Mapping the Neural Substrate of Anxiety

描述：(申请人提供)本提案的目的是 找出特质焦虑的神经基础。我们发现， GABAA受体y2亚单位基因杂合性导致微妙的 小鼠突触后GABA受体功能受损与特质焦虑。 Y20/~小鼠的选择行为和认知缺陷 关于条件性恐惧的神经回路和 GABAA受体缺陷在=y20/+小鼠中的区域分布，允许 关于大脑中哪些区域调节特质焦虑的预测。我们假设 大脑皮层和/或海马区GABAA受体缺失 小鼠导致特质焦虑，GABAA受体缺陷被混淆为 这些大脑区域将导致类似特质焦虑的行为，类似于 =y20/+小鼠的表型。为了绘制与特征有关的大脑区域图 焦虑，我们已经产生了一条老鼠线，允许时空受限 通过Cre/loxP系统使y2亚单位基因失活。在CRE上 诱导y2亚单位基因失活，GABAA受体功能将 在由Cre表达模式定义的选择性脑区域受损 组织特异性Cre转基因或通过立体定位应用Cre编码 病毒。随后，立体定向注射Cre-重组病毒将 用来进一步描述特质焦虑。这些实验将包括 γ-氨基丁酸的发育临界期的确定 缺陷会导致特质焦虑。此外，我们将确定是否 与特质焦虑相关的认知缺陷反映了 获得或表现出条件性恐惧。神经回路是 与苯二氮卓类药物的抗焦虑作用有关的有相当多 与已提出的特质焦虑和ARE神经回路的解剖学重叠 对治疗有兴趣。为了验证这一假设，Cre诱导的细胞失活 对于苯二氮卓类药物的作用至关重要的y2亚单位基因将被使用。 绘制介导苯二氮类药物抗焦虑作用的脑区图。

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.