The use of genetic "knockout" mice in behavioral endocrinology research.

The production of mice with specific deletion of targeted genes (knockouts) has provided a useful tool in understanding the mechanisms underlying behavior. There are many opportunities with this new tool for behavioral neuroendocrinology, specifically, and behavioral biology, generally. Although this genetic technique offers new opportunities to study the mechanisms of behavior, as with all behavioral techniques there are some potential limitations. For example, the products of many genes are essential to normal function, and inactivating the gene may prove lethal or induce gross morphological or physiological abnormalities that can complicate interpretation of discrete behavioral effects. Unexpected compensatory or redundancy mechanisms might be activated when a gene is missing and cloud interpretation of the normal contribution of the gene to behavior. Behavioral tests study the effects of the missing gene (and gene product), not the effects of the gene directly. This conceptual shortcoming can be overcome in the same way that it is overcome in other types of ablation studies, by collecting converging evidence using a variety of pharmacological, lesion, and genetic manipulations. Finally, because mammalian genome mapping is currently focused on mice (Mus musculus), standardized behavioral testing of mice should be adopted. Against those disadvantages are several important advantages to using knockout mice in behavioral research: (1) disabling a gene is often a very precise and "clean" ablation, (2) the effects of the gene product can be abolished without the side-effects of drugs, and (3) genetic manipulations may be the only way to determine the precise role of many endogenous factors on behavior. The use of new inducible knockouts, in which the timing and placement of the targeted gene disruption can be controlled, will be an extremely important tool in behavioral endocrinology research.