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：
10451599
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/10451599
关键词：
Adult Afferent Neurons Anatomy Attention Behavior Behavioral Brain Brain region Cells 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 Nervous System Physiology Neuraxis Neurodevelopmental Disorder 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 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 in vivo individuals with autism spectrum disorder inhibitory neuron insight mouse genetics mouse model neocortical optogenetics postnatal relating to nervous system repetitive behavior response sensory input sensory stimulus social social communication somatosensory transcriptome sequencing

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) 是一类非常普遍的神经发育障碍以社交沟通和互动障碍以及受限为特征的疾病，重复的行为。虽然 ASD 的病因和严重程度各不相同，但大多数患有 ASD 的人自闭症谱系障碍 (ASD) 对轻触的敏感性发生了改变。大多数自闭症谱系障碍研究都集中在大脑特定机制上和电路，很少关注周围神经系统和脊髓对自闭症谱系障碍的贡献表型。我们最近发现一系列 ASD 小鼠模型（Gabrb3、Mecp2 或 Shank3 突变）对轻触表现出过度反应，这种过敏是由于异常的外周体感引起的神经元功能。周围感觉神经元功能障碍导致的体感异常发育还会导致初级体感皮层（S1）功能以及社交功能的破坏成年小鼠的相互作用缺陷（Orefice 等人，Cell，2016；Orefice 等人，Cell，2019）。我们的研究结果揭示外周体感神经元是触觉功能障碍的关键部位自闭症谱系障碍 (ASD) 的过度反应以及周围感觉神经元功能障碍在大脑发育异常中的作用 ASD 模型中的异常社会行为。然而，外周体感的机制神经元功能障碍会改变大脑回路的发育并导致社交障碍仍然存在未知。我们假设与自闭症谱系障碍（ASD）相关的基因突变会破坏周围感觉神经元的功能，感觉通路早期阶段的触觉处理，导致大脑发育异常，导致自闭症患者的大脑功能受损和行为紊乱。我们提出外周感觉神经元功能障碍导致中枢神经系统感觉输入升高，从而导致 S1 功能异常并改变了 S1 和调节社会行为的大脑区域之间的远程连接，包括前额皮质（PFC），最终影响社交互动。在这个提案中，我们的目标是了解周围感觉神经元的机制功能障碍会导致大脑驱动的社会行为的变化。利用小鼠遗传学、行为学、组织学、病毒、测序、光遗传学和光纤光度测定技术，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距离躯干初级体感皮层（S1TR）的连接性； 2) 判断周围感觉神经元是否 ASD 模型的功能障碍会影响 S1TR 的感觉表征； 3) 识别是否是外围设备体感神经元功能障碍影响 ASD 模型中 S1TR-PFC 预测的发展。由于周围神经系统的可及性，从我们提出的研究中收集到的见解可能会为治疗过敏或厌恶社交的治疗方法带来机会自闭症谱系障碍患者的触摸、社会行为和神经系统功能的异常发展。