Chemical Profiles of Brain Synapses at Ages Vulnerable to Activity-Based Anorexia

易患活动性厌食症年龄的大脑突触的化学特征

• 批准号: 8145258
• 负责人: CHIYE J AOKI
• 金额: $ 14.73万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145258
• 关键词: Address; Adrenal Glands; Adult; Age; Age of Onset; Allopregnanolone; Amygdaloid structure; Animal Model; Anorexia; Anorexia Nervosa; Anxiety; Anxiety Disorders; Appetite Depressants; Behavior; Behavior assessment; Behavioral; Biochemical; Brain; Brain region; Cell membrane; Chemicals; Childhood; DSM-IV; Data; Dependence; Development; Drug Delivery Systems; Electrons; Exhibits; Family; Female; Glutamate Receptor; Goals; Healthcare Systems; Hippocampus (Brain); Hormonal Change; Hormones; Human; Individual; Isomerism; Life; Limbic System; Link; Measurement; Membrane; Mental disorders; Microscopic; Modeling; Molecular; Neurotransmitter Receptor; Neurotransmitters; Ovarian; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Population; Prefrontal Cortex; Process; Progesterone; Puberty; Rattus; Recovery; Relapse; Rodent; Running; Severities; Site; Staging; Steroids; Stress; Stressful Event; Structure; Synapses; System; Testing; Western Blotting; base; behavior test; body system; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; male; mortality; neural circuit; neurosteroids; novel; prepuberty; prevent; public health relevance; receptor; receptor density; receptor expression; sensory cortex; sex

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) is a psychiatric illness with no accepted pharmacological treatment [1] and with one of the highest mortality rates among the mental illnesses (10-20%) [2-4]. Even if not fatal, AN can cause life-long damages to multiple organ systems, creating an increased burden on the health care system. AN has a stereotypical age of onset at puberty, with 90-95% of cases occurring in females [5]. This developmental pattern suggests that hormonal changes in females associated with puberty may trigger changes in brain connections that increase an individual's vulnerability to stress, anxiety and AN. AN is also associated with frequent relapses[6], suggesting that anorectic behavior during this pivotal, final stage of brain development may cause long-lasting changes in brain connections. The long-term goal of this project is to identify developmental changes at central synapses that are linked to AN vulnerability among females entering puberty and to characterize changes that are induced further by this illness and following recovery. We will test a novel hypothesis - namely, that pubertal females are more vulnerable to AN due to fluctuation in the release of a neurosteroid, THP, that triggers an increased expression of a4b2d GABAA receptors at the plasma membrane of hippocampal pyramidal neurons which, in turn, renders the hippocampus hyper-excitable during stressful events. This THP-GABA hypothesis will be tested by using an animal model of AN, activity-based anorexia (ABA), which captures multiple key features of AN but for which the sex- and age-dependence have not been fully explored. We will first run behavioral tests to determine whether the two key factors that influence the human population - age and sex - also influence ABA vulnerability of rodents. This will be achieved by comparing the behavioral factors related to the development of ABA, recovery from ABA and ABA relapse across 3 developmental stages (prepubertal, pubertal, and adulthood) and 2 sexes (male and female). We will then use biochemical and electron microscopic immunocytochemical approaches to determine whether a4b2d GABAA receptor expressions in certain brain regions (biochemical data) and at synapses (EM data) correlate with ABA vulnerability, development, recovery and relapse. To further test the THP-GABA hypothesis, we will also determine whether ABA vulnerability and EM/Biochemical changes associated with the onset of puberty among females are reduced by pre-treatments that target the THP-GABA system. PUBLIC HEALTH RELEVANCE: Anorexia nervosa (AN) is a psychiatric illness occurring predominately among females entering puberty, with one of the highest mortality rates among mental illnesses (10-20%) and no accepted pharmacological treatment. The aim of this proposal is to test a novel hypothesis - namely, that females entering puberty are more vulnerable to AN because the limbic system of female brains at this stage in development express more of a particular type of neurotransmitter receptor that is sensitive to both GABA (an inhibitory neurotransmitter) and a stress-related hormone, THP (also called allopregnanolone). The results obtained from this study will provide the rationale for exploring a new pharmacologic treatment that targets the site of action of THP upon the GABAergic system within limbic pathways.

描述（由申请人提供）：神经性厌食症（AN）是一种精神疾病，没有接受药理治疗[1]，是精神疾病中死亡率最高的症状之一（10-20％）[2-4]。即使不是致命的，也可能会对多个器官系统造成终生的损害，从而增加医疗保健系统的负担。 A的青春期有刻板的发病年龄，其中90-95％的病例发生在女性中[5]。这种发育模式表明，与青春期相关的女性的激素变化可能会触发大脑联系的变化，从而增加个人对压力，焦虑和AN的脆弱性。 A也与频繁复发相关[6]，表明在这个关键的，大脑发育的最后阶段的厌食症行为可能会导致大脑连接的持久变化。该项目的长期目标是确定中央突触的发展变化，这些变化与进入青春期的女性之间的脆弱性有关，并表征这种疾病和康复后进一步引起的变化。 We will test a novel hypothesis - namely, that pubertal females are more vulnerable to AN due to fluctuation in the release of a neurosteroid, THP, that triggers an increased expression of a4b2d GABAA receptors at the plasma membrane of hippocampal pyramidal neurons which, in turn, renders the hippocampus hyper-excitable during stressful events.该THP-GABA假设将通过使用基于活动的厌食症（ABA）的动物模型来检验，该模型捕获了一个但尚未完全探索性别和年龄依赖性的多个关键特征。我们将首先进行行为测试，以确定影响人口年龄和性别的两个关键因素是否也影响啮齿动物的ABA脆弱性。这将通过比较与ABA发展，ABA和ABA复发的发展相关的行为因素，从3个发育阶段（青春期前，青春期和成年）和2个性别（男性和女性）进行比较。然后，我们将使用生化和电子显微镜免疫细胞化学方法来确定某些大脑区域中的A4B2D GABAA受体表达（生化数据）（生化数据）和突触（EM数据）是否与ABA脆弱性，发育，发育，恢复和复发相关。为了进一步检验THP-GABA假设，我们还将通过针对THP-GABA系统的预处理减少ABA脆弱性和与女性青春期开始相关的EM/生化变化。 公共卫生相关性：神经性厌食症（AN）是一种精神疾病，主要发生在进入青春期的女性中，这是精神疾病中死亡率最高（10-20％）的死亡率之一，没有接受的药理治疗。该提案的目的是检验一个新的假设 - 即，进入青春期的女性更容易受到一种更容易受到的影响，因为在此阶段，女性大脑的边缘系统在发育中表现出更大的类型的神经递质受体，它们对GABA敏感，对GABA敏感，对GABA（抑制性神经递质）和应激率是一种抗压力元素，也称为horm酮（也称为HORMON）（也称为HORMON）（也称为Hormol）（也称为Hormol and horm）（也称为HORMOR）（the）。从这项研究中获得的结果将为探索一种新的药物治疗提供理由，该治疗方法针对THP在边缘途径内对GABA能系统的作用部位。