Direct amygdala modulation of the dorsolateral striatum and compulsive behaviors

杏仁核对背外侧纹状体的直接调节和强迫行为

• 批准号: 10213147
• 负责人: JOSHUA L PLOTKIN
• 金额: $ 40.94万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213147
• 关键词: Amygdaloid structure; Anatomy; Anxiety; Anxiety Disorders; Basal Ganglia; Behavior; Behavioral; Biological; Brain; Brain region; Calcium; Cell Nucleus; Compulsive Behavior; Corpus striatum structure; Data; Dendrites; Development; Disease; Distress; Electrophysiology (science); Feedback; Fluoxetine; Genetic Models; Glutamates; Habits; Human; Image; Knockout Mice; Knowledge; Label; Laser Scanning Microscopy; Lateral; Link; Maps; Mediator of activation protein; Mission; Modeling; Motor; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Outcome; Pathologic; Pathology; Patients; Pattern; Physiological; Population; Presynaptic Terminals; Productivity; Psychophysics; Public Health; Quality of life; Research; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Shapes; Slice; Stereotyping; Symptoms; Synapses; Techniques; Testing; Thalamic structure; Therapeutic; Transgenic Mice; United States National Institutes of Health; Work; anxiety-like behavior; brain circuitry; common symptom; common treatment; daily functioning; design; disabling symptom; experimental study; habit learning; imaging study; improved; in vivo; insight; motor behavior; motor symptom; mouse model; nerve supply; neuropsychiatric disorder; novel; optogenetics; patient subsets; postsynaptic; putamen; response; therapeutic target; two photon microscopy; two-photon

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.

项目概要/摘要 强迫性运动行为（即重复刻板、不可抑制的行为）是一种常见的运动行为 广泛存在于神经退行性、神经发育和神经精神疾病中的症状。 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，但由于对疾病认识不足，治疗选择有限且往往无效 潜在的大脑回路和缺乏治疗靶点。纹状体（尾状核/壳核），主要输入 基底神经节核是人类和啮齿动物强迫运动行为的关键调节者。 强迫性运动行为通常与焦虑症同时发生，心理物理模型已经 提出这两者在机制上是相关的，这表明相应的大脑回路可能重叠。 然而，边缘系统相关的输入如何汇聚到纹状体的运动部分尚不清楚。这 该提案的目的是确定来自杏仁核基底核和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 背外侧纹状体加剧强迫性运动行为。背外侧纹状体包含两种类型 功能上相反的多刺投射神经元（SPN），主要接收来自 感觉运动皮层和丘脑，最终促进或抑制动作的启动。一个主要假设是 强迫性运动行为是由于 SPN 群体激活不平衡造成的，病理上 促进行动的启动。拟议的研究将确定 SPN 如何病理性地整合突触 来自 BLA 的输入在强迫性运动行为的互补小鼠模型中（由基因诱导） Slitrk5 或 Sapap3 的缺失，或通过重复过度激活 BLA 输入来实验诱导 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学。指导者 强大的初步数据和尖端技术（2光子激光扫描显微镜、树突钙 成像、切片电生理学、含有荧光标记 SPN 亚型的突变小鼠系，以及 空间局部光遗传学（离体切片和体内），拟议的研究将1）确定如何 Slitrk5 和 Sapap3 敲除小鼠中背外侧纹状体 SPN 群体的树突兴奋性发生改变，2) 功能性地绘制 SPN 树突如何与 BLA 结合，以及这如何影响突触整合 突变小鼠，3) 确定背外侧纹状体 BLA 输入重复体内激活的作用 诱发与突变小鼠中发现的行为和回路病理重叠并加剧的行为和回路病理，以及 识别通过行为治疗纠正的常见回路病理（在小鼠中，但只有一部分 患者）血清素再摄取抑制剂氟西汀。该提案的结果预计将揭示 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，有助于开发针对这种常见且令人衰弱的症状的改进疗法。