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required them to find a platform hidden under the surface of milky-
colored water. The impaired spatial learning was similar to that of normal
mice with hippocampus lesions. The hippocampus is a brain structure
crucial for forming memories. However, Silva et al. (1992a,b) found that
knocking out this gene affected more than just learning: the knock-outs
also had an abnormally enhanced acoustic startle response, and were more
likely to jump when they heard a sudden loud noise. In 1994, researchers
in another lab made a startling discovery of these same knock-out mutant
mice. Mice were sometimes found dead in their cages with broken backs.
The fighting behavior of these mice was so extreme that they suffered
broken backs ( Chen et al., 1994 ). This is another example of an unex-
pected effect. Knocking out the gene for calcium/calmodulin kinase II
affected more than just learning: it also completely removed fear causing
uninhibited fighting. Calcium/calmodulin kinase II is also involved in the
regulation of the neurotransmitter serotonin. The knock-outs had normal
behavior except in the area of defensive aggression. Defensive aggression
was measured by quantifying attacks by a resident mouse against a mouse
that was placed in its cage. Offensive aggression was measured by deter-
mining how hard an intruder mouse fought a resident. Since the knock-
outs had no fear, they continuously attacked a resident mouse when
placed in its cage. The heterozygote knock-outs with one knock-out gene
had abnormally high defensive aggression ( Chen et al., 1994 ). Offensive
aggression, which is attack aggression, was attenuated in the genetically
engineered mutants.
Researchers in another laboratory were also surprised by unexpected
results when a specific gene was blocked. Giros et al. (1996) found that
blocking the effects of the dopamine (neurotransmitter) gene in mice had
both predicted and unexpected results. Blocking the effect of the gene made
the mice produce an overabundance of dopamine in their brains. Dopamine
excess is believed to be responsible for some of the symptoms of schizophre-
nia in people. As expected, homozygous mice had two copies of the blocked
gene were hyperactive and ran around more compared to the heterozygous
(one copy of the gene), or normal, wild-type mice. Neither type of geneti-
cally altered mice had stereotypies. An unexpected finding was that injec-
tions of amphetamines had no effect on the homozygotes, and an eight-fold
increase in locomotor activity in the heterozygotes and normal, wild-type
mice ( Giros et al., 1996 ). This experiment provided important insights into
how pharmaceuticals work, and showed that the effects of drugs on behavior
are not simple and straightforward. Similar effects of fear may operate in
mice bred and selected by conventional methods. Male mice that were bred
to have heightened reactivity to stimulation were less aggressive ( Gariepy
et al., 1988 ). Since the first edition of this topic, researchers have developed
more sophisticated behavioral tests for use with all the new mouse models
( Crawley, 2007 ).
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