CRCNS: Spatio-temporal Dynamics of Dopamine Activated 2nd Messenger Pathways

CRCNS：多巴胺激活的第二信使通路的时空动力学

• 批准号: 7116994
• 负责人: Kim L Blackwell
• 金额: $ 24.99万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116994
• 关键词: AMPA receptors; DARPP; calcium flux; computational neuroscience; computer program /software; computer simulation; corpus striatum; dopamine; electrophysiology; enzyme activity; glutamates; laboratory rat; long term potentiation; model design /development; molecular psychobiology; neural plasticity; newborn animals; phosphoprotein phosphatase; protein kinase A; second messengers; substantia nigra; synapses; tissue /cell culture

Project Summary: The long term objective of the proposed research is to delineate the mechanisms underlying reinforcement learning in the striatum: specifically, the essential second messenger pathways and neuromodulatory interactions mediating synaptic plasticity and plasticity of intrinsic excitability of striatal neurons. This research is significant because reinforcement learning may play a role in alcohol addiction and relapse. As a first step toward achieving this goal, the proposed research evaluates the sensitivity of synaptic plasticity, and underlying second messenger pathways, to the temporal interval between cortical and dopaminergic inputs to striatal neurons spiny projection neurons. Aim 1: Evaluate the hypothesis that the calcium elevation in response to supra-threshold cortical stimulation is enhanced when it is followed by nigral (dopamine) stimulation. Aim 2: Evaluate the hypothesis that long term potentiation occurs only when supra-threshold cortical stimulation is followed by nigral (dopamine) stimulation. Both aims are evaluated using combined electrophysiological and computational modeling approaches. Computationally efficient computer algorithms for stochastic diffusion are developed to allow simulation of second messenger pathways in a multitude of spines on the dendritic tree of an entire neuron. The new algorithm is used to develop a spiny projection neuron model that includes not only in vivo like synaptic inputs, but also the spatio-temporal dynamics of calcium and second messengers activated by dopamine. Experiments are performed on cortex-substantia nigra-striatum organotypic cultures because this preparation has intact, functional cortical glutamatergic and nigral dopaminergic synaptic inputs, producing spontaneous in-vivo like activity in striatal neurons. For each of the specific aims, control experiments are used to adjust model parameters, then model simulations are performed to test the hypothesis, and after that, the model predictions are tested experimentally using the same stimulation protocols. Relevance: The proposed research may contribute to our understanding of alcohol addiction, because it investigates brain structures that respond to both alcohol and behaviors associated with prior alcohol use. Thus, the results of this research may help in the development of treatments for alcohol addiction.

项目概述：本研究的长期目标是描述纹状体中强化学习的机制：具体而言，第二信使通路和神经调节相互作用介导纹状体神经元突触可塑性和内在兴奋性可塑性。这项研究意义重大，因为强化学习可能在酒精成瘾和复发中发挥作用。作为实现这一目标的第一步，本研究评估了突触可塑性和潜在的第二信使通路对皮层和多巴胺能输入纹状体神经元的时间间隔的敏感性。