study extinction, a process used in the treatment of phobias, by which memories are weakened by repeated exposure to a relevant stimulus. We found the neurons that were originally activated by a fearful stimulus were no longer activated following extinction. We are now introducing genes to allow us to control the activity of the tagged neurons to allow us to address basic questions relating to the nature of the memory trace in a complex neuronal network.
Synaptic Tagging with Learning. The critical changes that underlie the memory trace likely occur at the level of individual synapses rather than the entire neuron. We have generated mice in which the expression of a GFP tagged glutamate receptor (GluR1) can be introduced into behaviorally activated neurons as discussed above. Using these mice we can follow the expression, trafficking, and turnover of GluR1 specifically in the neurons associated with a specific behavior. In initial studies we found that the distribution and turnover of GFP-GluR1 differs with dendritic spine type with greater trafficking of GluR1 to mushroom type spines following learning. By providing a molecular tag of synapses from behaviorally activated neurons that have received newly synthesized GluR1 we hope to use biochemical methods to characterize the molecular composition of these synapses as compared to synapses from inactive cells.
Mayford, M., Bach, M. E., Huang, Y. Y., Wang, L., Hawkins, R. D., and Kandel, E. R. (1996). Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678-1683.
Miller, S., Yasuda, M., Coats. J.K., Jones, Y. Martone, M.E. & Mayford, M. (2002) Disruption of Dendritic Translation of CaMKII Impairs Stabilization of Synaptic Plasticity and Memory Consolidation. Neuron, 36, 507-519.
Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961-972.
Yasuda M. & Mayford M. (2006) CaMKII activation in the entorhinal cortex disrupts previously encoded spatial memory. Neuron. 2006 Apr 20;50(2):309-18.
Reijmers, L. G., Perkins, B. L., Matsuo, N., and Mayford, M. (2007). Localization of a stable neural correlate of associative memory. Science 317, 1230-1233.