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.

项目摘要 纹状体是巴萨神经节的入口站。它调解了许多关键的大脑功能，包括 电动机控制，决策，学习和奖励。特别是，背纹纹状体起着重要的作用 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 直接支配基底神经节的输出核，以及向基础投射的间接途径 神经节输出核间接通过相关核。这两种途径形成了推动和弹跳系统， 促进运动计划的直接途径和抑制运动的间接途径。平衡 推动系统对于适当的电机执行至关重要，并且有缺陷的平衡与神经系统有关 疾病，例如帕金森氏病和亨廷顿氏病。 两条途径的平衡受神经调节剂的严格调节。多巴胺是最研究的 纹状体中的神经调节剂。运动意图与多巴胺释放有关 纹状体。多巴胺通过上调细胞内营地浓度和 在该途径的投影神经元中，cAMP依赖性激酶的功能，同时抑制另一个途径 通过抑制间接途径投影神经元中的cAMP和cAMP依赖性激酶的途径。 但是，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， 还知道在纹状体中扮演角色。腺苷接收器在纹状体中绝对表达。 但是，尚不清楚在动物行为期间是否以及何时释放腺苷，它如何影响 两种途径的投影神经元中的细胞内营地和cAMP依赖性激酶，以及如何这样 效果介导动物运动。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的活性的光学测量 在运动过程中，细胞内cAMP依赖性激酶在行为小鼠中的活性。我们的结果将添加一个 以前对纹状体中神经调节知识的知识的尺寸不足，这可能会加深 我们对纹状体功能和功能障碍的理解。