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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：
10273686
负责人：
Lauren Lynn Orefice
金额：
$ 37.34万
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/10273686
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 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.