Task-specific stress or anxiety-like states could also contribute to the current pattern of results, but the relationship to novelty depends on the circumstances of testing. Handling mice activates the hypothalamic–pituitary–adrenal axis, leading to elevations in circulating corticosterone. In the free exploration test, a task similar to the novel environment preference test used in the current experiments; mice that were habituated to one compartment for 24 h showed no elevations of corticosterone when allowed to explore a novel compartment. However, mice forced to remain in the novel compartment without escape had elevated corticosterone levels, as did mice placed into a different, novel environment (34, 35). In our studies, mice were habituated to the familiar compartment for only 15 min. Strains could prefer novel objects or locations because they are stressful, seeking to reduce stress through familiarity. Alternatively, strains could select a novel environment because the familiar one has become stressful (36).
