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

摘要 强迫症(OCD)和相关的强迫症(OC)谱系障碍 以无法抑制不想要的重复行为为特征的。人体成像检查显示皮质醇- 基底节回路在这些疾病中的作用，但关于特定的细胞类型或微回路的信息很少 牵涉其中。纹状体是BG的主要输入结构，接受大量的皮质神经支配。快速- 纹状体中的脉冲中间神经元(FSIS)与选择、抑制或选择的能力密切相关 行为，这是强迫症和强迫症谱系障碍的一个关键缺陷。此外，FSIS中的异常情况 与涉及异常行为抑制或选择的障碍有关。因此，我的中央 假设纹状体FSI功能缺陷会导致纹状体输出神经元和角色的过度活动 在类似强迫症的行为中扮演了一个角色。一种引人注目的强迫症样行为的小鼠模型(Sapap3-KO)被关联 皮质对主纹状体细胞的驱动力减弱。然而，这些主要细胞在体内是高度活跃的。 这表明，缺乏局部抑制会导致强迫症相关行为，而FSIS是最强的局部抑制 纹状体中的抑制性神经元。这项建议将1)检查纹状体FSI内在兴奋性的差异 SAPAP3-KO和健康WT小鼠，2)研究皮质纹状体与纹状体功能性突触的差异 在Sapap3-KO和健康的WT小鼠中，FSIS和FSI突触到MSN，3)直接确定 增加同步FSI活性可以恢复强迫症样小鼠的正常行为和神经元活动。这 研究的最终结果将是关于涉及强迫症样症状和纹状体FSI的特定微电路的知识 行为抑制的潜在功能。综合研究和培训计划将提供有价值的 在体外和体内电生理学、行为学和光遗传学方面的专业知识。这些技能对于 申请者的最终目标是转变为独立的调查员，并将电路、系统和 翻译神经科学，以了解OC谱系障碍的行为症状。

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.