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

描述（由申请人提供）：神经性厌食症（AN）是一种精神疾病，没有公认的药物治疗[1]，是精神疾病中死亡率最高的疾病之一（10-20%）[2-4]。即使不致命，AN也会对多个器官系统造成终身损害，增加医疗保健系统的负担。AN的典型发病年龄为青春期，90-95%的病例发生在女性[5]。这种发育模式表明，与青春期相关的女性荷尔蒙变化可能会引发大脑连接的变化，从而增加个体对压力，焦虑和AN的脆弱性。AN也与频繁复发有关[6]，这表明在大脑发育的这个关键的最后阶段，厌食行为可能会导致大脑连接的长期变化。该项目的长期目标是确定与进入青春期的女性中AN脆弱性相关的中央突触的发育变化，并描述这种疾病和恢复后进一步诱导的变化。我们将测试一个新的假设，即青春期女性更容易受到AN由于波动释放的神经类固醇，THP，触发增加表达的a4 b2 d GABAA受体在质膜的海马锥体神经元，这反过来又使海马过度兴奋在应激事件。将使用AN的动物模型，基于活动的厌食症（阿坝）来测试这种THP-GABA假设，该模型捕获了AN的多个关键特征，但尚未充分探索其性别和年龄依赖性。我们将首先进行行为测试，以确定影响人类人口的两个关键因素-年龄和性别-是否也影响啮齿动物的阿坝脆弱性。这将通过比较3个发育阶段（青春期前、青春期和成年期）和2种性别（男性和女性）中与阿坝发育、阿坝恢复和阿坝复发相关的行为因素来实现。然后，我们将使用生物化学和电子显微镜免疫细胞化学方法，以确定是否a4 b2 d GABAA受体表达在某些脑区（生化数据）和突触（EM数据）与阿坝的脆弱性，发展，恢复和复发。为了进一步测试THP-GABA假说，我们还将确定是否阿坝的脆弱性和EM/生化变化与青春期的开始，女性之间的目标THP-GABA系统的预处理减少。 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，是精神疾病中死亡率最高的疾病之一（10-20%），并且没有公认的药物治疗。这项提议的目的是测试一个新的假设-即，进入青春期的女性更容易受到AN的影响，因为在发育的这个阶段，女性大脑的边缘系统表达更多的一种特殊类型的神经递质受体，这种受体对GABA（一种抑制性神经递质）和一种与压力相关的激素THP（也称为别孕烯醇酮）敏感。从这项研究中获得的结果将为探索一种新的药理学治疗提供理论基础，该治疗靶向THP对边缘系统通路内GABA能系统的作用位点。

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.