Circuit Defects Underlying Sensory Hypersensitivity in Fragile X Syndrome

摘要/摘要 我们计划调查脆性X综合征(FXS)感觉过敏的潜在电路缺陷， 最常见的遗传性智力障碍和最常见的导致自闭症的单基因。在……里面 对感官刺激的过度唤醒，受影响的人深受声音、气味、视觉或触摸的困扰 这在其他人看来很正常。这会导致不良适应行为，包括回避反应，例如 触觉防御性。几乎所有FXS患者都患有触觉防御性和Fmr1基因敲除 (FMR1-/-)小鼠是FXS的动物模型，表现出明显的感觉高度唤醒迹象。澄清的类型 导致脆性X小鼠将某些刺激解释为厌恶/威胁的电路功能障碍，以及这是如何 最终导致回避反应，代表着FXS研究中的一个主要知识缺口。致信地址 为此，我们在Fmr1/-小鼠FXS模型中提出了一种新的症状-电路-神经元的方法，以便 研究在回路和单个神经元水平上导致感觉处理改变的干扰。在一个 最近的研究(他等人，J Neurosci，2017)，我们展示了如何响应重复的触觉刺激 胡须，Fmr1-/-小鼠表现出类似于人类触觉防御的感觉回避行为。 使用体内躯体感觉(S1)桶状皮质的钙成像，我们随后显示了重复的胡须 刺激导致2周龄和成年野生型(WT)小鼠神经元放电逐渐减少，但 在Fmr1-/-小鼠中不存在。因此，可以解释FXS中触觉防御的电路缺陷之一是 皮层神经元的神经元适应(简单地说，脆性X小鼠S1皮质的神经元不能 忽略持续的触觉刺激)。我们现在建议测试这种神经元适应性的丧失是否会导致 由于S1皮质中的小白蛋白(PV)或生长抑素(SST)GABA能中间神经元功能障碍，然后 以描绘位于S1皮质上游或下游的大脑区域的电路变化。这些 研究将使我们能够通过检查来生成FXS中感觉过度觉醒的更详细的线路图 感觉处理的三个阶段：丘脑(输入)、皮质(整合)和杏仁核(输出)。自始至终， 我们将研究在感觉处理的每一个阶段操控神经元活动是否可能 改善Fmr1-/-小鼠感觉高度觉醒相关的适应不良行为。我们的实验 设计采用了尖端技术，包括活体双光子钙成像，硅微探针， DREADDS和CRE-Lox遗传学，并寻求解决FXS中的重要知识空白。因为很多人 FXS中失调的信号通路也与其他神经发育有关 对于精神障碍，我们认为我们独特的症状a电路方法具有非常高的意义，并可能 对许多类型的自闭症和精神障碍具有广泛的重要性。

SUMMARY / ABSTRACT We plan to investigate circuit defects underlying sensory hypersensitivity in Fragile X syndrome (FXS), the most common inherited form of intellectual impairment and the most common single gene cause of autism. In hyperarousal to sensory stimuli, affected individuals are deeply troubled by sounds, smells, sights, or touches that seem normal to others. This leads to maladaptive behaviors, including avoidance responses, such as tactile defensiveness. Virtually all individuals with FXS suffer from tactile defensiveness and Fmr1 knockout (Fmr1-/-) mice, an animal model of FXS, exhibit clear signs of sensory hyperarousal. Elucidating the types of circuit dysfunction that cause fragile X mice to interpret certain stimuli as aversive/threatening, and how this eventually leads to an avoidance response, represents a major knowledge gap in FXS research. To address this, we propose a novel symptom-to-circuit-to-neuron approach in the Fmr1-/- mouse model of FXS in order to investigate disruptions at the circuit and single neuron levels that result in altered sensory processing. In a recent study (He et al., J Neurosci, 2017), we demonstrated how, in response to repetitive tactile stimulation of whiskers, Fmr1-/- mice display a sensory avoidance behavior analogous to tactile defensiveness in humans. Using in vivo calcium imaging in somatosensory (S1) barrel cortex, we then showed that repetitive whisker stimulation results in a gradual reduction in neuronal firing in 2-week-old and in adult wild-type (WT) mice, but not in Fmr1-/- mice. Thus, one of the circuit defects that could explain tactile defensiveness in FXS is a loss of neuronal adaptation in cortical neurons (simply put, neurons in S1 cortex of fragile X mice are not be able to tune out persistent tactile stimuli). We now propose to test whether this loss of neuronal adaptation results from a dysfunction in parvalbumin (PV) or somatostatin (SST) GABAergic interneurons in S1 cortex, and then to delineate circuit alterations in brain regions that are both upstream or downstream from S1 cortex. These studies will allow us to generate a more detailed wiring diagram of sensory hyperarousal in FXS, by examining three stages of sensory processing: thalamus (input), cortex (integration), and amygdala (output). Throughout, we will investigate whether manipulating neuronal activity at each of these stages of sensory processing might ameliorate maladaptive behaviors associated with sensory hyperarousal in Fmr1-/- mice. Our experimental design employs cutting edge techniques, including in vivo two-photon calcium imaging, silicon microprobes, DREADDs, and Cre-Lox genetics, and seeks to address important knowledge gaps in FXS. Because many of the signaling pathways that are dysregulated in FXS are also implicated in other neurodevelopmental disorders, we believe that our unique symptomàcircuit approach has a very high significance and is likely to be of broad importance to many types of autism and mental impairment.