“We were very surprised by our results, but we are excited about the questions they raise for future research,” Morris told ARF.

To test learning within a pre-existing mental schema, first author Dorothy Tse used the same paradigm as the researchers used earlier. Over several weeks, she trained rats to locate particular flavored foods buried in sand-wells in an arena. The animals learned to associate flavors with specific locations. The previous study showed that, when presented with a new flavor-location pair, the animals memorize the association after only one trial, and this knowledge occupies the cortex less than 48 hours later. Hippocampal activation remains essential for encoding the new associations.

For the new work, Tse and colleagues focused on two plasticity-associated genes, the zinc finger protein Zif268 and activity-regulated cytoskeleton-associated protein (Arc), which are known to activate after synaptic activity. The authors analyzed gene expression in various brain regions roughly one hour after learning. In cortical regions implicated in remote memory consolidation (that is, the prelimbic region, anterior cingulate, and retrosplenial cortex), both genes were expressed more highly in rats that had added new information to an existing schema, versus in rats that had not learned, or had learned associations not related to a previous schema. In addition, when Tse and colleagues inhibited gene activation by infusing glutamate receptor blockers into these cortical regions, the rats could no longer learn the new associations. Both AMPA and NMDA receptor blockers prevented learning. AMPA receptor blockade also kept the animals from recalling previously learned associations.

The data suggest that, when animals add information to an existing mental map, both the cortex and the hippocampus must process the new associations in parallel. “If information is being stored in two places at once, what is the nature of the different kinds of information in these different places, and why is the system organized in that way?” Morris asked. Although this question remains unanswered, the findings do suggest that prevailing models of memory formation need updating, he said.

The idea of cortical participation early in memory formation fits with the recent finding that areas of the cortex are somehow “tagged” at the time of learning (see ARF related news story on Lesburguères et al., 2011). “There are striking similarities between our studies and theirs,” Morris told ARF, but added there is also a key difference. Lesburguères and colleagues used experimentally naïve animals, and therefore saw the classic slow memory consolidation into cortex. Morris is known to the AD field in part for the widespread use of the water maze test named after him.

In sum, the data strengthen the idea that experience influences learning. “Our prior knowledge guides the encoding and consolidation of new information. That is, in a sense, a truism, but what is new here is that we are beginning to tackle the underlying neurobiology and neural mechanisms of that effect,” Morris said.—Madolyn Bowman Rogers.

Reference:
Tse D, Takeuchi T, Kakeyama M, Kajii Y, Okuno H, Tohyama C, Bito H, Morris RG. Schema-dependent gene activation and memory encoding in neocortex. Science. 2011 Jul 7. Abstract