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

抑郁症是一种精神障碍，情绪障碍是其显著特征。尽管 抑郁症的病因不明，5-羟色胺能和去甲肾上腺素能功能的改变 与这种情况有牵连。目前的Conte Center Grant建议从 人体功能成像、形态计量学和药物干预的前景 以及尽管小鼠的遗传、分子、生化、行为和电生理模型 抑郁的症状。本提案的总体目标是显示去甲肾上腺素(NE)如何 和5-羟色胺(5-羟色胺)系统在症状的发生和改善中相互依赖 并揭示导致这种疾病的新机制。主要有三个方面 目标。目的1：去甲肾上腺素转运体、5-羟色胺转运体和囊泡在抑郁症中的作用 将对单胺转运体2进行调查。抗抑郁药对单胺类药物的影响 我们将研究不同脑区的代谢物水平。信号的分子指纹图谱 转导通路将用于分析基因和抗抑郁药物治疗的效果。目标 2：分析糖原合成酶激酶-3β(GSK3b)在抑制中的作用。老鼠会成为 已开发出在CNS中选择性缺失GSK3b的基因。对动物的评估将根据 抗抑郁药的行为、神经递质和信号转导反应。目标3：老鼠会 在人类中发现的色氨酸羟化酶2(TPH2)具有相同的多态性 抑郁的病人。突变体将根据行为、神经递质和信号进行检查。 抗抑郁药物和电休克治疗的转导反应。

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.