BDNF in depression, antidepressant action, and memory

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）的增加，通过管理的各种类型的抗抑郁治疗和BDNF输注到大脑中具有抗抑郁作用的动物模型。此外，BDNF在海马和其他区域中的突触传递和突触可塑性的急性调节中的作用暗示了在学习和记忆范例中的作用。拟议的研究将检查BDNF在成年人大脑中的作用，以及对抗抑郁治疗的反应。这些研究还将筛选BDNF缺陷小鼠在两种学习和记忆模式中的缺陷。我们假设，在抑郁症的动物模型中，大脑中缺乏BDNF的小鼠将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肿瘤治疗的有益作用。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模式的缺陷。最后，我们将研究BDNF在支持成人脑中单胺能和多巴胺能投射中的作用。这些研究将增强我们对抑郁症的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。研究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，并可能导致临床记忆障碍（如阿尔茨海默病）的新治疗考虑。到目前为止，研究BDNF在行为模式中的作用一直很困难，因为组成性BDNF敲除小鼠的出生后早期致死性和感觉异常。我们的方法将是利用脑定向，诱导BNDF基因敲除小鼠，已产生在雀巢实验室。该系统避免了传统敲除方法的发育和外周效应。我们还建议利用局灶性注射表达Cre的AAV载体进入BDNF小鼠，以评估涉及更大的时间特异性的特定脑亚区。

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.