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：
7898602
负责人：
NIGEL Simon BAMFORD
金额：
$ 33.78万
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 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898602
关键词：
Acetylcholine Action Potentials Acute Affect Amphetamines Animals Basal Ganglia Behavior Behavioral Cell Nucleus Cells Cerebral cortex Characteristics Cholinergic Receptors Chronic Corpus striatum structure Depressed mood Disease Dopamine Dopamine D2 Receptor Dopamine Receptor Dorsal Drug Addiction Drug Exposure Dyskinetic syndrome Exocytosis Exposure to Frequencies Glutamates Goals Hypersensitivity Imagery Imaging Techniques Interneurons Investigation Knowledge Lead Length Long-Term Depression Measurement Mediating Mental Depression Midbrain structure Modeling Motor Movement Movement Disorders Mus Neocortex Neuronal Plasticity Neurons Nicotinic Receptors Optics Outcome Parkinson Disease Pathway interactions Pharmaceutical Preparations Physiological Play Preparation Presynaptic Terminals Probability Receptor Activation Relapse Reserpine Role Signs and Symptoms Slice Stimulus Substance Addiction Synapses Synaptic plasticity Transgenic Organisms Ventral Striatum Wild Type Mouse Withdrawal addiction alternative treatment base behavioral sensitization drug craving drug induced behavior drug withdrawal experience habit learning in vivo insight mouse model neuroadaptation neuropsychiatry neurotransmission novel therapeutics patch clamp postsynaptic presynaptic psychostimulant receptor receptor sensitivity response restoration transmission process

项目摘要

DESCRIPTION (provided by applicant): The basal ganglia play an important role in voluntary movement and substance dependence. Excitatory glutamatergic corticostriatal projections from the cerebral cortex innervate the basal ganglia at the striatal medium spiny neuron, which also receives modulatory dopamine projections from midbrain nuclei. Both dopamine and glutamate have been implicated in numerous neuropsychiatric disorders including Parkinson's disease and substance dependence. Using a newly developed imaging technique, we have recently shown that dopamine depresses the release of glutamate from a subset of cortical terminals providing filtering of cortical information to the striatum. We hypothesize that alterations in striatal dopamine release lead to long-term changes in striatal excitation mediated by dopamine receptor hypersensitivity and neuroplasticity. There are three major goals: 1) Using mouse models for dopamine depletion and dopamine excess, we will study the effect of altered dopamine availability on striatal synaptic plasticity, 2) we will define the mechanisms underlying these neuroplastic alterations, and 3) we will determine if drug-induced behaviors are determined by such adaptations. We will utilize a newly developed imaging technique that allows direct visualization of release from corticostriatal presynaptic terminals in murine striatal slice preparations. These optical studies will be integrated with whole-cell patch clamp recordings to delineate the characteristics of the corticostriatal pathway and the effects of dopamine transmission at the medium spiny neuron. In vivo manipulations of transgenic and wild-type mice will provide models with which to investigate synaptic plasticity that occurs with dopamine depletion and dopamine excess. The outcome of these investigations will demonstrate how alterations in dopamine release produce corticostriatal plasticity and show mechanistically how aberrant striatal excitation might lead to certain neuropsychiatric signs and symptoms. This project is expected to provide further insights into pharmacological alternatives for the treatment of movement disorders and addiction.

描述（由申请人提供）：基底神经节在自主运动和物质依赖中发挥着重要作用。来自大脑皮层的兴奋性谷氨酸能皮质纹状体投射支配纹状体中棘神经元处的基底神经节，该神经元还接收来自中脑核的调节性多巴胺投射。多巴胺和谷氨酸都与许多神经精神疾病有关，包括帕金森病和物质依赖。使用新开发的成像技术，我们最近发现多巴胺会抑制皮质末梢子集释放谷氨酸，从而为纹状体提供皮质信息过滤。我们假设纹状体多巴胺释放的改变导致由多巴胺受体超敏性和神经可塑性介导的纹状体兴奋的长期变化。有三个主要目标：1）使用多巴胺耗竭和多巴胺过量的小鼠模型，我们将研究多巴胺可用性改变对纹状体突触可塑性的影响，2）我们将定义这些神经可塑性改变的机制，3）我们将确定如果药物引起的行为是由这种适应决定的。我们将利用一种新开发的成像技术，可以直接可视化小鼠纹状体切片制剂中皮质纹状体突触前末梢的释放。这些光学研究将与全细胞膜片钳记录相结合，以描绘皮质纹状体通路的特征以及多巴胺在中棘神经元传递的影响。转基因和野生型小鼠的体内操作将为研究多巴胺耗尽和多巴胺过量时发生的突触可塑性提供模型。这些研究的结果将证明多巴胺释放的改变如何产生皮质纹状体可塑性，并从机制上显示异常的纹状体兴奋如何可能导致某些神经精神体征和症状。该项目预计将为治疗运动障碍和成瘾的药物替代方案提供进一步的见解。