Investigating the microcircuit role of striatal fast-spiking interneurons in Obsessive-Compulsive disorder

研究纹状体快速尖峰中间神经元在强迫症中的微电路作用

• 批准号: 9533357
• 负责人: Victoria L Corbit
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9533357
• 关键词: Address; Affect; Age; Anxiety; Basal Ganglia; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Cells; Compulsive Behavior; Computer Simulation; Corpus striatum structure; Data; Disease; Disease model; Electrophysiology (science); Foundations; Functional disorder; Future; Generations; Goals; Grooming; Human; Human Genetics; Hyperactive behavior; Interneuron function; Interneurons; Knockout Mice; Knowledge; Lateral; Link; Measures; Mus; Neurons; Neurosciences; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Output; Pathologic; Pathology; Phenotype; Physiology; Play; Population; Production; Property; Research; Research Personnel; Research Training; Role; Running; Slice; Source; Structure; Symptoms; Synapses; System; Testing; Transgenic Mice; Transgenic Organisms; Work; awake; base; cell type; clinical translation; experimental study; human imaging; in vivo; inhibitory neuron; mouse model; nerve supply; neuropsychiatric disorder; optogenetics; repetitive behavior; response; skills; translational neuroscience

ABSTRACT Obsessive-compulsive disorder (OCD), and related obsessive-compulsive (OC) spectrum disorders, are characterized by an inability to suppress unwanted repetitive behaviors. Human imaging work implicates cortico- basal ganglia circuits in these disorders, but there is little information about the specific cell-types or microcircuitry involved. The striatum is the main input structure of the BG and receives massive cortical innervation. Fast- spiking interneurons (FSIs) in the striatum are strongly implicated in the ability to choose suppress or select behaviors, which is a key deficit in OCD and OC spectrum disorders. Additionally, abnormalities in FSIs have are associated with disorders involving aberrant behavioral suppression or selection. Thus, my central hypothesis is that deficient striatal FSI function causes hyperactivity in striatal output neurons and plays a role in OCD-like behaviors. A compelling mouse model of OCD-like behaviors (Sapap3-KO) is associated with decreased cortical drive onto principal striatal cells. These principal cells, however, are hyperactive in vivo. This suggests deficient local inhibition leads to OCD-relevant behaviors, and FSIs are the strongest local inhibitory neurons in striatum. This proposal will 1) examine differences in striatal FSI intrinsic excitability between Sapap3-KO and healthy WT mice, 2) investigate differences in corticostriatal functional synapses onto striatal FSIs and FSI synapses onto MSNs in Sapap3-KO and healthy WT mice, and 3) determine whether directly increasing synchronous FSI activity can restore normal behavioral and neuronal activity in OCD-like mice. This research will culminate in knowledge on specific microcircuits involved in OCD-like symptoms and striatal FSI function underlying behavioral suppression. The integrated research and training plan will provide valuable expertise in ex vivo and in vivo electrophysiology, behavior, and optogenetics. These skills are critical for the applicant’s ultimate goals of transitioning into an independent investigator, and integrating circuit, systems, and translational neuroscience to understand behavioral symptoms of OC spectrum disorders.

摘要 强迫症（OCD）和相关的强迫症（OC）谱系障碍， 以不能抑制不想要的重复行为为特征。人体成像表明皮质- 基底神经节电路在这些疾病中，但很少有关于特定细胞类型或微电路的信息 涉案纹状体是BG的主要输入结构，并接受大量的皮质神经支配。快- 纹状体中的尖峰中间神经元（FSI）与选择抑制或选择的能力密切相关 行为，这是强迫症和OC谱系障碍的关键缺陷。此外，FSI的异常 与涉及异常行为抑制或选择的疾病有关。因此，我的中央 一种假说认为，纹状体FSI功能缺陷导致纹状体输出神经元过度活跃， 在强迫症样行为中扮演的角色强迫症样行为（Sapap 3-KO）的引人注目的小鼠模型与 皮质对主纹状体细胞的驱动力减少。然而，这些主要细胞在体内是过度活跃的。 这表明局部抑制不足导致OCD相关行为，FSI是最强的局部抑制， 纹状体抑制性神经元这项建议将1）检查纹状体FSI内在兴奋性的差异， Sapap 3-KO和健康WT小鼠，2）研究皮质纹状体功能性突触与纹状体功能性突触之间的差异， Sapap 3-KO和健康WT小鼠中MSN上的FSI和FSI突触，以及3）确定是否直接 增加同步FSI活性可以恢复OCD样小鼠的正常行为和神经元活性。这 研究将最终在特定的微电路涉及强迫症样症状和纹状体FSI的知识 行为抑制的潜在功能综合研究和培训计划将提供宝贵的 在离体和体内电生理学、行为学和光遗传学方面的专业知识。这些技能对于 申请人的最终目标是过渡到一个独立的调查，并整合电路，系统， 转化神经科学，以了解OC谱系障碍的行为症状。