Mouse Models, KOs, Transgenics, and Gene Expression Monoamine Systems

抑郁症是一种精神疾病，其中情绪障碍是一个突出的特点。虽然 抑郁症的病因尚不清楚，肾上腺素能和去甲肾上腺素能功能的改变， 与病情有关目前的康特中心赠款建议检查抑郁症， 功能成像，形态测量学和人类药理学干预的观点， 以及通过小鼠遗传、分子、生物化学、行为和电生理模型， 抑郁症本提案的总体目标是显示去甲肾上腺素（NE） 和5-羟色胺（5-HT）系统在症状的发展和改善中是相互依赖的 并揭示导致这种疾病的新机制。有三大 目标。目的1：探讨NE转运体、5-HT转运体和囊泡转运体在抑郁症中的作用 将研究单胺转运蛋白2。抗抑郁药对单胺和 将研究不同脑区域中的代谢物水平。信号分子指纹 转导途径将用于分析基因型和抗抑郁治疗的影响。目的 2：分析糖原合成酶激酶-3 β（GSK 3b）在抑制中的作用。小鼠将被 开发了在CNS中选择性缺失GSK 3b的细胞。将根据以下标准评价动物 行为、神经递质和信号转导对抗抑郁药的反应。目的3：小鼠将 其具有与在人类中发现的色氨酸羟化酶2（Tph 2）相同的多态性 抑郁症患者。将根据行为、神经递质和信号检查突变体 抗抑郁药和电休克疗法的转导反应。

Depression is a psychiatric disorder where disturbance of mood is a prominent feature. Although the etiology of depression is unknown, alterations in serotonergic and noradrenergic function are implicated in the condition. The present Conte Center Grant proposes to examine depression from perspectives of functional imaging, morphometrics, and pharmacological interventions in humans, as well as though mouse genetic, molecular, biochemical, behavioral, and electrophysiological models of depression. The overall objective of the present proposal is to show how the norepinephrine (NE) and serotonin (5-HT) systems are interdependent in the development and amelioration of symptoms of depression, and to reveal novel mechanisms that contribute to the disorder. There are three major Aims. AIM 1: The roles in depression of the NE transporter, 5-HT transporter, and vesicular monoamine transporter 2 will be investigated. Effects of antidepressants on monoamine and metabolite levels in various brain regions will be studied. Molecular fingerprinting of signal transduction pathways will be used to analyze effects of genotype and antidepressant treatment. AIM 2: The role in depression of glycogen synthase kinase-3beta (GSK3b) will be analyzed. Mice will be developed that have GSK3b selectively deleted in the CNS. Animals will be evaluated according to behavioral, neurotransmitter, and signal transduction responses to antidepressants. AIM 3: Mice will be made that bear the same polymorphisms in tryptophan hydroxylase 2 (Tph2) found in human depressed patients. Mutants will be examined according to behavioral, neurotransmitter, and signal transduction responses to antidepressants and electroconvulsive therapy.