Neuromodulation in the striatum

纹状体的神经调节

• 批准号: 10592372
• 负责人: Haining Zhong
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592372
• 关键词: ADORA2A gene; Acute; Adenosine; Affect; Animal Behavior; Animals; Astrocytes; Basal Ganglia; Behavior; Behavioral; Brain; Calcium; Cell Nucleus; Cells; Concentration Camps; Corpus striatum structure; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Decision Making; Dimensions; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Equilibrium; Event; Exhibits; Fiber; Functional disorder; Ganglia; Genetic; Huntington Disease; Image; Intention; Kinetics; Knock-out; Knowledge; Learning; Locomotion; Measurement; Mediating; Modality; Modernization; Monitor; Motor; Movement; Mus; Needles; Neuroglia; Neuromodulator; Neuronal Plasticity; Neurons; Optics; Output; PKA inhibitor; Parkinson Disease; Pathway interactions; Phosphotransferases; Photometry; Play; Property; Proteins; Purinergic P1 Receptors; Resolution; Rewards; Role; Running; Signal Transduction; Source; Specificity; Structure; System; Technology; Testing; Translating; Visualization; antagonist; cell type; extracellular; genetic approach; imaging capabilities; in vivo; indexing; lens; motor control; motor learning; mouse genetics; nervous system disorder; neuronal excitability; neuropsychiatric disorder; neuroregulation; optogenetics; pharmacologic; response; selective expression; sensor; tool; treadmill

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.

项目总结 纹状体是基底节的入口点。它调节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。纹状体输出到两条不同的路径：一条直接的路径， 直接支配基底节的输出核，以及投射到基底节的间接通路 神经节通过相关核团间接输出核团。这两条路径形成了一个推拉系统， 直接通路促进运动启动，间接通路抑制运动。收支平衡 推拉系统对正确的运动执行至关重要，而平衡缺陷与神经学有关 疾病，如帕金森氏病和亨廷顿病。 这两条通路的平衡受到神经调节剂的严格调控。多巴胺是研究最多的 纹状体中的神经调节剂。运动意图与大脑皮层多巴胺释放增加有关 纹状体。多巴胺通过上调细胞内cAMP浓度和 CAMP依赖的激酶在这条通路的投射神经元中的作用，同时抑制另一条通路 通过抑制间接通路投射神经元中的cAMP和cAMP依赖的激酶来实现间接通路。 然而，多巴胺并不是纹状体中唯一的神经调节剂。其他神经调节剂，如腺苷， 也已知在纹状体中起作用。腺苷受体在纹状体中大量表达。 然而，目前还不知道在动物行为过程中腺苷是否以及何时被释放，它如何影响 细胞内cAMP和cAMP依赖的激酶在这两个通路的投射神经元中，以及如何做到这一点 影响调节动物的运动。我们的建议旨在通过使用现代成像或 细胞外腺苷浓度和细胞类型特异性活性的光学测量 运动过程中行为小鼠细胞内cAMP依赖的激酶活性。我们的结果将增加一个 以前对纹状体神经调节知识的探索不足，这可能会加深 我们对纹状体功能和功能障碍的理解。