When Mouse plays Dice

RIKEN researchers working in the US with American colleagues have developed a technique for switching individual nerve circuits on and off, and employed it to determine the role of an important pathway used in forming memories. In specially bred mice, the international research team found the tri-synaptic pathway (TSP) in the hippocampal region of the brain is integral to rapid formation of functional memory, but not necessary for incremental learning. Decline of the TSP is thought to be associated with ageing and neurodegenerative conditions such as Alzheimer’s disease. The TSP is one of two parallel nerve circuits known to be involved in learning and memory. It carries information from the entorhinal cortex (EC) through the three major processing regions of the hippocampus—the dentate gyrus, CA3 and CA1—before returning to the EC (Fig. 1). The other circuit, the monosynaptic pathway (MSP), simply takes information from the EC to the CA1 and back again. Previously, researchers studied what happened when cells in each of these regions are destroyed, and when specific nerve receptors are blocked. But these methods can only provide partial understanding of the role of each pathway. In a recent paper in Science¹, the team of researchers from the RIKEN-MIT Neuroscience Research Center in Cambridge, Massachusetts, led by Susumu Tonegawa, outlines how they developed a technique to block and unblock the transmission of impulses across a specific nerve junction in the TSP by controlling the expression of the tetanus toxin gene using the antibiotic doxycycline. The team then used its technique—named DICE-K after a Japanese major league baseball pitcher—to study the ability of mice with or without a functional TSP to perform tasks involving different types of learning and memory. The researchers found that the MSP alone is sufficient for the incremental acquisition and recall of spatial learning and memory associated with the Morris water maze, where over repeated trials mice learn to associate the position of an escape platform hidden underwater with landmarks placed outside the tank. But the TSP is crucial to the more sophisticated acquisition of memory in tasks where rapid learning is required—in novel environments, for instance. “Using this technology, we can shut down communication between nerve cells whenever we want, during or after memory acquisition,” says team member Toshiaki Nakashiba. “We can also apply it to circuits other than the TSP. It provides a level of experimental accuracy never achieved before.”