a + , knockout increases aggression; —, knockout decreases aggression; +(=), increase but depending on background/paradigm/test day; —?, possible decrease; + /—, increase/decrease depending on design/type of aggression dramatically affects a trait on one background, whereas it has no or a different effect on another background. This phenomenon, in which gene(s) influences the effect of another (i.e., the background genes interact with the knockout gene), is called epistasis and has been found in aggression research. For instance, the effect of the Y chromosome on aggressive behavior depends on the genetic background to which it has been backcrossed. Third, traditional knockouts are constitutive: They lack the gene in every cell and tissue from conception on. This means that in practice one cannot study the effects of genes that affect complex traits that are also essential for normal development. Such knockouts simply die at or before birth.

Joe Tsien at Princeton University developed a method to overcome these problems. He encountered this problem when he knocked out various subunits of the NMDA receptor. This receptor is thought to increase the synaptic strength between two nerve cells, a process called long-term potentiation (LTP), which is fundamental for learning and memory. By coincidence, he engineered NMDA knockout mice that lacked the subunit in a specific section of their hippocampus termed the CA1 region, which appears to be essential for memory. Hence, these so-called conditional, regionally restricted knockouts lack an essential "memory" gene, but only in a specific part of the brain and nowhere else in the body. As expected, it appeared that these animals demonstrated not only decreased LTP but also poor spatial memory.

Genetic engineering can be used not only to knock out genes but also to insert extra copies of a gene. This method is called transgenic integration. One of the more convincing behavioral examples comes from the same laboratory that developed the conditional NMDA knockouts. Instead of inactivating a gene, they inserted an extra copy of another memory gene. This gene codes for an NMDA subunit called NR2B, which is more strongly expressed in young people and stays open longer than the ''old people's'' NR2A, a phenomenon that might explain the age-related differences in learning and memory. Indeed, transgenic mice that had an extra copy of the gene for this receptor learned certain tasks better than did normal mice.

The development of both knockout and transgenic integration techniques has certainly deepened our knowledge about the effects of specific genes on complex traits. However, in addition to the previously mentioned, more pragmatic problems (flanking gene effects, genetic background, and temporal and spatial limits), there is another, more theoretical pitfall. Fundamentally, two types of genes coexist in nature: polymorphic and monomorphic genes. When studying genes that in nature are monomorphic, we generally deal with underlying mechanisms common to most or even all members of a species. In contrast, when studying natural genetic variation, we investigate mechanisms underlying spontaneous individual differences (i.e., polymorphic genes). Analysis of this natural genetic variation may thus enable us to identify genes that modify behavioral and neural function to a degree that is not grossly disadvantageous to the individual that carries such alleles. In short, whereas one type of question addresses, for example, how animals store information, the other type of question asks why some individuals perform better in a given task than others.

Artificially induced mutations (e.g., knockouts and transgenes) can be used to study both types of genes, but it should be realized that the results of knockout or transgenesis studies do not contribute to the explanation of naturally occurring interindividual variation in cases in which the genes investigated are monomorphic in nature. In fact, most null mutations are not found to occur spontaneously in natural populations.

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