BDNF in depression, antidepressant action, and memory.

BDNF 在抑郁、抗抑郁作用和记忆中的作用。

• 批准号: 6711633
• 负责人: Craig M Powell
• 金额: $ 17万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711633
• 关键词: amygdala; antidepressants; behavior test; behavioral /social science research tag; brain derived neurotrophic factor; depression; emotions; gene targeting; genetically modified animals; hippocampus; in situ hybridization; laboratory mouse; learning; memory; neural transmission; neurons; polymerase chain reaction; prefrontal lobe /cortex; synapses; transfection

DESCRIPTION (provided by applicant): The neurologic basis of depression and response to antidepressant treatment remain uncertain. Recent evidence suggests that the brain derived neurotrophic factor (BDNF) is increased by administration of various classes of antidepressant treatments and BDNF infusion into the brain has antidepressant effects in animal models. Furthermore, BDNF's role in acute regulation of synaptic transmission and synaptic plasticity in the hippocampus and other areas, implicates a role in learning and memory paradigms. The proposed studies will examine the role of BDNF in the adult brain in depression and response to antidepressant treatments. These studies will also screen BDNF deficient mice for deficits in two learning and memory paradigms. We hypothesize that mice lacking BDNF in the brain will exhibit increased susceptibility stress effects in animal models of depression and that these mice will be less susceptible to beneficial effects of anitidepressant therapy. We further hypothesize that mice lacking BDNF in the brain will exhibit deficits in learning and memory paradigms. Finally, we will examine the role of BDNF in support of monoaminergic and serotonergic projections in the adult brain. These studies will enhance our understanding of the pathophysiology of depression and mechanisms of antidepressant action. This knowledge may lead to new therapeutic targets in depression. Experiments examining the role of BDNF in spatial and emotional learning and memory will further our understanding of how neurotrophic factors can influence learning and memory and may lead to new therapeutic considerations in clinical disorders of memory such as Alzheimer's disease. To date, studies examining the role of BDNF in behavioral paradigms have been difficult due to the early postnatal lethality and sensory abnormalities of constitutive BDNF knockout mice. Our approach will be to make use of brain-directed, inducible BNDF knockout mice that have been generated in the Nestler laboratory. This system avoids developmental and peripheral effects of traditional knockout approaches. We also propose to make use of focal injection of Cre-expressing AAV vectors into flox-BDNF mice to assess the specific brain subregions involved with greater temporal specificity.

描述（由申请人提供）：抑郁症的神经学基础和抗抑郁药治疗的反应仍不确定。最近的证据表明，脑源性神经营养因子 (BDNF) 通过施用各种类型的抗抑郁药物而增加，并且在动物模型中将 BDNF 输注到大脑中具有抗抑郁作用。此外，BDNF 在海马体和其他区域的突触传递和突触可塑性的急性调节中的作用，暗示了其在学习和记忆范式中的作用。拟议的研究将探讨 BDNF 在成人大脑中在抑郁症中的作用以及抗抑郁治疗的反应。这些研究还将筛查 BDNF 缺陷小鼠在两种学习和记忆范式中的缺陷。我们假设大脑中缺乏 BDNF 的小鼠在抑郁症动物模型中表现出增加的易感性应激效应，并且这些小鼠将不太容易受到抗抑郁治疗的有益效果的影响。我们进一步假设大脑中缺乏 BDNF 的小鼠将表现出学习和记忆范式的缺陷。最后，我们将研究 BDNF 在支持成人大脑中单胺能和血清素能投射中的作用。这些研究将增强我们对抑郁症病理生理学和抗抑郁作用机制的理解。这些知识可能会导致抑郁症的新治疗目标。检查 BDNF 在空间和情感学习和记忆中的作用的实验将进一步加深我们对神经营养因子如何影响学习和记忆的理解，并可能为阿尔茨海默病等临床记忆障碍带来新的治疗考虑。迄今为止，由于 BDNF 基因敲除小鼠的产后早期致死率和感觉异常，研究 BDNF 在行为范式中的作用一直很困难。我们的方法是利用雀巢实验室培育的大脑定向、可诱导的 BNDF 敲除小鼠。该系统避免了传统敲除方法的发育和外围效应。我们还建议将表达 Cre 的 AAV 载体局部注射到 flox-BDNF 小鼠中，以评估涉及更大时间特异性的特定大脑亚区域。