Hippocampus, V: Studying Hippocampal Behaviors

The hippocampus is one of several CNS structures important for learning and memory. Its critical role in memory was first noted in a patient who lost the capacity for forming new memories after a bilateral hippocampectomy for uncontrollable seizures. A delineation of the exact role of the hippocampus in learning and memory has been pursued ever since. Laboratory rodents are good subjects for experiments in learning and memory because they learn new knowledge quickly and reliably in a fashion similar to humans. Different aspects of memory have been associated not only with frontal, hippocampal, and striatal structures, but also with the specific hippocampal subfields and their cortical layers. Recently developed transgenic techniques allow very selective molecular lesions to be made within the hippocampus to answer specific questions about the regions and transmitters involved in memory formation. The figure shows the hippocampus of a transgenic mouse, stained for a single molecule (NR1 mRNA) that directs the expression of this essential subunit of the NMDA receptor protein. Note that on the left side, there is an absence of NR1 mRNA (in the CA1 field of the hippocampus) compared with the right side. The area lacking the molecule is enlarged and stained with a nuclear stain to show there is no cell damage. Such a deletion of the essential subunit of the NMDA-sensitive glutamate receptor blocks information transmission at that receptor in that region. The molecular lesion is accomplished using a genetically engineered mouse that has inserted nuclear tags placed around the gene of interest (called loxP nucleotide sequences). A viral vector (an engineered adeno-associated virus that expresses Cre recombinase) is used to induce the removal of the tagged gene but only in the region where the viral vector is injected. This molecular approach is more selective and precise than other mechanisms of blockade, whether by pharmacological approach or by nonconditional knockouts. When we explored the behavioral consequences of such a knockout in CA3, we found that this lesion totally inhibits the ability of an animal to quickly learn a new set of facts within a specific context, but it does not interfere with the animal’s use of information already learned. These animal data suggest that CA3 in the human hippocampus contributes to our human ability to quickly gain a familiarity with a new set of facts relating to a given context and to remember them as related in this manner. This may be particularly important in social contexts to learn that some interpersonal responses are appropriate in particular contexts but inappropriate in others.

Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NC5.914, Dallas, TX 75390-9070; [email protected] (e-mail).