Vulnerability for Self-Injurious Behavior: Neurobiological Mechanisms

描述（由申请人提供）：自残行为（SIB）是一种在智障人群中常见的毁灭性障碍。我们建议使用SIB的动物模型，pemoline模型，来检查SIB背后的神经生物学机制。Pemoline是一种间接的单胺激动剂，它阻断单胺通过各自的转运体的再摄取。因此，要彻底地描述pemoline对大脑的影响，需要我们整个实验室的共同努力。本研究的重点是研究佩莫林对中脑和前脑突触前多巴胺能神经元的影响。我们最近发现，反复使用佩莫林治疗的大鼠细胞内多巴胺浓度降低。在这个应用中，我们建议研究多巴胺能神经传递的两个最重要的调节因子，酪氨酸羟化酶（TH）和多巴胺转运蛋白（DAT）的区域表达和功能激活。我们将使用原位杂交来测定TH和DAT的区域表达，并使用western blots和放射自显影来分别测量TH和DAT蛋白的功能激活。由于大鼠对pemolin诱导的SIB的易感性不同，我们将比较pemolin处理的自伤大鼠、非损伤大鼠和载具大鼠TH和DAT的区域表达和功能激活。这一信息可以指导未来的研究，调查导致特定发育障碍人群（如自闭症、Lesch-Nyhan综合征、Prader-Willi综合征和Rett综合征）自残的神经生物学机制。这些项目也可能揭示SIB药物治疗的新靶点。公共卫生相关性：自残是许多发育障碍的一种行为特征，可导致永久性组织损伤或组织丢失。自我伤害阻碍了社会化和认知发展，自我伤害者需要专门护理和专业干预（如行为矫正治疗）。这些拟议的项目将开始阐明导致自我伤害表达的一些神经生物学机制，并可能导致新的药物治疗的发展……

DESCRIPTION (provided by applicant): Self-injurious behavior (SIB) is a devastating disorder that is common in intellectually handicapped populations. We propose to use an animal model of SIB, the pemoline model, to examine the neurobiological mechanisms which underlie SIB. Pemoline is an indirect monoamine agonist, which blocks the reuptake of monoamines by their respective transporters. Consequently, a thorough characterization of pemoline's effects on the brain will take collaborative efforts from our entire laboratory. This proposal focuses on the effects of pemoline on presynaptic dopaminergic neurons in areas of the midbrain and forebrain. We have recently identified that rats treated repeatedly with pemoline have reduced intracellular dopamine concentrations. In this application we propose to examine the regional expression and functional activation of two of the most important regulators of dopaminergic neurotransmission, tyrosine hydroxylase (TH) and the dopamine transporter (DAT). We will use in situ hybridization to assay the regional expression of TH and DAT and western blots and autoradiography to measure the functional activation of the TH and DAT proteins, respectively. Because rats differ in their vulnerability to develop pemoline-induced SIB, we will compare the regional expression and functional activation of TH and DAT between pemoline-treated self-injurious, pemoline-treated non-injurious and vehicle-treated rats. This information may guide future studies investigating the neurobiological mechanisms which lead a subset of people with particular developmental disorders (e.g. autism, Lesch-Nyhan, Prader-Willi and Rett syndromes) to self-injure. These projects may also reveal new targets for SIB pharmacotherapies. PUBLIC HEALTH RELEVANCE: Self-injury, a behavioral trait of numerous developmental disorders, can lead to permanent tissue damage or tissue loss. Self-injury interrupts socialization and cognitive development and the self-injurers require specialized care and professional interventions (e.g. behavior modification therapy). These proposed projects will begin to elucidate some of the neurobiological mechanisms that lead to the expression of self-injury and may lead to the development of new pharmacotherapies...