GENETIC MODEL ROLE NEUROGENESIS ANTIDEPRESSANT RESPONSE

遗传模型作用神经发生抗抑郁反应

• 批准号: 7141802
• 负责人: ROBERT DAVID BEECH
• 金额: $ 23.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141802
• 关键词: amitriptyline; antidepressants; behavior test; behavioral /social science research tag; bromodeoxyuridine; cell proliferation; disease /disorder model; fluoxetine; genetic models; genetically modified animals; hippocampus; laboratory mouse; major depression; neurogenesis; neuropharmacology; neurotransmitter antagonist; norepinephrine; pharmacogenetics; psychological stressor; psychopharmacology; serotonin inhibitor; tissue /cell culture; transcription factor; tricyclic antidepressant

DESCRIPTION (provided by applicant): Patients with major depression, bipolar disorder and schizophrenia have all been found to have decreased hippocampal volumes, suggesting that decreased hippocampal cell number may be a common endophenotype in multiple mental illnesses. Several classes of psychotropic medications including antidepressants, mood stabilizers and atypical antipsychotics have also been shown to increase neurogenesis in the adult hippocampus. The relationship between adult neurogenesis and the behavioral response to psychotropic medications remains unclear, however recent evidence suggests that generation of new neurons may be critical for antidepressant action. To investigate the role of hippocampal neurogenesis in antidepressant-response we will make use of a novel genetic model for deficits in adult neurogenesis: BF- 1/FoxG1 heterozygous mice. BF-1/FoxG1 is a transcriptional represser that inhibits signaling through the Smad/TGF-beta pathway, and is required for the normal development of the cerebral hemispheres. Mice lacking both copies of the BF-1/FoxG1 gene die shortly before birth (E18.5). Heterozygous BF-1/FoxG1 mice survive, but do not produce new neurons as adults. Thus, these mice offer a genetic model for an endophenotype common to several metal illnesses. To explore the hypothesis that increasing adult neurogenesis is critical for response to antidepressant medications we will treat BF-1/FoxG1 heterozygous mice with different classes of antidepressant medications including tricyclic antidepressants (amitriptyline), serotonin-specific reuptake inhibitors (fluoxetine) and norepinephrine-specific reuptake inhibitors (reboxetine), either subchronically or chronically and characterize both the behavioral response and the effects (if any) on neurogenesis. Preliminary results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, follow up studies will extend these studies to other classes of medications including atypical antipsychotics, which may similarly be dependent on adult neurogenesis for their clinical effects. These studies should lead to a better understanding of the mechanism of action of existing antidepressant medications. This, in turn, should allow for a more rational search for new medications for the treatment of depression, and potentially other mental illnesses as well.

描述（申请人提供）：重度抑郁症、双相情感障碍和精神分裂症患者均被发现海马体积减少，表明海马细胞数量减少可能是多种精神疾病的常见内表型。包括抗抑郁药、情绪稳定剂和非典型抗精神病药在内的几类精神药物也被证明可以增加成人海马体的神经发生。成人神经发生和对精神药物的行为反应之间的关系仍不清楚，但最近的证据表明新神经元的产生可能对于抗抑郁作用至关重要。为了研究海马神经发生在抗抑郁药反应中的作用，我们将利用一种针对成年神经发生缺陷的新型遗传模型：BF-1/FoxG1 杂合小鼠。 BF-1/FoxG1 是一种转录抑制因子，通过 Smad/TGF-β 途径抑制信号传导，是大脑半球正常发育所必需的。缺乏 BF-1/FoxG1 基因两个拷贝的小鼠在出生前不久死亡 (E18.5)。杂合 BF-1/FoxG1 小鼠能够存活，但成年后不会产生新的神经元。因此，这些小鼠为几种金属疾病常见的内表型提供了遗传模型。为了探索增加成年神经发生对于抗抑郁药物反应至关重要的假设，我们将使用不同类别的抗抑郁药物治疗 BF-1/FoxG1 杂合小鼠，包括三环类抗抑郁药（阿米替林）、血清素特异性再摄取抑制剂（氟西汀）和去甲肾上腺素特异性药物再摄取抑制剂（瑞波西汀），无论是亚慢性还是长期，并表征行为反应和效果（如果任何）关于神经发生。这些研究的初步结果应导致 RO1 提案旨在扩展这些研究结果。简而言之，后续研究将把这些研究扩展到其他类别的药物，包括非典型抗精神病药物，这些药物的临床效果可能同样依赖于成人神经发生。这些研究应该有助于更好地了解现有抗抑郁药物的作用机制。反过来，这应该允许更合理地寻找治疗抑郁症和其他潜在精神疾病的新药物。