Circuit Disruptions Underlying Atypical Sensory Processing in Fragile X Syndrome

脆性 X 综合征中非典型感觉处理背后的电路中断

• 批准号: 10033726
• 负责人: Craig Erickson
• 金额: $ 47.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033726
• 关键词: Address; Adult; Affect; Anxiety; Arousal; Attentional deficit; Auditory; Behavioral; Biological; Brain; Cells; Characteristics; Clinic; Clinical Research; Clinical Trials; Collaborations; Coupling; Cre-LoxP; Data; Defect; Discrimination; Down-Regulation; Electroencephalography; Engineering; Epilepsy; Exhibits; Experimental Designs; FMR1; Fragile X Syndrome; Frequencies; Functional disorder; Future; Genes; Genetic; Goals; Human; Hypersensitivity; Imaging Techniques; Impairment; Individual; Inherited; Intellectual functioning disability; Interneurons; Investigation; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Link; Methodology; Molecular; Morphology; Mus; Nature; Neurodevelopmental Disorder; Neurons; Neurosciences; Output; Paper; Participant; Parvalbumins; Pathogenesis; Pathway interactions; Performance; Phase; Population Dynamics; Publishing; Quality of life; Reporting; Research; Research Personnel; Role; Running; Sensory; Silicon; Stimulus; Symptoms; Synapses; Tactile; Task Performances; Techniques; Testing; Time; Universities; Vasoactive Intestinal Peptide; Visual; Visual impairment; area striata; autism spectrum disorder; awake; base; behavioral impairment; behavioral phenotyping; cell type; designer receptors exclusively activated by designer drugs; distraction; experimental study; hippocampal pyramidal neuron; human subject; improved outcome; in vivo calcium imaging; in vivo imaging; inhibitory neuron; innovation; insight; migration; mouse model; neuroregulation; novel; novel strategies; relating to nervous system; sensory discrimination; sensory input; sex; translational approach; translational study

SUMMARY The underlying brain defects in Fragile X Syndrome (FXS) are not well understood. We have been investigating the specific circuit alterations that lead to a variety of symptoms in FXS, including attention deficit, anxiety, hyperarousal, sensory hypersensitivity and delayed learning. We focus on FXS, the most common inherited cause of autism and intellectual disability, because most investigators use the same Fmr1 knockout mouse model to investigate it, and because it lacks neuropathological features that often confound investigations in other neurodevelopmental disorders (e.g., severe epilepsy, neuronal migration defects, etc.). We strive to overcome limitations of previous studies by comparing the performance of humans and mice with FXS on analogous behavioral tasks. Our goal is to identify shared deficits in sensory processing and learning across both species that will hopefully improve outcomes of future clinical trials in FXS. Here, we will determine the impact of sensory distractors on behavioral performance in both humans and mice using a visual discrimination task. We will also identify specific alterations in population dynamics of pyramidal neurons and different subtypes of inhibitory interneurons that are responsible for deficits in sensory discrimination in Fmr1 knockout mice. Building on our recently published study in Nature Neuroscience (Goel et al., 2018), we will address the following important questions: 1. Does distraction worsen performance in a sensory discrimination task in Fmr1 knockout mice and in adult subjects with FXS? (Aim 1)? 2. Is the firing of parvalbumin (PV)- and vasoactive intestinal polypeptide (VIP)-expressing interneurons disrupted in Fmr1 knockout mice during the sensory discrimination task, especially in the presence of sensory distractors? (Aim 2A)? 3. Can silencing VIP interneurons (or exciting PV neurons) with DREADDs rescue behavioral performance in Fmr1 knockout mice? (Aim 2B)? 4. Do mice and humans with FXS share similar deficits in neural oscillations (Aim 3)? The mouse studies will be performed in the laboratory of established FXS investigator Carlos Portera-Cailliau (PI) at UCLA. Craig Erickson (co-I), who runs the world’s 3rd largest FXS clinic at the University of Cincinnati, will conduct the human studies. The experimental design exploits cutting edge in vivo imaging techniques (e.g., chemogenetics, in vivo two-photon calcium imaging, Cre-Lox genetics, silicon probe recordings, phase- amplitude coupling analysis of EEG) and seeks to address important knowledge gaps in ASD pathogenesis.

总结 脆性X综合征（FXS）的潜在脑缺陷尚未得到很好的理解。我们一直 研究导致FXS各种症状的特定回路改变，包括注意力缺陷， 焦虑、过度觉醒、感觉超敏和延迟学习。我们专注于FXS，最常见的 自闭症和智力残疾的遗传原因，因为大多数研究人员使用相同的Fmr 1敲除 小鼠模型来研究它，因为它缺乏神经病理学特征， 对其他神经发育障碍的研究（例如，严重癫痫、神经元迁移缺陷等）。 我们通过比较人类和小鼠的表现， 模拟行为任务的FXS。我们的目标是找出感觉处理和学习的共同缺陷 这将有望改善未来FXS临床试验的结果。在这里，我们将 确定感官干扰对人类和小鼠行为表现的影响，使用视觉 辨别任务我们还将确定锥体神经元群体动力学的特定改变， 不同亚型的抑制性中间神经元，负责Fmr 1中感觉辨别的缺陷 敲除小鼠基于我们最近在《自然神经科学》上发表的研究（Goel et al.，2018年，我们将 解决以下重要问题：1.分心会使感觉辨别能力恶化吗 在Fmr 1基因敲除小鼠和FXS成人受试者中的任务？(Aim（1）？2.是小清蛋白（PV）的发射-和 血管活性肠多肽（VIP）表达的中间神经元在Fmr 1敲除小鼠中被破坏， 感觉辨别任务，尤其是在存在感觉干扰物的情况下？(Aim 2A）？3.罐消音VIP 中间神经元（或兴奋PV神经元）与DREADD拯救Fmr 1敲除小鼠的行为表现？ (Aim 2B）？4.患有FXS的小鼠和人类在神经振荡方面有相似的缺陷吗？鼠标 研究将在FXS研究者卡洛斯波特拉-卡里奥（PI）的实验室进行， 加州大学洛杉矶分校克雷格埃里克森（co-I）在辛辛那提大学经营着世界第三大FXS诊所， 进行人类研究。实验设计利用了尖端的体内成像技术（例如， 化学遗传学，体内双光子钙成像，Cre-Lox遗传学，硅探针记录，相位- EEG的振幅耦合分析），并寻求解决ASD发病机制中的重要知识缺口。