Presynaptic Regulation of Striatal Excitation

纹状体兴奋的突触前调节

基本信息

批准号：
7216246
负责人：
NIGEL Simon BAMFORD
金额：
$ 17.98万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216246
关键词：
Acetylcholine Action Potentials Acute Affect Award Basal Ganglia Cell Nucleus Cells Cerebral cortex Characteristics Childhood Cholinergic Agents Chronic Corpus striatum structure Depressed mood Development Disease Dopamine Dopamine D2 Receptor Dopamine Receptor Dorsal Drug Sensitization Fostering Glutamates Goals Growth Hypersensitivity Image Imagery Imaging Techniques Investigation Laboratories Lead Long-Term Depression Mediating Mental Depression Methamphetamine Methods Midbrain structure Movement Movement Disorders Mus Neocortex Neurologist Neurons Neurotransmitters Nucleus Accumbens Optics Outcome Parkinson Disease Pathway interactions Pediatric Neurology Pharmaceutical Preparations Play Preparation Presynaptic Terminals Probability Process Purpose Regulation Relapse Research Personnel Reserpine Role Slice Substance Addiction Synapses Techniques Transgenic Mice Translating Universities Ventral Striatum Washington Withdrawal addiction cholinergic excitatory neuron insight interest mouse model nervous system disorder neuropsychiatry novel patch clamp presynaptic prevent professor psychostimulant receptor sensitivity response skills transmission process

项目摘要

DESCRIPTION (provided by applicant): Nigel Bamford, MD is a pediatric neurologist and Assistant Professor in Pediatrics and Neurology at the University of Washington. The purpose of this proposal is to foster the scientific development and laboratory skills of the candidate. The technical skills acquired during this Award will contribute to the candidate's growth as an independent investigator. The objective of this proposal is to determine how the cerebral cortex communicates with the basal ganglia and how this process is altered in certain neurological diseases that affect dopamine (DA) transmission. 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 (MSN), which also receives modulatory DA projections from midbrain nuclei. Both DA and glutamate (GLU) have been implicated in numerous neuropsychiatric disorders including Parkinson's disease and substance dependence. Using a newly developed imaging technique, the candidate has recently shown that DA depresses the release of GLU from a subset of cortical terminals providing filtering of cortical information to the striatum. The candidate hypothesizes that alterations in striatal DA release lead to long-term changes in striatal excitation mediated by DA-receptor hypersensitivity. There are three major goals: 1) Using mouse models for acute and chronic DA depletion, we will determine how DA receptors modify subsets of cortical terminals in the dorsal striatum, 2) we will determine how changes in pre-synaptic release are expressed post-synaptically, and 3) we will determine how methamphetamine sensitization and reinstatement affects MSN excitation in the ventral striatum. Our methods will utilize a novel imaging technique that allows direct visualization of activity from corticostriatal pre-synaptic terminals in murine striatal slice preparations. These optical studies will be integrated with whole-cell patch clamp recordings to precisely delineate the characteristics of the corticostriatal pathway and the effects of DA transmission at the MSN. The outcome of these investigations will demonstrate how alterations in DA release result in corticostriatal plasticity, and show mechanistically how certain neurological diseases cause aberrant striatal excitation. 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）：Nigel Bamford，医学博士是华盛顿大学儿科神经病学家和儿科和神经病学助理教授。该提案的目的是促进候选人的科学发展和实验室技能。在此奖项期间获得的技术技能将有助于候选人作为独立研究者的成长。该提案的目的是确定大脑皮层如何与基底神经节通讯，以及在影响多巴胺 (DA) 传输的某些神经系统疾病中该过程如何改变。基底神经节在随意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 (MSN) 的基底神经节，该神经元还接收来自中脑核的调节性 DA 投射。 DA 和谷氨酸 (GLU) 都与许多神经精神疾病有关，包括帕金森病和物质依赖。该候选人最近使用一种新开发的成像技术表明，DA 可以抑制皮质末梢子集释放 GLU，为纹状体提供皮质信息过滤。候选者假设纹状体 DA 释放的改变会导致 DA 受体超敏性介导的纹状体兴奋的长期变化。有三个主要目标：1）使用急性和慢性 DA 耗竭的小鼠模型，我们将确定 DA 受体如何修改背侧纹状体中的皮质末端亚群，2）我们将确定突触前释放的变化如何在突触后表达。突触方面，3）我们将确定甲基苯丙胺敏化和恢复如何影响腹侧纹状体中的 MSN 兴奋。我们的方法将利用一种新颖的成像技术，该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活动。这些光学研究将与全细胞膜片钳记录相结合，以精确描绘皮质纹状体通路的特征以及 MSN 上 DA 传输的影响。这些研究的结果将证明 DA 释放的变化如何导致皮质纹状体可塑性，并从机制上显示某些神经系统疾病如何导致异常纹状体兴奋。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。