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

项目摘要：本研究的长期目标是描述纹状体强化学习的机制：具体地说，纹状体神经元中重要的第二信使通路和神经调节相互作用介导突触可塑性和内在兴奋性的可塑性。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，拟议的研究评估了突触可塑性和潜在的第二信使通路对纹状体神经元的皮质和多巴胺能输入之间的时间间隔的敏感性。 目的1：评估一种假说，即当刺激黑质(多巴胺)时，对阈值以上皮质刺激的钙升高反应增强。 目的2：评估长时程增强仅在阈值以上皮层刺激后黑质(多巴胺)刺激时才发生的假说。 这两个目标都是使用电生理和计算建模相结合的方法来评估的。开发了用于随机扩散的计算高效的计算机算法，以允许模拟整个神经元的树突树上的许多刺中的第二信使路径。新算法被用来建立一个棘突投射神经元模型，该模型不仅包括体内类似突触的输入，而且还包括由多巴胺激活的钙和第二信使的时空动力学。实验在皮质-黑质-纹状体器官型培养上进行，因为这种制剂具有完整的、功能正常的皮质谷氨酸能和黑质多巴胺能突触输入，在纹状体神经元中产生自发的体内类似活动。针对每个特定的目标，通过控制实验调整模型参数，然后进行模型模拟来验证假设，然后使用相同的刺激方案对模型预测进行实验验证。 相关性：这项拟议的研究可能有助于我们对酒精成瘾的理解，因为它调查了对酒精和与先前饮酒相关的行为做出反应的大脑结构。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。

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.