Direct amygdala modulation of the dorsolateral striatum and compulsive behaviors

项目摘要/摘要 强迫运动行为(即重复的刻板印象的、不可抑制的行为)是一种常见的运动 症状见于广泛的神经退行性、神经发育和神经精神疾病。 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 然而，治疗选择有限，而且往往无效，这是因为对 潜在的大脑回路和缺乏治疗靶点。纹状体(尾状核/壳核)是主要的输入 基底神经节的核，是人类和啮齿动物强迫运动行为的关键中介。 强迫性运动行为通常与焦虑症并存，而心理物理模型 提出两者是机械联系的，这表明相应的大脑回路可能会重叠。 然而，边缘相关的输入如何汇聚到纹状体的运动部，目前尚不清楚。这个 这项提议的目的是确定来自杏仁核基底核和外侧核的突触输入是如何 (BLA)影响背外侧纹状体功能，如果BLA传入的病理性突触整合通过 背外侧纹状体加剧强迫运动行为。背外侧纹状体含有两种类型的 功能上相反的棘突投射神经元(SPN)，主要接受来自 感觉运动皮质和丘脑，并最终促进或抑制动作的发起。一个重要的假设是 强迫性运动行为是由于SPN群体的不平衡激活，从病理上讲 推动行动启动。这项拟议的研究将确定SPN如何在病理上整合突触 在强迫性运动行为的补充性小鼠模型中来自血乳酸的输入(由 Slitrk5或Sapap3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。指导原则 强大的初步数据和尖端技术(双光子激光扫描显微镜、树枝状钙 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 在体外切片和体内的空间定位光遗传学)，拟议的研究将1)确定 Slitrk5和Sapap3基因敲除小鼠背外侧纹状体SPN群体的树突状突起兴奋性改变，2) 从功能上映射BLA如何参与SPN树突，以及这如何影响脑内突触整合 突变小鼠，以及3)在体内重复激活背外侧纹状体的BLA输入的作用 在诱发与突变小鼠中发现的重叠和加剧的行为和电路病理中，以及 确定由行为治疗性疗法纠正的常见电路病理(在小鼠中，但仅为 患者)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问题 一种广泛使用但不完善的强迫症治疗的新病理位点和潜在机制 运动行为，有助于开发针对这种常见且令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.