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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

基本信息

批准号：
10676802
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
项目类别：
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/10676802
关键词：
Ablation Animals Arousal Behavior Behavior Control Brain Brain region Calcium Signaling Characteristics Classification Cognitive Corpus striatum structure Disease Disease model Dopamine Dopamine Receptor Dystonia Electrophysiology (science)Fiber Functional disorder Genetic Gilles de la Tourette syndrome Grooming Human Hygiene Individual Interneurons Islands of Calleja Lead Lesion 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 nerve supply nervous system disorder neural neural circuit neuropsychiatric disorder neuroregulation novel optogenetics repetitive behavior response sensor social communication stress reduction virtual

项目摘要

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进化上保守的结构，参与认知和边缘系统的运动调节，控制纹状体回路与行为学相关的运动输出的启动和执行有关，从探索性动作到高度刻板的运动模式。这些回路的功能障碍导致经常表现为过度重复行为的运动控制异常。自我指导的梳理，一种高度定型的重复运动模式，几乎在所有动物中都可以观察到，卫生维护、体温调节、去唤醒、减压和社会交流。异常重复理毛是在许多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，更好地了解梳理的神经控制可能会产生对大脑如何控制正常和患病的重复运动输出的基本见解条件我们的初步工作表明，在嗅觉神经元中，结节（OT;纹状体的最腹侧部分），主要位于Calleja岛（IC），涉及调解这种行为。纹状体具有相当均匀的细胞组成，其中约95%的神经元是神经元。棘状投射神经元（spiny projection neurons，SPN），根据多巴胺受体分为D1或D2型，快车这种一致性的一个例外是进化上保守的IC的存在，密集的- 包装的GABA能颗粒细胞，表达D3多巴胺受体。通过光遗传学操作，我们已经表明，OT D3神经元的激活通过抑制其他替代的持续行为。相反，这些神经元的失活会停止正在进行的梳理。这些这些发现导致了一个中心假设，即OT D3神经元在控制理毛行为中起着关键作用。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，神经回路跟踪，和行为），我们将追求三个具体目标，以确定（1）在 OT D3神经元和SPNs在梳理和其他行为中的活动模式，（2）OT D3的贡献神经元梳理与其他大脑区域的关系，和（3）多巴胺释放到OT的影响，梳理行为总的来说，这个项目将提供深入了解IC/OT D3神经元的神经回路以及它在神经生物学控制一种非常重要的运动模式中的作用。