Circuit Defects Underlying Sensory Hypersensitivity in Fragile X Syndrome

总结/摘要 我们计划研究脆性X综合征（FXS）感觉超敏反应的潜在回路缺陷， 最常见的遗传形式的智力障碍和最常见的单基因自闭症的原因。在 对感官刺激过度兴奋，受影响的个体被声音，气味，视觉或触觉深深困扰 在其他人看来很正常这会导致适应不良的行为，包括回避反应，如 触觉防御几乎所有FXS患者都患有触觉防御和Fmr 1敲除 FXS的动物模型（Fmr 1-/-）小鼠表现出明显的感觉过度觉醒迹象。阐明了 电路功能障碍导致脆性X小鼠将某些刺激解释为厌恶/威胁，以及这是如何发生的。 最终导致回避反应，代表了FXS研究中的一个主要知识缺口。解决 为此，我们提出了一种新的神经元-电路-神经元方法，用于FXS的Fmr 1-/-小鼠模型， 研究导致感觉处理改变的回路和单个神经元水平的中断。中 最近的研究（He等人，J Neurosci，2017），我们证明了如何响应重复的触觉刺激， Fmr 1-/-小鼠显示出类似于人类触觉防御的感觉回避行为。 使用在体感觉（S1）桶皮质钙成像，我们发现重复晶须， 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 而不是在Fmr 1-/-小鼠中。因此，可以解释FXS中触觉防御性的电路缺陷之一是 皮质神经元的神经元适应（简单地说，脆性X小鼠S1皮质中的神经元不能适应 关掉持续的触觉刺激）。我们现在打算测试这种神经适应的丧失是否会导致 S1皮层小清蛋白（PV）或生长抑素（SST）GABA能中间神经元功能障碍，然后 来描绘S1皮层上游或下游的脑区回路变化。这些 研究将使我们能够通过检查FXS中感觉过度觉醒的更详细的布线图， 感觉处理的三个阶段：丘脑（输入）、皮层（整合）和杏仁核（输出）。自始至终， 我们将研究在感觉处理的每个阶段操纵神经元活动是否可能 改善与Fmr 1-/-小鼠感觉过度觉醒相关的适应不良行为。我们的实验 设计采用尖端技术，包括体内双光子钙成像，硅微探针， DREADDs和Cre-Lox遗传学，并寻求解决FXS中的重要知识差距。因为许多 FXS中失调的信号通路也涉及其他神经发育过程， 我们相信，我们独特的双回路方法具有非常高的意义， 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.