Increased vulnerability of BDNF deficient mice to mild stress

BDNF 缺陷小鼠对轻度应激的脆弱性增加

• 批准号: 7459258
• 负责人: JULIE Gorton HENSLER
• 金额: $ 18.54万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459258
• 关键词: Acute; Adult; Anhedonia; Antidepressive Agents; Anxiety; Architecture; Atrophic; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Characteristics; Chronic; Complex; Consumption; Corticosterone; Corticotropin; Data; Desipramine; Disease; Environmental Risk Factor; Estrogens; Etiology; Exhibits; Female; Fibrinogen; Genes; Genetic; Genetic Polymorphism; Hand; Hippocampus (Brain); Hour; Human; Individual; Injection of therapeutic agent; Intraperitoneal Injections; Major Depressive Disorder; Measures; Mental disorders; Messenger RNA; Modeling; Mus; Neurobiology; Neurons; Physiological; Plasma; Play; Predisposition; Procedures; Prosencephalon; Proteins; Role; Saline; Solutions; Stress; Sucrose; Swimming; Synaptic plasticity; Syndrome; Testing; Time; Tricyclic Antidepressive Agents; Wild Type Mouse; behavior test; depression; depressive symptoms; indexing; interest; male; neurochemistry; public health relevance; research study; response; stressor

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.

描述（由申请人提供）：脑衍生的神经营养因子（BDNF）在确定成人大脑中神经元的可塑性和功能结构方面起着基本作用。最近已经确定了人类BDNF基因中常见的非保守多态性，这导致BDNF的分泌受损，并且可能是增加个人对由压力带来的精神疾病敏感性的因素，例如大抑郁症。小鼠提供了一个独特的机会，可以在确定行为时检查环境因素（例如压力和遗传因素（例如BDNF）缺乏）之间的相互作用。我们有有趣的初步数据，表明盐水的轻度压力和注射盐水不会改变野生型小鼠的行为，会在雄性BDNF（）小鼠中产生类似抑郁症的行为。我们的总体假设是，与野生型小鼠相比，BDNF缺乏小鼠更容易受到轻度应激的影响。我们将使用腹膜内注射盐水作为轻度处理应力。注射盐水将用作临时和简单的压力源，小鼠很容易习惯。由于BDNF促进了依赖活性的突触可塑性，并且可能在调节反复应力的反应中起作用，因此我们假设缺乏BDNF的小鼠不会习惯于重复注射盐水。我们将测量肾上腺皮质激素（ACTH）和皮质酮的血浆水平，作为BDNF（）小鼠反应性在急性后立即进行压力的生理指示（3盐水24小时内3注射盐水）和慢性（一旦每天每天对盐水造成7天的伤害）处理压力程序（特定于盐水）。在这种探索性应用中，我们将模拟严重抑郁症的复杂综合征，而是对抑郁症的症状进行建模，这些症状是这种疾病的标志，例如（a）绝望，以及（b）（b）对正常令人愉悦的活动或抗痛苦的兴趣丧失。为此，我们将在强制游泳测试（特定的AIM 2）和两瓶选择测试中的bdnf（）小鼠（特定目标2）中测量不动的小鼠（特定的AIM 3）。我们还假设行为抑郁症的迹象将被三环抗抑郁剂甲状胺逆转。由于雌激素在海马和皮质中阳性调节BDNF mRNA和蛋白质，这可能会使雌性小鼠对压力的有害影响较小，因此我们将在雄性和雌性小鼠中进行这些拟议的探索实验。 BDNF（）小鼠似乎表现出与主要抑郁症的理论或拟议病因一致的特征。在此探索性应用中，我们通过确定轻度处理应力对经常使用的行为抑郁指数的影响进一步研究了该模型的有效性。该模型的有效性将使在BDNF（）小鼠中进一步研究神经生物学和神经化学机制，BDNF缺乏症给压力脆弱性带来了极大的兴趣。公共卫生相关性：大脑中脑衍生的神经营养因子（BDNF）的表达会因压力而降低，并通过慢性抗抑郁治疗增加。最近已经确定了人类BDNF基因中常见的非保守多态性，这导致BDNF的分泌受损，并且可能是增加个人对压力带来的精神疾病的敏感性的一个因素。因此，与压力相关的精神疾病（例如严重抑郁症）可能是由于大脑中BDNF反应性神经元功能的细微萎缩或功能降低而引起的。