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.

项目摘要/摘要 强迫运动行为（即重复定型，不可抑制的行为）是一种常见的电动机 在各种神经退行性，神经发育和神经精神疾病中发现的症状。 这些运动症状干扰了超过1％以上的日常运作，生产率和生活质量 人口，但是治疗方案是有限的，并且由于对 潜在的脑回路和缺乏治疗靶标。纹状体（尾状/梭子鱼），主要输入 基底神经节的核是人和啮齿动物中强迫运动行为的关键介体。 强迫性运动行为通常与焦虑症共同发生，心理物理模型具有 提出两者是机械上的联系，表明相应的脑电路可能重叠。 然而，边缘相关的输入如何在纹状体的运动部分收敛。这 该提议的目的是确定如何从杏仁核的基底和侧核的突触输入 （BLA）影响背外侧纹状体功能，以及是否通过病理突触整合BLA输入 背外侧纹状体加剧了强迫运动行为。背外侧纹状体包含两种类型 功能相反的棘投射神经元（SPNS），主要接收来自 感觉运动皮层和丘脑，并最终促进或抑制作用启动。主要假设是 这种强迫性运动行为是由于SPN种群的激活不平衡引起的 促进行动启动。拟议的研究将确定SPNS如何在病理上整合突触 在强迫运动行为的互补小鼠模型中，BLA的输入（由遗传诱导 删除slitrk5或sapap3，或通过重复性过度激活BLA输入到实验引起的 背外侧纹状体）。这种方法将揭示常见的，独立的电路病理。指导 强的初步数据和尖端技术（2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-填充物的突变小鼠系和 在体内切片和体内的空间定位的光遗传学），拟议的研究将确定如何确定如何确定 在slitrk5和sapap3敲除小鼠中，背外侧纹状体SPN种群的树突状兴奋性改变了，2） 在功能上绘制了BLA如何参与SPN树突，这如何影响突触集成 突变小鼠和3）确定重复性在BLA输入对背外侧纹状体的体内活化的作用 在诱导行为和电路病理中，与突变小鼠中发现的那些重叠并加剧了行为， 确定通过行为治疗纠正的常见电路病理（在小鼠中，但只有一个子集 患者）5-羟色胺再摄取抑制剂氟西汀。该提案的结果有望揭示 新颖的病理基因座和广泛使用但不完善的治疗方法的潜在机制 运动行为，有助于开发这种常见和使人衰弱的症状的改进疗法。