The effects of somatosensory experience on brain development and function in autism spectrum disorders

项目摘要：自闭症谱系障碍(ASD)是一种非常普遍的神经发育类型 以社会交流和互动障碍为特征的障碍，以及受限的， 重复的行为。虽然自闭症在病因和严重性上是不同的，但大多数患有自闭症的人 ASD表现出对光接触的改变的敏感性。大多数自闭症研究都集中在大脑特有的机制上。 和回路，很少注意周围神经系统和脊髓在ASD中的作用 表型。我们最近发现了一系列ASD小鼠模型(GABRB3、MeCP2或Shank3突变) 表现出对轻触碰的过度反应，这种过敏是由于外周躯体感觉异常所致 神经元功能。外周感觉神经元功能障碍所致的躯体感觉异常 发育还会导致初级躯体感觉皮质(S1)功能的中断，以及社交功能的中断 成年小鼠的相互作用缺陷(Orefice等人，Cell，2016；Orefice等人，Cell，2019)。 我们的发现揭示了外周体感神经元是触觉功能障碍的关键部位。 ASD的过度反应以及外周感觉神经元功能障碍在脑发育异常中的作用 以及ASD模型中的异常社交行为。然而，外周躯体感觉的机制 神经元功能障碍改变大脑回路发育，并导致社交障碍 未知。我们假设与ASD相关的基因突变破坏了周围感觉神经元的功能，并 在感觉通路的最早阶段进行触觉处理，导致大脑发育异常， 导致ASD患者大脑功能受损和行为紊乱。我们认为外周感觉神经元 功能障碍导致中枢神经系统感觉输入增加，从而导致S1功能异常 并改变了S1和大脑区域之间的远程连接，这些区域调节着社会行为，包括 前额叶皮质(PFC)，最终影响社会互动。 在这个提议中，我们的目标是了解外周感觉神经元 功能障碍会导致大脑驱动的社会行为发生变化。利用老鼠的遗传学、行为学、 组织学、病毒、测序、光遗传学和纤维光度技术，以及体外和体内 电生理学方法，我们将：1)表征微电路的发展和远程性 躯干初级躯体感觉皮层的连通性；2)决定周围感觉神经元 ASD模型中的功能障碍影响S1TR中的感觉表征；以及3)确定外周是否 躯体感觉神经元功能障碍影响ASD模型中S1TR-PFC投射的发展。 由于周围神经系统的可及性，从我们拟议的研究中收集的见解可能 为治疗社交过敏或厌恶社交提供治疗方法的机会 触摸，以及ASD的社会行为和神经系统功能的异常发展。

Project Summary: Autism spectrum disorders (ASD) are a highly prevalent class of neurodevelopmental disorders characterized by impairments in social communication and interactions, as well as restricted, repetitive behaviors. While ASDs are heterogeneous in etiology and severity, the majority of individuals with ASD exhibit altered sensitivity to light touch. Most ASD research has focused on brain-specific mechanisms and circuits, with little attention to the contributions of the peripheral nervous system and spinal cord to ASD phenotypes. We recently found that a range of ASD mouse models (Gabrb3, Mecp2 or Shank3 mutations) exhibit over-reactivity to light touch, and this hypersensitivity is due to abnormal peripheral somatosensory neuron function. Somatosensory abnormalities resulting from peripheral sensory neuron dysfunction during development also lead to disruptions in primary somatosensory cortex (S1) function, as well as social interaction deficits in adult mice (Orefice et al., Cell, 2016; Orefice et al., Cell, 2019). Our findings reveal peripheral somatosensory neurons as a key locus of dysfunction underlying tactile over-reactivity in ASD, and a role for peripheral sensory neuron dysfunction in abnormal brain development and aberrant social behaviors in ASD models. Yet, the mechanisms by which peripheral somatosensory neuron dysfunction alters brain circuit development and results in social impairments remain unknown. We hypothesize that ASD-related genetic mutations disrupt peripheral sensory neuron function and tactile processing at the earliest stages of sensory pathways, leading to abnormal brain development, which results in impaired brain function and disrupted behaviors in ASD. We propose that peripheral sensory neuron dysfunction leads to elevated sensory inputs to the central nervous system that leads to abnormal S1 function and altered long-range connectivity between S1 and brain regions that modulate social behaviors, including prefrontal cortex (PFC), which ultimately impacts social interactions. In this proposal, we aim to understand the mechanisms through which peripheral sensory neuron dysfunction contributes to changes in brain-driven social behaviors. Using mouse genetics, behavioral, histological, viral, sequencing, optogenetics, and fiber photometry techniques, as well as in vitro and in vivo electrophysiological approaches, we will: 1) characterize the microcircuit development and long-range connectivity of trunk primary somatosensory cortex (S1TR); 2) determine whether peripheral sensory neuron dysfunction in ASD models impacts sensory representation in S1TR; and 3) identify whether peripheral somatosensory neuron dysfunction impacts the development of S1TR-PFC projections in ASD models. Because of the accessibility of the peripheral nervous system, insights gleaned from our proposed studies may lead to opportunities for therapeutic approaches for the treatment of hypersensitivity or aversion to social touch, as well as the abnormal development of social behaviors and nervous system function in ASD.