Uncovering antidepressive mechanisms of glutamatergic antagonism through neurocircuit, metabolic and morphological brain changes in a genetical rat model of depression

重度抑郁症仍然是一个紧迫的临床问题，导致长期残疾，并构成了相当大的治疗挑战，因为只有约三分之二的患者对标准抗抑郁药有反应。优化治疗需要更好地定义所涉及的脑回路的功能和特异性。有越来越多的证据表明，这是一个重要的神经系统。一项在难治性抑郁症（TRD）患者中进行的随机临床试验显示，谷氨酸能N-甲基D-天冬氨酸受体拮抗剂氯胺酮具有快速的抗抑郁作用。这种快速反应与传统抗抑郁药的临床时间进程形成鲜明对比，后者需要数周时间，并为显着的治疗改善提供了希望。我们将使用先天性习得无助株（congenital learned helpful strain，cLH）作为一种有效的TRD遗传动物模型，以回答以下问题：1.氯胺酮攻击后，脑中发生了哪些功能、形态和代谢变化，这些变化中哪些可以解释其抗抑郁作用？2.高剂量与低剂量氯胺酮对脑功能连接、形态学和代谢的影响有何差异？3.引起快速抗抑郁反应的最佳氯胺酮剂量是多少？4.急性和长期（慢性）氯胺酮是否引起持续的抗抑郁作用？5.急性或慢性给药时氯胺酮的作用有什么区别？将通过静息状态功能磁共振成像检测脑功能变化，并通过磁共振波谱和基于体素的形态测定检测代谢和形态学变化。将测试大鼠的习得性无助，并将其在该范例中的行为与脑功能变化相关联。

Major depression remains a pressing clinical problem responsible for long-term disability and poses a considerable therapeutic challenge since only about two thirds of patients respond to standard antidepressants. Optimizing treatment requires better definition of the function and specificity of the brain circuits involved. There is a growing body of evidence implicating a role for the glutamatergic system. A randomized clinical trial in treatment-resistant depressed (TRD) patients revealed that glutamatergic NmethylDaspartate receptor antagonist ketamine elicits rapid antidepressant effects. This rapid response contrasts markedly with the clinical time course of conventional antidepressants, which takes weeks, and offer the hope for significant therapeutic improvements. We will use the congenital learned helpless strain (cLH) as a validated genetic animal model of TRD to answer the following questions: 1.What functional, morphological and metabolic changes occur in the brain after ketamine challenge and which of these changes could explain its antidepressant effect? 2.What is the difference in the effects of high versus low dose of ketamine on brain functional connectivity, morphology and metabolism? 3.What is the optimum ketamine dose to elicit a rapid antidepressant response? 4.Does acute and long-term (chronic) ketamine elicit a sustained antidepressant effect? 5.What is the difference in ketamine effects when administered acutely or chronically?Brain functional changes will be detected by resting state functional magnetic resonance imaging, and metabolic and morphological alterations by magnetic resonance spectroscopy and voxel based morphometry. Rats will be tested for learned helplessness, and their behavior in this paradigm will be correlated with brain functional changes.