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.

项目概要 纹状体是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、学习和奖励尤其重要。 在运动执行和运动学习中，纹状体输出到两个不同的途径：直接途径 直接神经支配基底神经节的输出核，以及投射到基底神经节的间接通路 神经节通过相关核间接输出核，这两条通路形成推拉系统。 直接途径促进运动启动，间接途径抑制运动。 推拉系统对于正确的运动执行至关重要，平衡缺陷与神经系统相关 疾病，例如帕金森氏病和亨廷顿氏病。 这两种途径的平衡受到神经调节剂的严格调节，这是研究最多的。 纹状体中的神经调节剂与运动意图增加的多巴胺释放有关。 多巴胺通过上调细胞内 cAMP 浓度和增强直接通路功能。 cAMP 依赖性激酶在该通路的投射神经元中的功能，同时抑制其他通路 通过抑制间接途径投射神经元中的 cAMP 和 cAMP 依赖性激酶来抑制途径。 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，例如腺苷， 已知腺苷受体在纹状体中大量表达。 然而，尚不清楚腺苷在动物行为过程中是否以及何时释放，以及它如何影响 两条通路的投射神经元中的细胞内 cAMP 和 cAMP 依赖性激酶，以及如何实现这一点 我们的建议旨在通过使用现代成像或技术来回答这些问题。 细胞外腺苷浓度和细胞类型特异性活性的光学测量 我们的结果将增加小鼠运动过程中细胞内 cAMP 依赖性激酶的活性。 先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。