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：
7673624
负责人：
AMBER M Muehlmann
金额：
$ 3.09万
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/7673624
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 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 Rattus Regulation Reporting Rett Syndrome Self-Injurious Behavior Skin Socialization Stress Substantia nigra structure 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 public health relevance 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）：自我伤害行为（SIB）是一种毁灭性疾病，在智力残障人群中很常见。我们建议使用SIB的动物模型（Pemoline模型）来检查SIB构成的神经生物学机制。 Pemoline是一种间接的单胺激动剂，可阻止其各自的转运蛋白的单胺再摄取。因此，对Pemoline对大脑影响的彻底表征将采取整个实验室的协作努力。该提案侧重于中脑和前脑区域对突触前多巴胺能神经元的影响。我们最近确定，用脱甲米反复治疗的大鼠细胞内多巴胺浓度降低。在此应用中，我们建议检查两个最重要的多巴胺能神经传递，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分别测定TH和DAT的区域表达，以及蛋白质印迹和自显影术分别测量TH和DAT蛋白的功能激活。由于大鼠在开发Pemoline诱导的SIB的脆弱性方面有所不同，因此我们将比较TH和DAT的区域表达和功能激活与Pemoline治疗的经过pemoline的自我伤害，pemoline治疗的非妇女治疗和车辆处理的大鼠。该信息可能指导未来的研究，研究了研究神经生物学机制，这些神经生物学机制将特定发育障碍的人（例如自闭症，莱斯·尼汉（Lesch-nyhan），普拉德·威利（Prader-Willi）和雷特综合症（Rett Syndromes））进行自我伤害。这些项目还可能揭示SIB药物治疗的新目标。公共卫生相关性：自我伤害是众多发育障碍的行为特征，可以导致永久性组织损伤或组织损失。自我伤害中断社会化和认知发展，自我伤害者需要专业的护理和专业干预措施（例如行为修改疗法）。这些提议的项目将开始阐明导致自我伤害表达的某些神经生物学机制，并可能导致新的药物治疗的发展...