Vulnerability for Self-Injurious Behavior: Neurobiological Mechanisms

描述(申请人提供)：自伤行为(SIB)是一种破坏性的疾病，在智力障碍人群中很常见。我们建议使用SIB的动物模型，即Pemoline模型，来研究SIB的神经生物学机制。Pemoline是一种间接的单胺激动剂，它能阻断各自转运体对单胺的再摄取。因此，要彻底描述佩莫林对大脑的影响，将需要我们整个实验室的共同努力。这项建议侧重于佩莫林对中脑和前脑区域突触前多巴胺能神经元的影响。我们最近发现，反复使用培莫林治疗的大鼠降低了细胞内多巴胺的浓度。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)和多巴胺转运体(DAT)的区域表达和功能激活。我们将用原位杂交检测TH和DAT的区域表达，用免疫印迹和放射自显影分别检测TH和DAT蛋白的功能激活。由于大鼠对佩莫林诱导的SIB易感性不同，我们将比较佩莫林治疗的自伤大鼠、佩莫林治疗的非损伤大鼠和赋形剂治疗的大鼠之间TH和DAT的局部表达和功能激活。这些信息可能会指导未来研究导致特定发育障碍患者(如自闭症、Lesch-Nyhan、Prader-Willi和Rett综合征)自我伤害的神经生物学机制。这些项目还可能揭示SIB药物疗法的新靶点。公共卫生相关性：自我伤害是许多发育障碍的一种行为特征，可能导致永久性组织损伤或组织丢失。自我伤害会中断社会化和认知发展，自伤者需要专门的护理和专业干预(例如，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疗法的开发。

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...