Increased vulnerability of BDNF deficient mice to mild stress

描述(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发挥着重要作用。最近发现了一种频繁的、非保守的人类BDNF基因多态性，它导致BDNF的分泌受损，可能是增加个体对应激引起的精神疾病(如重度抑郁症)的易感性的因素之一。在决定行为方面，老鼠提供了一个独特的机会来检查环境因素(如压力)和遗传因素(如脑源性神经营养因子缺乏)之间的相互作用。我们有有趣的初步数据表明，温和的处理和注射生理盐水的应激不会改变野生型小鼠的行为，但会在雄性BDNF()小鼠中产生抑郁样行为。我们的总体假设是，BDNF缺陷小鼠比野生型小鼠更容易受到温和应激的影响。我们将使用腹腔注射生理盐水作为温和的处理压力。注射生理盐水将被用作一种时间离散的简单应激源，小鼠很容易习惯于这种应激源。由于BDNF促进活性依赖的突触可塑性，并可能在调节对重复应激的反应中发挥作用，我们假设BDNF缺陷的小鼠不会习惯于重复注射生理盐水。我们将检测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小时内注射3次生理盐水)和慢性(每天注射生理盐水7天)处理应激程序(特定目标1)后立即对应激反应的生理指标。在这一探索性应用中，我们将模拟抑郁症的特征症状，例如(A)绝望和(B)对通常令人愉快的活动或快感丧失兴趣，而不是试图对严重抑郁症的复杂症状进行建模。为此，我们将在BDNF()小鼠中测量强迫游泳测试中的不动(特定目标2)和两瓶选择测试中的蔗糖消耗量(特定目标3)。我们还假设，行为抑郁的迹象将被三环类抗抑郁剂地塞帕明逆转。由于雌激素正向调节海马区和皮质内的BDNF mRNA和蛋白质，这可能会使雌性小鼠不太容易受到压力的有害影响，因此我们将在雄性和雌性小鼠身上进行这些拟议的探索性实验。BDNF()小鼠似乎表现出与严重抑郁障碍的理论或建议的病因学一致的特征。在这一探索性应用中，我们通过确定温和的操作压力对常用的行为抑郁指数的影响，进一步检验了该模型的有效性。这一模型的有效性将使人们对进一步研究BDNF()小鼠的神经生物学和神经化学机制产生极大的兴趣，BDNF缺乏通过这种机制使人容易受到压力的影响。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，而经慢性抗抑郁药物治疗后增加。最近发现了一种频繁的、非保守的人类BDNF基因多态性，它导致BDNF的分泌受损，可能是增加个体对应激引起的精神障碍的易感性的因素之一。因此，与压力相关的精神障碍，如严重的抑郁症，可能是由于大脑中BDNF反应神经元的轻微萎缩或功能减弱造成的。

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.