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 纹状体是进化上保守的结构，参与运动的认知和边缘调节。 控制力。纹状体回路参与启动和执行与行为相关的运动输出， 从探索性动作到高度刻板印象的运动模式。这些回路的功能障碍会导致 经常表现为过度重复行为的运动控制异常。自我导向的整容， 一种高度刻板的重复运动模式，几乎在所有动物中都能观察到，在 保持卫生、调节体温、解除唤醒、减轻压力和社交。反常的 重复梳理是一种中枢行为表型，在许多神经病学和 神经精神疾病。因此，更好地理解梳理的神经控制可能会产生 对大脑如何控制正常和疾病患者重复运动输出的基本见解 条件。我们的初步工作表明，嗅觉内未被充分研究的中间神经元群体 结节(OT；纹状体最腹侧部分)，主要位于卡列哈群岛(IC)，参与 调停这一行为。纹状体具有相当均匀的细胞组成，约95%的神经元是 棘突投射神经元(SPN)，根据它们的多巴胺受体被分为D1型或D2型 快递。这种一致性的一个例外是存在进化上保守的IC，即密集的- 包装好的GABA能颗粒细胞，表达D3多巴胺受体。通过光遗传的方式 我们已经证明，OT D3神经元的激活通过抑制 其他可供选择的持续行为。相反，这些神经元的失活会阻止正在进行的梳理。这些 这些发现导致了一个中心假设，即OT D3神经元在控制梳理行为方面发挥着关键作用。 通过一系列现代神经科学方法(光遗传学、体外和体内电生理学、 纤维光度学、神经回路追踪和行为)，我们将追求三个具体目标来确定(1)在 OT D3神经元和SPN在梳理和其他行为中的活体活动模式，(2)OT D3的贡献 神经元与其他脑区的关系，以及(3)多巴胺释放到催产素的影响。 梳理行为。总体而言，该项目将提供对IC/OT D3神经元的神经电路的深入了解 以及它在一种非常重要的运动模式的神经生物控制中的作用。