The Mouse Brain

The common house mouse (scientific name Mus Musculus) is one of the most studied and well understood of mammals. It is a model organism for researching many aspects of biology, including neurobiology. Recent studies by Professor Joe Tsien, and colleagues at Princeton University, have been using the mouse to reveal the molecular basis of learning and memory. As a result of their experiments they have produced genetically modified mice which are 4 to 5 times as intelligent as normal mice.

The Theory of Memory:
The current theory of learning and memory formation is known as Hebbian learning. This theory was first put forward by Donald Hebb in the 1940's. The theory states that when two neurons, which are in electrical contact, are electrically active at the same time, then the connections between them are strengthened.

This kind of strengthening of synapses has been shown to occur in an area of the brain called the Hippocampus. The phenomenon is known as Long-Term Potentiation (LTP), meaning increased synapse strengths are maintained for a long time. The opposite of LTP is Long-Term Depression (LDP). It is thought that LTP and LDP are responsible for the acquisition and erasing of memory.

Professor Tsien has gone on to prove the molecular basis of LTP. It turns out that it is a single molecule which plays the central role in memory formation. This molecule, called the NMDA Receptor, spans the neural cell membrane at post synaptic terminals. It acts as a pore which can open or close depending on the presence of an incoming synaptic signal and the polarisation state of its surrounding membrane. When two neurons either side of a synapse are simultaneously active then the NMDA pore is opened. This opening then somehow strengthens the connection. It is this coincidence detector of both synaptic signal and polarisation state which is thought to be responsible for associative memory.

Super-intelligent Mice:
Professor Tsien and colleagues were able to prove the above NMDA theory of learning by making genetically engineered mice which had memories 4 to 5 times as long as normal mice. The technique they used was to insert a single gene into the mouse's genome. This gene caused an increased production of the protein known as NR2B. This protein is a sub-unit from the NMDA receptor and is responsible for opening the receptor's pore.

The NMDA receptors in these genetically engineered mice were seen to open for twice as long as normal and stronger connections were made in the Hippocampus. The mice displayed the ability to recognise an object and to remember it for longer. This strain of mouse was named Doogie (after the TV character Doogie Howser, MD).

The above experiment was reported in the journal Nature in September 1999. Tsien, together with collaborators at MIT and Washington University, is now investigating just how the opening of the NMDA receptor strengthens memory and how this memory formation is transferred from the Hippocampus to the cerebral cortex.

Links:
Molecular Biology, Princeton: http://www.molbio.princeton.edu/faculty/tsien.php
Mouse Brain Library: http://www.nervenet.org/