The objective of this proposal is to identify the neural substrates underlying trait anxiety. We have found that heterozygosity of the GABAA receptor y2 subunit gene leads to a subtle impairment of postsynaptic GABAA receptor function and trait anxiety in mice. The selective behavioral and cognitive deficits of y20/~ mice, together with established knowledge on the neural circuitry of conditioned fear and the regional distribution of the GABAA receptor deficit in =y2 0/+ mice, allow predictions as to which brain regions mediate trait anxiety. We hypothesize that GABAA receptor deficits in the cerebral cortex and/or hippocampus of y2 0/ mice lead to trait anxiety and that a GABAA receptor deficit that is confmed to these brain regions will result in trait anxiety-like behavior similar to the phenotype of =y2 0/+ mice. In order to map the brain regions that mediate trait anxiety, we have generated a mouse line that allows spatiotemporally restricted inactivation of the y2 subunit gene by means of the Cre/loxP system. Upon Cre induced inactivation of the y2 subunit gene, GABAA receptor function will be impaired in selective brain regions defined by the Cre expression pattern of tissue-specific Cre-transgenes or by stereotaxically applied Cre-encoding virus. Subsequently, stereotaxic injection of Cre-recombinant virus will be used to further characterize trait anxiety. These experiments will include determination of the critical stage during development during which GABAergic deficits lead to trait anxiety. In addition, we will determine whether the cognitive deficits associated with trait anxiety reflect alteration of the acquisition or expression of conditioned fear. The neural circuits that are implicated in the anxiolytic action of the benzodiazepines have considerable anatomical overlap with the proposed neural circuits of trait anxiety and are of therapeutic interest. To test this hypothesis, Cre-induced inactivation of the y2 subunit gene, which is essential for benzodizepine action, will be used to map the brain regions mediating the anxiolytic effect of benzodiazepines.
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