Vulnerability for Self-Injurious Behavior: Neurobiological Mechanisms

描述（由申请人提供）：自我伤害行为（SIB）是一种在智力残疾人群中常见的破坏性疾病。我们建议使用SIB的动物模型，pemoline模型，研究SIB的神经生物学机制。匹莫林是一种间接单胺激动剂，可阻断单胺被其各自的转运蛋白再摄取。因此，彻底表征pemoline对大脑的影响将需要我们整个实验室的合作努力。该提案的重点是匹莫林对中脑和前脑区域的突触前多巴胺能神经元的影响。我们最近发现，反复用匹莫林治疗的大鼠细胞内多巴胺浓度降低。在这个应用程序中，我们建议检查的区域表达和功能激活的两个最重要的调节多巴胺能神经传递，酪氨酸羟化酶（TH）和多巴胺转运蛋白（DAT）。我们将使用原位杂交来测定TH和DAT的区域表达和蛋白质印迹和放射自显影来测量TH和DAT蛋白的功能激活，分别。由于大鼠在发展匹莫林诱导的SIB方面的脆弱性不同，我们将比较匹莫林治疗的自伤大鼠、匹莫林治疗的非损伤大鼠和溶媒治疗的大鼠之间TH和DAT的区域表达和功能激活。这些信息可能会指导未来的研究，调查导致特定发育障碍（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：自伤是许多发育障碍的行为特征，可导致永久性组织损伤或组织损失。自伤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（例如行为矫正疗法）。这些拟议的项目将开始阐明一些导致自我伤害表达的神经生物学机制，并可能导致新的药物疗法的发展。

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...