Mice lacking the serotonin 1A receptor (5-HT1A receptor knockout) display increased anxiety-like behavior in the open field, elevated-plus maze, and novelty-suppressed feeding tests, and serve as a genetic model of anxiety disorders. In order to determine in which brain region this receptor functions to modulate anxiety-like behavior, we have used gene targeting technology to create mice with conditional expression of the 5-HT1A receptor restricted to the forebrain. These forebrain """"""""rescue"""""""" mice behave like wild-type mice in the open field, elevated-plus maze, and novelty-suppressed feeding tests, suggesting that receptor in this region is sufficient to restore anxiety-like behavior. Turning off expression of the 5-HT1A receptor in these mice would be expected to revert their anxiety-like behavior to that found in knockout animals. Instead, 5-HT1A receptor inducible rescue mice, in which 5-HT1A receptor expression was completely turned off during adulthood, continue to behave like wild-type mice suggesting that receptor expression to the adult is not required for normal anxiety-like behavior. This result can be explained if the 5HT1A receptor functions during a critical time period in development to establish normal anxiety-like behavior in the adult. This hypothesis is a radical departure from previous notions of the role of the 5-HT1A receptor in fear behavior, and is the starting point for the proposed investigations. First, the 5-HT1A receptor is hypothesized to be required during the first and second postnatal week (PO-P14) to establish normal anxiety-like behaviors in the adult. The 5-HT1A receptor forebrain rescue mice will be used to define more precisely the critical time period for 5-HT1A receptor function. Second, novel transgenic strategies will be applied to define more specifically the critical tissue mediating the expression of anxiety behavior. Either the cortex, hippocampus, or amygdala are hypothesized to be the critical structures because these regions show receptor expression in the 5-HT1A rescue mice and because of their known involvement in anxiety and depression in rodents and humans. Third, changes in anxiety-like behavior in the knockout and transgenic mice will be associated with changes in the expression of specific genes which mediate the function of the 5-HT1A receptor. An unbiased search for such candidate genes will be performed using gene expression profiling techniques.
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