Analysis of the neural substrate of anxiety

描述(申请人提供)：特质焦虑描述了一种人格特质，其特征是基础焦虑水平升高，这代表了焦虑症和各种形式的抑郁的易感因素。困扰人类的焦虑症包括广泛性焦虑症(GAD)、恐慌、各种恐惧症和创伤后应激障碍(PTSD)，这些疾病加在一起，是最常见和代价高昂的精神疾病。我们研究的长期目标是阐明焦虑症的分子和细胞机制。GABA-A受体被广泛认为在焦虑状态的调节中具有把关功能，特别是在GAD和惊恐障碍中。带有GABA-A受体GMA2亚单位基因杂合突变的小鼠已经被建立为这种焦虑的动物模型，这种焦虑表现出类似于人类GAD的行为和认知缺陷。在胚胎发育期间锥体前脑神经元中有条件地缺失该基因，而在青春期小鼠中没有条件缺失该基因，会导致成年人过度的特质焦虑。与特质焦虑的发育机制一致，伽马2亚单位杂合子小鼠表现出海马神经发生和5-羟色胺能传递减少。基于这些观察，我们假设(I)特质焦虑是由于特定类型的海马神经元在发育过程中的丧失所致。我们进一步假设(Ii)GABA-A受体缺陷导致5-羟色胺能传递缺陷，从而导致特质焦虑的表现。我们还预测(Iii)用抗抑郁剂和促进神经发生的药物治疗年轻突变小鼠可以防止成人特质焦虑的发展。最后，(Iv)我们假设，海马区和大脑皮层中的GABA-A受体缺陷与杏仁核中的缺陷无关，从而建立了焦虑样的表型。总而言之，这些研究将极大地促进我们对焦虑和抑郁障碍潜在机制的了解。

DESCRIPTION (provided by applicant): Trait anxiety describes a personality trait characterized by an elevated basal level of anxiety that represents a vulnerability factor for anxiety disorders and various forms of depression. Anxiety-disorders that afflict humans include generalized anxiety disorder (GAD), panic, diverse phobias and posttraumatic stress disorder (PTSD) which, together, are among the most frequent and costly psychiatric illnesses. The longterm goal of our research is to elucidate the molecular and cellular mechanisms underlying anxiety disorders. GABA-A receptors are widely recognized to hold a gatekeeper function in the modulation of anxiety state, especially in GAD and panic disorder. Mice with a heterozygous mutation of the GABA-A receptor gamma 2 subunit gene have been established as an animal model of that anxiety that exbits behavioral and cogntive deficits reminiscent of GAD in humans. Conditional deletion of this gene in pyramidal forebrain neurons during embryogenesis but not in adolescent mice leads to excessive trait anxiety in adults. In agreement with a developmental mechanism underlying trait anxiety, gamma 2 subunit heterozygous mice exhibit reduced hippocampal neurogenesis and serotonergic transmission. Based on these observations we hypothesize (I) that trait anxiety is due to the loss of specific types of hippocampal neurons during development. We further hypothesize (II) that the GABA-A receptor deficit leads to a deficit in serotonergic transmission that contributes to the manifestation of trait anxiety. We also predict (III) that treatment of young mutant mice with antidepressant and neurogenesis-enhancing drugs prevents development of trait anxiety in adults. Finally, (IV) we hypothesize that GABA-A receptor deficits in the hippocampus and cerebral cortex act independently of deficits in the amygdala to establish an anxiety-like phenotype. Together these studies will greatly advance our undestanding of the mechanism underlying anxiety and depressive disorders.