Circuit Disruptions Underlying Atypical Sensory Processing in Fragile X Syndrome

摘要 脆性X综合征(FXS)的潜在脑缺陷尚不清楚。我们一直在 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、感觉过敏和学习延迟。我们专注于FXS，这是最常见的 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Fmr1基因敲除 用小鼠模型来研究它，因为它缺乏经常令人困惑的神经病理特征 研究其他神经发育障碍(例如，严重癫痫、神经元迁移缺陷等)。 我们努力克服以前研究的局限性，将人类和老鼠的表现与 关于类似行为任务的FXS。我们的目标是找出感官处理和学习的共同缺陷 在这两个物种中，这有望改善FXS未来临床试验的结果。在这里，我们将 通过视觉测试确定感觉干扰物对人类和小鼠行为表现的影响 辨别任务。我们还将确定锥体神经元种群动力学的具体变化和 与Fmr1感觉辨别缺陷相关的不同亚型抑制性中间神经元 基因敲除老鼠。在我们最近发表在《自然神经科学》(Goel等人，2018)研究的基础上，我们将 回答以下重要问题：1.分心是否会恶化感觉辨别能力的表现 Fmr1基因敲除小鼠和患有FXS的成人受试者的任务？(目标1)？2.激发小白蛋白(PV)--以及 Fmr1基因敲除小鼠血管活性肠多肽(VIP)表达的中间神经元在 感觉辨别任务，尤其是在有感觉干扰物的情况下？(目标2A)？3.让VIP沉默可以吗？ 使用DREADDS的中间神经元(或兴奋性PV神经元)能否挽救Fmr1基因敲除小鼠的行为表现？ (目标2B)？4.患有FXS的小鼠和人类在神经振荡方面是否存在类似的缺陷(目标3)？鼠标 研究将在著名FXS调查员Carlos Portera-Cailliau(PI)的实验室进行，地点为 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，他将 进行人体研究。实验设计利用了最先进的活体成像技术(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- 脑电的幅度耦合分析)，并试图解决ASD发病机制中的重要知识空白。

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.