The Effects of Somatosensory Experience on Brain Development and Function in Autism Spectrum Disorders

体感体验对自闭症谱系障碍患者大脑发育和功能的影响

基本信息

批准号：
10653701
负责人：
Lauren Lynn Orefice
金额：
$ 39.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653701
关键词：
Adult Afferent Neurons Anatomy Attention Behavior Behavioral Brain Brain region Cells Central Nervous System DNA Sequence Alteration Data Development Disease model Electrophysiology (science)Etiology Exhibits Fiber Functional Imaging Functional disorder Gene Deletion Gene Mutation Glean Goals Histologic Histology Human Hypersensitivity Impairment In Vitro Interneurons Investigation Jaw Lead Lifestyle-related condition Light Measures Methods Methyl-CpG-Binding Protein 2 Mus Mutation Neocortex Nervous System Physiology Neurodevelopmental Disorder Neuronal Dysfunction Neurons Output Pathway interactions Pattern Peripheral Peripheral Nervous System Phenotype Photometry Prefrontal Cortex Process Property Reporting Research Role Sensory Severities Shapes Skin Social Behavior Social Development Social Interaction Somatosensory Cortex Specific qualifier value Spinal Cord Structure of trigeminal ganglion Synapses Tactile Techniques Therapeutic Touch sensation Translating Vibrissae Viral Wild Type Mouse Work autism spectrum disorder barrel cortex brain abnormalities brain dysfunction conditional mutant experience frontal lobe in vivo individuals with autism spectrum disorder inhibitory neuron insight mouse genetics mouse model neocortical neural optogenetics postnatal repetitive behavior response sensory input sensory stimulus social social communication somatosensory transcriptome sequencing

Adult Afferent Neurons Anatomy Attention Behavior Behavioral Brain Brain region Cells Central Nervous System DNA Sequence Alteration Data Development Disease model Electrophysiology (science)Etiology Exhibits Fiber Functional Imaging Functional disorder Gene Deletion Gene Mutation Glean Goals Histologic Histology Human Hypersensitivity Impairment In Vitro Interneurons Investigation Jaw Lead Lifestyle-related condition Light Measures Methods Methyl-CpG-Binding Protein 2 Mus Mutation Neocortex Nervous System Physiology Neurodevelopmental Disorder Neuronal Dysfunction Neurons Output Pathway interactions Pattern Peripheral Peripheral Nervous System Phenotype Photometry Prefrontal Cortex Process Property Reporting Research Role Sensory Severities Shapes Skin Social Behavior Social Development Social Interaction Somatosensory Cortex Specific qualifier value Spinal Cord Structure of trigeminal ganglion Synapses Tactile Techniques Therapeutic Touch sensation Translating Vibrissae Viral Wild Type Mouse Work autism spectrum disorder barrel cortex brain abnormalities brain dysfunction conditional mutant experience frontal lobe in vivo individuals with autism spectrum disorder inhibitory neuron insight mouse genetics mouse model neocortical neural optogenetics postnatal repetitive behavior response sensory input sensory stimulus social social communication somatosensory transcriptome sequencing

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项目摘要

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.

项目摘要：自闭症谱系障碍（ASD）是一类高度普遍的神经发育类以社会交流和互动障碍以及受限制的疾病为特征重复行为。尽管ASD在病因和严重性方面是异质的，但大多数患有 ASD表现出对轻触摸的敏感性的改变。大多数ASD研究都集中在大脑特异性机制上和电路，很少关注周围神经系统和脊髓对ASD的贡献表型。我们最近发现一系列ASD小鼠模型（GABRB3，MECP2或Shank3突变）表现出对轻触的过度反应性，这种超敏反应是由于外周体积异常引起的神经元功能。周围感觉神经元功能障碍导致的体感异常开发还会导致主要体感皮质（S1）功能以及社交中断成年小鼠的相互作用缺陷（Orefice等，Cell，2016; Orefice等，Cell，2019）。我们的发现揭示了周围体感神经元是功能障碍触觉的关键轨迹 ASD的过度反应，以及外周感觉神经元功能障碍在异常脑发育中的作用和ASD模型中的异常社会行为。然而，周围体感的机制神经元功能障碍改变了脑电路的发展，并导致社会障碍仍然存在未知。我们假设与ASD相关的基因突变破坏了周围的感觉神经元功能和在感官途径的最早阶段进行触觉处理，导致脑发育异常，这是导致ASD中的大脑功能受损和行为破坏。我们提出了周围感觉神经元功能障碍导致中枢神经系统的感觉输入升高，导致S1功能异常并改变了调节社会行为的S1和大脑区域之间的远程连通性，包括前额叶皮层（PFC），最终会影响社会互动。在此提案中，我们旨在了解周围感觉神经元的机制功能障碍会导致脑驱动社会行为的变化。使用鼠标遗传学，行为，组织学，病毒，测序，光遗传学和纤维光度计技术以及体外和体内电生理方法，我们将：1）表征微电路的发展和远程躯干主要体感皮质（S1TR）的连通性; 2）确定外围感觉神经元是否 ASD模型中的功能障碍会影响S1TR中的感觉表示。 3）确定是否外围体感神经元功能障碍会影响ASD模型中S1TR-PFC预测的发展。由于周围神经系统的可及性，我们提出的研究收集的见解可能为治疗过敏或厌恶社会的治疗方法带来机会触摸以及社会行为的异常发展和神经系统在ASD中的功能。