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: 7237931
• 负责人: Kim L Blackwell
• 金额: $ 24.23万
• 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/7237931
• 关键词: AMPA Receptors; Affect; Alcohol consumption; Alcohol dependence; Algorithms; Basal Ganglia; Brain; Calcium; Computer Simulation; Computers; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diffusion; Dopamine; Dopamine D2 Receptor; Elevation; Glutamates; Goals; Interdisciplinary Study; Learning; Long-Term Potentiation; Measures; Mediating; Modeling; Neurons; Parkinson Disease; Pathway interactions; Play; Preparation; Protein phosphatase; Protocols documentation; Psychological reinforcement; Relapse; Research; Research Personnel; Rewards; Role; Second Messenger Systems; Signal Pathway; Simulate; Structure; Substantia nigra structure; Synapses; Synaptic plasticity; Testing; Trees; Vertebral column; alcohol behavior; in vivo; models and simulation; predictive modeling; programs; research study; response; second messenger; simulation; therapy development

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.

项目摘要：拟议的研究的长期目标是描述纹状体中强化学习的机制：具体来说，介导术语神经元的内在兴奋性的突触可塑性和可塑性的必不可少的第二允许途径和神经调节性相互作用。这项研究很重要，因为增强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，拟议的研究评估了突触可塑性的灵敏度，以及基本的第二信使途径，对皮质和多巴胺能输入对纹状体神经元刺刺射型神经元之间的时间间隔。 AIM 1：评估以下假设：响应上阈值皮质刺激的钙升高后，随后是nigral（多巴胺）刺激。 AIM 2：评估假设长期增强仅在上阈值皮层刺激之后是nigral（多巴胺）刺激时发生的。 使用合并的电生理和计算建模方法评估这两个目标。开发了用于随机扩散的计算有效的计算机算法，以允许在整个神经元的树突树上的众多刺中模拟第二信使途径。新算法用于开发一种刺皮投影神经元模型，该模型不仅包括体内的突触输入，还包括钙的时空动力学和多巴胺激活的第二使者。实验是对尼格拉斯纹状体构型培养物进行的，因为这种制剂具有完整的，功能性的皮质谷氨酸能和多巴胺能突触输入，从而在纹状体神经元中产生自发性的自发性活动活性。对于每个特定目标，使用控制实验来调整模型参数，然后进行模型模拟以检验假设，然后使用相同的刺激协议对模型预测进行实验测试。 相关性：拟议的研究可能有助于我们对酒精成瘾的理解，因为它研究了对酒精和先前使用酒精相关的行为的大脑结构。因此，这项研究的结果可能有助于开发酒精成瘾的治疗方法。