Vulnerability for Self-Injurious Behavior: Neurobiological Mechanisms

自残行为的脆弱性：神经生物学机制

基本信息

批准号：
7485861
负责人：
AMBER M Muehlmann
金额：
$ 3万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-16 至 2010-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7485861
关键词：
Acute Address Adenylate Cyclase Agonist Amber Anabolism Animal Model Animals Antibodies Area Attenuated Autistic Disorder Autoradiography Autoreceptors Axon Behavior Behavior Disorders Behavior Therapy Behavioral Binding Sites Biochemical Biological Assay Bone callus Brain Brain region Caregivers Caring Characteristics Chronic Clinical Cognitive Contusions Cyclic AMP-Dependent Protein Kinases Daily Data Detection Development Disabled Persons Disease Dopamine Dopamine Receptor Dose Down-Regulation Environment Exhibits Face Future Head High Pressure Liquid Chromatography Household Human In Situ Hybridization Individual Individual Differences Injection of therapeutic agent Intervention Investigation Laboratories Lead Life Light Measures Messenger RNA Midbrain structure Modeling Negative Reinforcements Neurobiology Nucleus Accumbens Outcome Pan Genus Pattern Pemoline Pharmaceutical Preparations Pharmacotherapy Population Positive Reinforcements Presynaptic Terminals Prosencephalon Proteins Public Health Rattus Regulation Reporting Rett Syndrome Self-Injurious Behavior Skin Socialization Stress Substantia nigra structure Synapses Syndrome Tegmentum Mesencephali Tissue Sample Tissues Tyrosine 3-Monooxygenase Ventral Tegmental Area Western Blotting base caudate nucleus developmental disease dopamine transporter dopaminergic neuron extracellular frontal lobe handicapping condition injured man monoamine neurobiological mechanism neurochemistry neuropathology neurotransmission novel postsynaptic presynaptic research study response reuptake social trait

项目摘要

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...

描述（由申请人提供）：自残行为（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 动物模型（pemoline 模型）来检查 SIB 背后的神经生物学机制。 Pemoline 是一种间接单胺激动剂，可阻止单胺被各自的转运蛋白再摄取。因此，全面表征匹莫林对大脑的影响需要我们整个实验室的共同努力。该提案的重点是匹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，反复接受匹莫林治疗的大鼠细胞内多巴胺浓度降低。在本申请中，我们建议检查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，并使用蛋白质印迹和放射自显影术来分别测量 TH 和 DAT 蛋白的功能激活。由于大鼠发生pemoline诱导的SIB的脆弱性不同，我们将比较pemoline治疗的自伤大鼠、pemoline治疗的非伤害大鼠和媒介物治疗的大鼠之间TH和DAT的区域表达和功能激活。这些信息可能会指导未来研究导致部分患有特定发育障碍（例如自闭症、Lesch-Nyhan、Prader-Willi 和 Rett 综合征）的人进行自残的神经生物学机制。这些项目还可能揭示 SIB 药物疗法的新目标。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。自残会扰乱社交和认知发展，自残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一些导致自伤表现的神经生物学机制，并可能导致新药物疗法的开发......