Novel Role of a Ventral Striatal Circuit in Motor Control

腹侧纹状体电路在运动控制中的新作用

• 批准号: 10469310
• 负责人: Marc V Fuccillo
• 金额: $ 48.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469310
• 关键词: Ablation; Animals; Arousal; Behavior; Behavior Control; Brain; Brain region; Calcium Signaling; Characteristics; Cognitive; Corpus striatum structure; Cytoplasmic Granules; Disease; Disease model; Dopamine; Dopamine Receptor; Dystonia; Electrophysiology (science); Fiber; Functional disorder; Genetic; Gilles de la Tourette syndrome; Grooming; Hygiene; Individual; Interneurons; Islands of Calleja; Lead; Lesion; Light; Maintenance; Mammals; Measures; Mediating; Midbrain structure; Modernization; Monitor; Motor; Motor output; Neurobiology; Neurological Models; Neurons; Neurosciences; Neurotransmitters; Obsessive-Compulsive Disorder; Olfactory tubercle; Output; Pathologic; Patients; Pattern; Photometry; Physiologic Thermoregulation; Play; Population; Regulation; Rodent Diseases; Role; Self-Direction; Signal Transduction; Stereotyping; Structure; Synapses; Testing; Ventral Striatum; Work; autism spectrum disorder; behavioral phenotyping; dopamine D3 receptor; dopaminergic neuron; granule cell; in vivo; insight; mind control; motor behavior; motor control; nervous system disorder; neural circuit; neuropsychiatric disorder; neuropsychiatry; neuroregulation; novel; optogenetics; relating to nervous system; repetitive behavior; response; sensor; social; social communication; stress reduction; virtual

Project Summary The striatum is an evolutionarily conserved structure involved in cognitive and limbic regulation of motor control. Striatal circuits are implicated in the initiation and execution of ethologically relevant motor output, ranging from exploratory actions to highly stereotyped motor patterns. Dysfunction of these circuits leads to motor control abnormalities that frequently manifest as excessive repetitive behaviors. Self-directed grooming, a highly stereotyped repetitive motor pattern, is observed in virtually all animals, serving vital functions in hygiene maintenance, thermoregulation, de-arousal, stress reduction, and social communication. Abnormally repetitive grooming is a central behavioral phenotype observed in numerous models for neurological and neuropsychiatric diseases. A better understanding of the neural control of grooming may thus yield fundamental insights into how the brain controls repetitive motor output in both normal and diseased conditions. Our preliminary work suggests that an understudied population of interneurons within the olfactory tubercle (OT; the most ventral part of the striatum), predominantly in the Islands of Calleja (IC), is involved in mediating this behavior. The striatum has a fairly uniform cellular composition, with ~95% of the neurons being spiny projection neurons (SPNs), classified as D1- or D2-type according to the dopamine receptors they express. One exception to this uniformity is the existence of evolutionarily conserved IC, clusters of densely- packed, GABAergic granule cells, which express the D3 dopamine receptor. By means of optogenetic manipulations, we have shown that activation of OT D3 neurons initiates robust grooming behavior via arrest of other alternative ongoing behaviors. In contrast, inactivation of these neurons halts ongoing grooming. These findings lead to the central hypothesis that OT D3 neurons play critical roles in controlling grooming behavior. Through an array of modern neuroscience approaches (optogenetics, ex vivo and in vivo electrophysiology, fiber photometry, neural circuit tracing, and behavior), we will pursue three specific aims to determine (1) in vivo activity patterns of OT D3 neurons and SPNs in grooming and other behaviors, (2) contributions of OT D3 neurons to grooming in relation to other brain regions, and (3) the effects of dopamine release into the OT on grooming behavior. Overall, this project will provide insights into the neural circuitry of the IC/OT D3 neurons and its role in neurobiological control of a highly important motor pattern.

项目摘要 纹状体是一种参与运动的认知和边缘调节的进化保守结构 控制。纹状体电路与伦理上相关的电动机输出的启动和执行有关， 从探索性动作到高度定型的运动模式。这些电路的功能障碍导致 运动控制异常经常表现为过度重复行为。自我指导的修饰， 几乎所有动物都观察到高度定型的重复运动模式，在 卫生维护，温度调节，消除，减轻压力和社交交流。异常 重复修饰是在许多神经和神经系统模型中观察到的中心行为表型 神经精神疾病。因此，更好地了解修饰的神经控制可能会产生 关于大脑如何控制正常和患病的重复运动输出的基本见解 状况。我们的初步工作表明，嗅觉中的中间神经元人口进行了研究 结节（OT；纹状体的最腹侧部分），主要是在Calleja岛（IC），参与 调解这种行为。纹状体具有相当均匀的细胞组成，约95％的神经元为 根据多巴胺受体分类为d1或d2型的刺刺射神经元（SPNS） 表达。这种统一性的一个例外是存在进化保守的IC，密集的簇 挤满了D3多巴胺受体的GABA能细胞。通过光遗传学 操纵，我们已经表明，OT D3神经元的激活通过逮捕来启动强大的修饰行为 其他替代行为。相反，这些神经元的失活停止了正在进行的修饰。这些 发现导致了一个中心假设，即OT D3神经元在控制修饰行为中起关键作用。 通过一系列现代神经科学方法（光遗传学，体内和体内电生理学， 纤维光度法，神经回路跟踪和行为），我们将追求三个特定的目标，以确定（1） OT D3神经元和SPN的体内活性模式在修饰和其他行为中，（2）OT D3的贡献 与其他大脑区域相关的神经元，以及（3）多巴胺释放到OT上的影响 修饰行为。总体而言，该项目将提供有关IC/OT D3神经元神经电路的见解 及其在非常重要的运动模式的神经生物学控制中的作用。