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中起着重要作用。最近发现了人类BDNF基因中一个频繁的、非保守的多态性，它导致BDNF分泌受损，可能是增加个体对压力引起的精神疾病（如重度抑郁症）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）在决定行为方面的相互作用。我们有有趣的初步数据表明，在处理和注射生理盐水的轻微压力下，野生型小鼠的行为不会改变，但雄性BDNF（）小鼠会产生类似抑郁的行为。我们的总体假设是BDNF缺乏的小鼠比野生型小鼠更容易受到轻度压力的影响。我们将使用腹腔内注射生理盐水作为轻度处理压力。生理盐水的注射将被用作暂时离散和简单的应激源，小鼠很容易适应。由于BDNF促进活动依赖的突触可塑性，并可能在对重复应激反应的调节中发挥作用，我们假设缺乏BDNF的小鼠不会习惯于重复注射生理盐水。我们将测量血浆促肾上腺皮质激素（ACTH）和皮质酮水平，作为BDNF（）小鼠在急性（24小时内3次注射生理盐水）和慢性（每天1次注射生理盐水，持续7天）处理应激过程（具体目标1）后对应激反应性的生理指标。在这个探索性的应用中，我们不是试图模拟严重抑郁症的复杂综合症，而是将模拟抑郁症的症状，这些症状是这种疾病的标志，如(a)绝望，(b)对正常愉快的活动失去兴趣或快感缺乏。为此，我们将在强迫游泳试验（Specific Aim 2）和两瓶选择试验（Specific Aim 3）中测量BDNF小鼠的不动性。我们还假设，三环抗抑郁药地西帕明可以逆转行为抑郁症的症状。由于雌激素正向调节海马和皮质内的BDNF mRNA和蛋白，这可能使雌性小鼠更不容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拟议的探索性实验。BDNF（）小鼠似乎表现出与理论或提出的重度抑郁症病因学一致的特征。在这个探索性应用中，我们通过确定轻度处理压力对行为抑郁常用指标的影响来进一步检验该模型的有效性。该模型的有效性将使进一步研究BDNF（）小鼠中BDNF缺乏导致应激易感性的神经生物学和神经化学机制具有重要意义。公共卫生相关性：脑源性神经营养因子（BDNF）在大脑中的表达因压力而降低，并因慢性抗抑郁治疗而增加。人类BDNF基因中一个频繁的、非保守的多态性最近被发现，它导致BDNF分泌受损，可能是增加个体对压力引起的精神疾病易感性的一个因素。因此，与压力相关的精神疾病，如重度抑郁症，可能是由大脑中BDNF反应神经元的细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.