BDNF Mutants: Genetic Models for Depressive Disorders

BDNF 突变体：抑郁症的遗传模型

• 批准号: 6876085
• 负责人: Maribel Rios
• 金额: $ 35.66万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876085
• 关键词: behavior test; behavioral /social science research tag; behavioral genetics; brain derived neurotrophic factor; brain mapping; disease /disorder model; dopamine; electrophysiology; genetic models; laboratory mouse; microarray technology; mood disorders; mutant; neural plasticity; neural transmission; neurogenetics; norepinephrine; serotonin; stress

DESCRIPTION (provided by applicant): Depressive disorders are debilitating conditions that affect millions of individuals and create an enormous burden on society. Close to 100 billion dollars per year are spent treating patients with severe and mild forms of depression in the United States alone. However, the underlying molecular mechanisms that trigger depression remain to be elucidated so that treatment alternatives for patients that are unresponsive to the current forms of therapy can be created. A potential target for the design of novel treatment strategies is brain derived neurotrophic factor (BDNF). Compelling evidence shows that BDNF modulates affective behavior but the specific role and the mechanism of action of this neurotrophin remain elusive. We recently generated conditional mutations of BDNF using the cre recombinase/IoxP system. These mice have a pre or postnatal depletion of BDNF in the central nervous system that does not compromise their viability as the global depletion of BDNF does. These mutants display dramatic changes in behavior including hyperaggression and hypersensitivity to stress, both of which are often symptoms of depression. We propose using these mutants, and others that we are currently generating, as genetic models of depressive disorders to dissect the role of BDNF in the regulation of behavior. Different lines of mutants that through genetic manipulation have depletion or over expression of BDNF in different regions of the brain associated with mood disorders will be tested using standard behavioral models for depression and aggression.

描述（由申请人提供）：抑郁症是一种使人衰弱的疾病，影响数百万人并给社会造成巨大负担。仅在美国，每年就有近 1000 亿美元用于治疗重度和轻度抑郁症患者。然而，引发抑郁症的潜在分子机制仍有待阐明，以便为对当前治疗形式无反应的患者创造治疗替代方案。设计新型治疗策略的潜在目标是脑源性神经营养因子（BDNF）。令人信服的证据表明 BDNF 调节情感行为，但这种神经营养蛋白的具体作用和作用机制仍然难以捉摸。我们最近使用 cre 重组酶/IoxP 系统生成了 BDNF 的条件突变。这些小鼠在出生前或出生后中枢神经系统中 BDNF 缺失，但不会像整体 BDNF 缺失那样损害它们的生存能力。这些突变体表现出巨大的行为变化，包括过度攻击性和对压力过度敏感，这两者通常都是抑郁症的症状。我们建议使用这些突变体以及我们目前正在产生的其他突变体作为抑郁症的遗传模型来剖析 BDNF 在行为调节中的作用。通过基因操作，在与情绪障碍相关的大脑不同区域中 BDNF 缺失或过度表达的不同突变体系将使用抑郁和攻击性的标准行为模型进行测试。