Mapping the Neural Substrate of Anxiety

描述：（由申请人提供）本提案的目的是 识别特质焦虑的神经基础。我们发现 GABAA受体γ 2亚基基因的杂合性导致了一种微妙的 突触后GABAA受体功能受损与小鼠特质焦虑 Y20/~小鼠的选择性行为和认知缺陷，以及 关于条件性恐惧的神经回路和 GABAA受体缺陷在= γ 2 0/+小鼠中的区域分布，允许 预测哪些大脑区域介导特质焦虑。我们假设 γ-氨基丁酸受体在大脑皮层和/或海马中的缺陷， 小鼠导致特质焦虑，GABAA受体缺陷， 这些大脑区域会导致类似于焦虑的行为， =y2 0/+小鼠的表型。为了绘制出大脑中调节特质的区域 焦虑，我们已经产生了一个鼠标线，允许时空限制 通过Cre/loxP系统灭活γ 2亚基基因。在Cre 诱导γ 2亚基基因失活，GABAA受体功能将被破坏。 在由Cre表达模式定义的选择性脑区受损， 组织特异性Cre转基因或通过立体定向应用的Cre编码 病毒随后，将Cre-重组病毒的立体定位注射用于 用于进一步表征特质焦虑。这些实验将包括 确定GABA能在发育过程中的关键阶段， 缺陷导致特质焦虑。此外，我们将确定 与特质焦虑相关的认知缺陷反映了 获得或表达条件性恐惧。这些神经回路 与苯二氮卓类的抗焦虑作用有关的药物具有相当大的 解剖学上与特质焦虑的神经回路重叠， 有治疗意义的为了验证这一假设，Cre诱导的 将使用苯并二氮平作用所必需的Y2亚基基因 绘制了介导苯二氮卓类药物抗焦虑作用的大脑区域。

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.