Neuromodulation in the striatum

项目摘要 纹状体作为基底神经节的入口站。它介导许多关键的大脑功能，包括 运动控制、决策、学习和奖励。特别是，背外侧纹状体起着至关重要的作用， 在运动执行和运动学习方面。纹状体输出到两个不同的通路：一个直接通路， 直接支配基底神经节的输出核团，以及投射到基底神经节的间接通路。 神经节通过相关核团间接输出。这两条路径形成推拉系统， 直接途径促进运动起始，间接途径抑制运动。的平衡 推拉系统对正确的运动执行至关重要，而平衡缺陷与神经系统有关。 疾病，如帕金森病和亨廷顿病。 这两种途径的平衡受到神经调质的严格调节。多巴胺是研究最多的 纹状体中的神经调质运动意图与脑内多巴胺释放增加有关。 纹状体多巴胺通过上调细胞内cAMP浓度增强直接途径功能， cAMP依赖性激酶在这条通路投射神经元中的功能，同时抑制其他 通过抑制间接途径投射神经元中的cAMP和cAMP依赖性激酶来抑制cAMP途径。 然而，多巴胺并不是纹状体中唯一的神经调质。其他神经调节剂，如腺苷， 也在纹状体中发挥作用。腺苷受体在纹状体中大量表达。 然而，目前还不知道腺苷是否以及何时在动物行为过程中释放，它如何影响 细胞内cAMP和cAMP依赖性激酶在投射神经元的两个途径，以及如何这样的 影响动物的运动。我们的建议旨在通过使用现代成像或 光学测量细胞外腺苷浓度和细胞类型特异性 在运动过程中表现良好的小鼠中细胞内cAMP依赖性激酶的活性。我们的结果将增加一个 以前未充分探索的层面，以了解纹状体的神经调节，这可能会加深 我们对纹状体功能和功能障碍的理解。

PROJECT SUMMARY The striatum serves as the entry station of the basal ganglia. It mediates many critical brain functions, including motor control, decision making, learning, and reward. In particular, the dorsolateral striatum plays essential roles in locomotion execution and motor learning. The striatum outputs to two distinct pathways: a direct pathway that directly innervates the output nuclei of the basal ganglia, and an indirect pathway that projects to the basal ganglia output nuclei indirectly via related nuclei. These two pathways form a push-and-pull system, with the direct pathway promoting movement initiation, and the indirect pathway inhibiting movement. The balance of the push-and-pull system is critical to proper motor execution, and defective balance is associated with neurological disorders, such as Parkinson’s disease and Huntington’s disease. The balance of the two pathways is tightly regulated by neuromodulators. Dopamine is the most studied neuromodulator in the striatum. Locomotion intention is associated with increased dopamine release in the striatum. Dopamine enhances the direct pathway function by upregulate intracellular cAMP concentrations and the function of cAMP-dependent kinase in the projection neurons of this pathway, while suppressing the other pathway by inhibiting cAMP and cAMP-dependent kinase in the projection neurons of the indirect pathway. However, dopamine is not the only neuromodulator in the striatum. Other neuromodulators, such as adenosine, are also known to play roles in the striatum. Adenosine receptors are abundantly expressed in the striatum. However, it is not known whether and when adenosine is released during animal behavior, how it affects intracellular cAMP and cAMP-dependent kinase in the projection neurons of the two pathways, and how such effects mediate animal locomotion. Our proposal aims to answer these questions by using modern imaging or optical measurements of the activities of both extracellular adenosine concentrations and the cell type-specific activity of intracellular cAMP-dependent kinases in behaving mice during locomotion. Our results will add a previously underexplored dimension to the knowledge of neuromodulation in the striatum, which may deepen our understanding of the striatal function and dysfunction.