Analysis of the neural substrate of anxiety

描述（由申请人提供）：特质焦虑描述了一种人格特征，其特征是焦虑的基础水平升高，这是焦虑障碍和各种形式抑郁的脆弱因素。困扰人类的焦虑症包括广泛性焦虑症（GAD）、恐慌症、各种恐惧症和创伤后应激障碍（PTSD），它们是最常见和最昂贵的精神疾病。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起着守门人的作用，特别是在广泛性焦虑症和惊恐障碍中。GABA-A受体γ - 2亚基基因杂合突变的小鼠已被建立为这种焦虑的动物模型，这种焦虑表现出与人类广泛性焦虑症相似的行为和认知缺陷。胚胎发育过程中锥体前脑神经元中这种基因的条件缺失导致成年小鼠过度的特质焦虑。与特质焦虑的发育机制一致，γ - 2亚基杂合小鼠表现出海马神经发生和血清素能传递减少。基于这些观察，我们假设(1)特质焦虑是由于在发育过程中海马神经元的特定类型的损失。我们进一步假设（II） GABA-A受体缺陷导致血清素能传递缺陷，从而导致特质焦虑的表现。我们还预测（III）用抗抑郁药和神经发生增强药物治疗年轻突变小鼠可以防止成年小鼠的特质焦虑的发展。最后，（IV）我们假设海马和大脑皮层的GABA-A受体缺陷独立于杏仁核的缺陷来建立焦虑样表型。总之，这些研究将极大地促进我们对焦虑和抑郁障碍的机制的理解。

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.