Direct amygdala modulation of the dorsolateral striatum and compulsive behaviors

项目总结/摘要 强迫性运动行为（即重复刻板，无法抑制的行为）是一种常见的运动 在广泛神经变性、神经发育和神经精神障碍中发现的症状。 这些运动症状干扰了超过1%的人的日常功能，生产力和生活质量。 人口，但治疗选择有限，往往无效，由于缺乏足够的了解， 潜在的大脑回路和缺乏治疗目标。纹状体（尾状核/壳核），主要输入 基底神经节的核，是人类和啮齿类动物中强迫性运动行为的关键介导者。 强迫性运动行为通常与焦虑症同时发生，心理物理模型 提出这两者在机制上是联系在一起的，这表明相应的大脑回路可能会重叠。 然而，与边缘相关的输入是如何汇聚到纹状体的运动部分的，目前还不清楚。的 本研究的目的是确定杏仁核基底核和外侧核的突触输入如何 (BLA)影响背外侧纹状体功能，如果BLA输入的病理性突触整合， 背外侧纹状体加重了强迫性运动行为。背外侧纹状体包含两种类型的 功能上相反的多刺投射神经元（SPNs），主要接收来自 感觉运动皮层和丘脑，并最终促进或抑制动作启动。一个主要的假设是 强迫性运动行为是由于SPN群体的不平衡激活， 促进行动启动。这项拟议中的研究将确定SPN如何在病理上整合突触， 在强迫性运动行为的互补小鼠模型中来自BLA的输入（由 Slitrk 5或Sapap 3的缺失，或通过重复过度激活BLA输入到 背外侧纹状体）。这种方法将揭示常见的，与模型无关的电路病理。指导 强大的初步数据和尖端技术（双光子激光扫描显微镜，树突状钙 成像、切片电生理学、含有荧光标记的SPN亚型的突变小鼠系，以及 在离体切片和体内的空间定位光遗传学），所提出的研究将1）确定 在Slitrk 5和Sapap 3敲除小鼠中，背外侧纹状体SPN群体的树突兴奋性改变，2） 在功能上绘制SPN树突如何与BLA接合，以及这如何影响突触整合， 突变小鼠，和3）确定BLA输入到背外侧纹状体的重复体内激活的作用 在诱导行为和电路病理重叠和加剧那些发现在突变小鼠，和 识别由行为治疗剂校正的常见回路病理（在小鼠中，但仅是 5-羟色胺再摄取抑制剂氟西汀。这项提案的结果预计将揭示这两个方面 新的病理位点和广泛使用但不完善的强迫症治疗的潜在机制， 运动行为，帮助开发针对这种常见和使人衰弱的症状的改进疗法。

Project Summary/Abstract Compulsive motor behaviors (i.e. repetitive stereotyped, insuppressible behaviors) are a common motor symptom found in a wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders. These motor symptoms interfere with the daily functioning, productivity and quality of life of over 1% of the population, yet treatment options are limited and often ineffective, due to insufficient understanding of the underlying brain circuits and lack of therapeutic targets. The striatum (caudate/putamen), the major input nucleus of the basal ganglia, is a key mediator of compulsive motor behaviors in both humans and rodents. Compulsive motor behaviors commonly co-occur with anxiety disorders, and psychophysical models have proposed that the two are mechanistically linked, suggesting the corresponding brain circuitries may overlap. How limbic-associated inputs converge on the motor portions of the striatum, however, is unclear. The objective of this proposal is to determine how synaptic inputs from the basal and lateral nuclei of the amygdala (BLA) influence dorsolateral striatum function, and if pathological synaptic integration of BLA inputs by the dorsolateral striatum exacerbates compulsive motor behaviors. The dorsolateral striatum contains two types of functionally opposing spiny projection neurons (SPNs), which predominantly receive synaptic inputs from the sensorimotor cortex and thalamus, and ultimately promote or suppress action initiation. A leading hypothesis is that compulsive motor behaviors are due to imbalanced activation of SPN populations, pathologically promoting action initiation. The proposed research will determine how SPNs pathologically integrate synaptic inputs from the BLA in complementary mouse models of compulsive motor behavior (genetically induced by deletion of Slitrk5 or Sapap3, or experimentally induced by repetitive over-activation of BLA inputs to the dorsolateral striatum). This approach will reveal common, model-independent circuit pathologies. Guided by strong preliminary data and cutting edge techniques (2-photon laser scanning microscopy, dendritic calcium imaging, slice electrophysiology, mutant mouse lines containing fluorescently tagged SPN-subtypes, and spatially localized optogenetics in ex vivo slices and in vivo), the proposed research will 1) determine how the dendritic excitability of dorsolateral striatum SPN populations is altered in Slitrk5 and Sapap3 knockout mice, 2) functionally map how SPN dendrites are engaged by the BLA, and how this impacts synaptic integration in mutant mice, and 3) determine the role of repetitive in vivo activation of BLA inputs to the dorsolateral striatum in inducing behavior and circuit pathologies overlapping with and exacerbating those found in mutant mice, and identify the common circuit pathologies corrected by the behaviorally therapeutic (in mice, but only a subset of patients) serotonin reuptake inhibitor fluoxetine. The results from this proposal are expected to reveal both novel pathological loci and the underlying mechanisms of a widely used but imperfect treatment for compulsive motor behaviors, aiding in the development of improved therapies for this common and debilitating symptom.