Increased vulnerability of BDNF deficient mice to mild stress

描述（由申请人提供）：脑源性神经营养因子（BDNF）在决定成人大脑神经元的可塑性和功能结构方面起着重要作用。最近已经鉴定了人BDNF基因中的一种频繁的非保守多态性，其导致BDNF分泌受损，并且可能是增加个体对由压力引起的精神障碍（例如重性抑郁症）的易感性的一个因素。小鼠提供了一个独特的机会来研究环境因素（如压力）和遗传因素（如BDNF缺乏）之间的相互作用，以决定行为。我们有有趣的初步数据表明，轻微的压力处理和注射生理盐水，这不会改变野生型小鼠的行为，产生抑郁样行为的雄性BDNF（）小鼠。我们的总体假设是，BDNF缺陷小鼠比野生型小鼠更容易受到轻度应激的影响。我们将使用腹膜内注射生理盐水作为轻度处理应激。注射生理盐水将用作小鼠容易适应的时间离散和简单的应激源。由于BDNF促进活动依赖性突触可塑性，并且可能在调节对重复应激的反应中起作用，因此我们假设BDNF缺陷的小鼠不会习惯于重复注射盐水。我们将测量促肾上腺皮质激素（ACTH）和皮质酮的血浆水平，作为BDNF（）小鼠在急性（24小时内注射3次盐水）和慢性（每天注射一次盐水，持续7天）处理应激程序（具体目标1）后立即对应激反应性的生理指标。在这个探索性的应用中，我们并不试图对复杂的重性抑郁症综合征进行建模，而是将对这种疾病的标志性抑郁症症状进行建模，例如（a）绝望，（B）对正常愉快的活动失去兴趣或快感缺乏。为此，我们将在强迫游泳测试（特定目标2）中测量BDNF（）小鼠的不动性，并在两瓶选择测试（特定目标3）中测量蔗糖消耗。我们还假设行为抑郁症的症状将被三环类抗抑郁药地昔帕明逆转。由于雌激素积极调节海马和皮质内的BDNF mRNA和蛋白质，这可能使雌性小鼠不易受到压力的有害影响，我们将在雄性和雌性小鼠中进行这些探索性实验。BDNF（）小鼠表现出与重性抑郁症的理论或提出的病因学一致的特征。在这个探索性的应用程序中，我们进一步研究这个模型的有效性，通过确定经常使用的行为抑郁指数的影响，轻度处理压力。这一模型的有效性将使进一步研究BDNF（）小鼠的神经生物学和神经化学机制，BDNF缺乏赋予脆弱性的压力，极大的兴趣。公共卫生相关性：脑源性神经营养因子（BDNF）在大脑中的表达因应激而减少，并因慢性抗抑郁治疗而增加。最近已经鉴定了人BDNF基因中的频繁的非保守多态性，其导致BDNF分泌受损，并且可能是增加个体对由压力引起的精神障碍的易感性的一个因素。因此，与压力相关的精神疾病，如重度抑郁症，可能是由脑中BDNF反应神经元的轻微萎缩或功能减弱引起的。

DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) plays a fundamental role in determining the plasticity and functional architecture of neurons in the adult brain. A frequent, non-conservative polymorphism in the human BDNF gene has been recently identified, which results in impaired secretion of BDNF and may be one factor that increases the susceptibility of an individual to psychiatric disorders brought about by stress, such as major depression. Mice offer a unique opportunity to examine interactions between environmental factors, such as stress, and genetic factors, such as a deficiency in BDNF, in determining behavior. We have interesting preliminary data that indicate that the mild stress of handing and injection of saline, which does not alter behavior in wild-type mice, produces depression-like behavior in male BDNF() mice. Our overall hypothesis is that BDNF deficient mice are more vulnerable to the effects of mild stress than the wild-type mice. We will use intraperitoneal injection of saline as a mild handling stress. The injection of saline will be used as a temporally discrete and simple stressor to which mice easily habituate. Because BDNF promotes activity- dependent synaptic plasticity, and may have a role in the modulation of responses to repeated stress, we hypothesize that mice deficient in BDNF will not habituate to repeated injections of saline. We will measure plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone as a physiological indication of the reactivity of BDNF() mice to stress immediately following the acute (3 injections of saline over 24 hours) and chronic (once daily injection of saline for 7 days) handling stress procedures (Specific Aim 1). In this exploratory application, rather than attempt to model the complex syndrome of major depression, we will model symptoms of depression that are hallmarks of this disorder such as (a) despair, and (b) loss of interest in normally pleasurable activities or anhedonia. To this end, we will measure in BDNF() mice immobility in the forced swim test (Specific Aim 2) and sucrose consumption in a two bottle choice test (Specific Aim 3). We also hypothesize that signs of behavioral depression will be reversed by the tricyclic antidepressant desipramine. Because estrogen positively modulates BDNF mRNA and protein within the hippocampus and cortex, which may make female mice less vulnerability to the deleterious effects of stress, we will conduct these proposed exploratory experiments in both male and female mice. BDNF() mice appear to exhibit characteristics consistent with theoretical or proposed etiology of major depressive disorder. In this exploratory application we further examine the validity of this model by determining the effect of mild handling stress on often used indices of behavioral depression. The validity of this model will make it of great interest to further examine in BDNF() mice the neurobiological and neurochemical mechanisms by which BDNF deficiency confers vulnerability to stress. PUBLIC HEALTH RELEVANCE: Brain-derived neurotrophic factor (BDNF) expression in the brain is decreased by stress and increased by chronic antidepressant treatments. A frequent, non-conservative polymorphism in the human BDNF gene has been recently identified, which results in impaired secretion of BDNF and may be one factor that increases the susceptibility of an individual to psychiatric disorders brought about by stress. Thus, stress-related psychiatric disorders, such as major depression, may result from a subtle atrophy or diminished function of BDNF- responsive neurons in the brain.