Dopamine-Induced Striatal Synaptic Plasticity

多巴胺诱导的纹状体突触可塑性

基本信息

批准号：
8961444
负责人：
NIGEL Simon BAMFORD
金额：
$ 4.03万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8961444
关键词：
AMPA Receptors Acetylcholine Action Potentials Address Adult Anti-Cholinergics Area Autoreceptors Behavior Behavior Control Behavioral Biochemical Bradykinesia Brain Brain Diseases Brain Injuries Cations Cells Cerebral cortex Child Cholinergic Receptors Clinical Corpus striatum structure Cues Defect Development Disease Dopamine Dopamine Receptor Dorsal Dyskinetic syndrome Feedback Functional disorder Future Genetic Engineering Glutamates Goals Homeostasis Impairment Impulse Control Disorders Inherited Interneuron function Interneurons Investigation Learning Levodopa Measures Mediating Membrane Potentials Messenger RNA Methods Midbrain structure Modeling Molecular Molecular Target Motor Movement Movement Disorders Mus Muscarinics N-Methyl-D-Aspartate Receptors National Institute of Neurological Disorders and Stroke Neuromodulator Neuronal Plasticity Optics Parkinson Disease Parkinsonian Disorders Pattern Pharmacological Treatment Physiological Policy Research Population Process Regulation Resistance Rest Rest Tremor Ribosomes Role Series Signal Transduction Signs and Symptoms Source Structure Symptoms Synapses Synaptic plasticity Techniques Technology Testing Thalamic structure Time Work cell type disability hyperpolarization-activated cation channel improved innovation motor control motor disorder motor impairment motor learning neural circuit neuropsychiatry neurotransmission novel optogenetics polarized cell prevent public health relevance receptor expression research study response restoration signal processing stem

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is caused by the degeneration of midbrain dopamine (DA) producing cells and results in motor and non-motor impairments. Congenital and acquired forms of Parkinsonism, caused by inherited defects in DA synthesis or brain injury and disease, also produce profound immobility and disability. The hallmarks of Parkinsonism include bradykinesia, resting tremor, and postural instability that stem from a reduced supply of DA from the midbrain to the motor striatum, a brain structure required for motor control and cue-dependent learning. In turn, this loss of striatal DA prevents the normal spike-timing of the sparse population of tonically-active acetylcholine (ACh)-releasing interneurons (TANs) that provide the sole source of striatal ACh and are essential to many aspects of brain function. The resulting change in DA-ACh reciprocity contributes to the clinical symptoms and signs of Parkinsonism. Treatments that enhance DA availability or activate DA receptors incompletely restore motor function, become less successful over time, and are limited in efficacy due to induction of impulse control disorders and dyskinesias that are caused by neuroplasticity in TANs. Therefore, the precise targeting of ACh-releasing cells, while correcting for the decline in DA, would improve treatment and disability in Parkinsonism. TANs have been implicated in the pathophysiology of PD and treatment-dependent dyskinesias, but the mechanism whereby TANs participate in these movement disorders remains unclear. In this competing continuation, we will pursue an integrated series of molecular, electrophysiological, optical, and behavioral experiments in genetically engineered DA-deficient mice. Our goal is to show how DA deficiency promotes a long-lasting change in ACh release from TANs which contributes to motor features of Parkinsonism. We will test the hypotheses that 1) DA deficiency reduces autonomous firing in TANs by altering hyperpolarization-activated cation (HCN) channels that re-polarize the cell toward its resting membrane potential following each action potential; 2) DA replenishment provokes a paradoxical increase in TAN activity through DA and ACh auto-regulatory signal processing; and 3) DA deficiency produces plasticity in excitatory thalamostriatal inputs that contributes to the physiological and behavioral change. The central role of ACh in normal and abnormal movements has only recently been identified, despite clues from decades of empirical findings using anticholinergics. We now know that this is an important downstream response to DA deficiency. We will use innovative ways to measure transcribed mRNA and novel optical approaches to directly address alterations TAN function. These experiments provide a targeted molecular and circuit-level approach to cell-type specific effects which previous methods were not able to discern. By the end of this work, we will know the molecular and physiological mechanisms that regulate striatal ACh in DA deficiency and we will uncover pharmacological treatment targets that will improve DA-ACh reciprocity and motor function in children and adults with Parkinsonism.

描述（由申请人提供）：帕金森病 (PD) 是由中脑多巴胺 (DA) 产生细胞变性引起的，并导致运动和非运动损伤，由 DA 合成或遗传缺陷引起的先天性和后天性帕金森病。脑损伤和疾病也会导致严重的不动和残疾。帕金森症的特征包括运动迟缓、静止性震颤和姿势不稳定，这些都是由于 DA 供应减少而导致的。中脑到运动纹状体，这是运动控制和线索依赖性学习所需的大脑结构，反过来，纹状体 DA 的丧失会阻止稀疏的强效活性乙酰胆碱 (ACh) 释放中间神经元 (TAN) 的正常尖峰计时。）是纹状体 ACh 的唯一来源，对大脑功能的许多方面都至关重要。由此产生的 DA-ACh 相互作用的变化会导致临床症状和体征。增强 DA 可用性或激活 DA 受体的治疗不能完全恢复运动功能，随着时间的推移，效果会变得较差，并且由于 TAN 神经可塑性引起的冲动控制障碍和运动障碍而导致疗效有限。乙酰胆碱释放细胞的数量，在纠正 DA 下降的同时，将改善帕金森病的治疗和残疾，TAN 与帕金森病和治疗依赖性运动障碍的病理生理学有关，但是。 TAN 参与这些运动障碍的机制仍不清楚。在这个竞争性的延续中，我们将在基因工程 DA 缺陷小鼠中进行一系列综合的分子、电生理、光学和行为实验。我们的目标是展示 DA 缺乏如何促进。 TAN 释放的 ACh 发生持久变化，导致帕金森病的运动特征。我们将测试以下假设：1) DA 缺乏通过改变超极化激活的阳离子来减少 TAN 的自主放电。 (HCN) 通道在每次动作电位后将细胞重新极化至静息膜电位；2) DA 补充通过 DA 和 ACh 自动调节信号处理引起 TAN 活性的反常增加；3) DA 缺乏会产生兴奋性可塑性；丘脑纹状体输入有助于生理和行为变化尽管几十年来的经验发现提供了线索，但直到最近才确定了乙酰胆碱在正常和异常运动中的核心作用。我们现在知道这是对 DA 缺乏的重要下游反应，我们将使用创新的方法来测量转录的 mRNA 和新颖的光学方法来直接解决 TAN 功能的改变。在这项工作结束时，我们将了解调节 DA 缺乏时纹状体 ACh 的分子和生理机制，并且我们将发现改善 DA-ACh 相互作用的药物治疗目标。帕金森病儿童和成人的运动功能。