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

描述(申请人提供)：神经性厌食症(AN)是一种没有接受药物治疗的精神疾病[1]，是精神疾病中死亡率最高的疾病之一(10-20%)[2-4]。即使不是致命的，也会对多个器官系统造成终身损害，给医疗保健系统带来更大的负担。AN的典型发病年龄是青春期，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，从而增加个人对压力、焦虑和焦虑的脆弱性。AN还与频繁的复发有关[6]，这表明在大脑发育的关键最后阶段，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的脆弱性有关的中央突触的发育变化，并表征这种疾病和康复后进一步诱导的变化。我们将检验一个新的假设，即青春期女性更容易受到压力的影响，这是由于一种神经类固醇THP的释放波动，它触发了海马体锥体神经元质膜上4b2d GABAA受体的表达增加，这反过来又使海马区在应激事件中高度兴奋。这一THP-GABA假说将通过基于活动的厌食症(ABA)的动物模型进行验证，该模型捕捉了AN的多个关键特征，但其性别和年龄相关性尚未得到充分研究。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ABA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个性别(男性和女性)与ABA发育、ABA恢复和ABA复发相关的行为因素来实现。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特定脑区(生化数据)和突触(EM数据)中4b2d GABAA受体的表达是否与ABA易感性、发育、恢复和复发有关。为了进一步测试THP-GABA假说，我们还将确定针对THP-GABA系统的预处理是否减少了与女性青春期开始相关的ABA脆弱性和EM/生化变化。 公共卫生相关性：神经性厌食症(AN)是一种主要发生在进入青春期的女性中的精神疾病，是精神疾病中死亡率最高的疾病之一(10%-20%)，而且没有接受药物治疗。这项建议的目的是检验一种新的假设，即进入青春期的女性更容易受到创伤的影响，这是因为处于发育阶段的女性大脑边缘系统更多地表达一种特定类型的神经递质受体，该受体对GABA(一种抑制性神经递质)和应激相关激素THP(也称为别孕酮)都敏感。这项研究的结果将为探索一种新的药物治疗提供理论基础，该药物以THP对边缘通路内GABA能系统的作用部位为靶点。

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.