Novel Role of a Ventral Striatal Circuit in Motor Control

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。

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.