Mapping the Neural Substrate of Anxiety

Project: Research project

Project Details


DESCRIPTION: (provided by applicant) 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.
Effective start/end date5/1/014/30/02


  • National Institute of Mental Health: $230,731.00

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