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The Role of Layer I Interneurons in the Activity-Dependent Assembly of the Somatosensory Cortex

第一层中间神经元在体感皮层活动依赖性组装中的作用

基本信息

批准号：
10425441
负责人：
Andrew Ferdynand Iannone
金额：
$ 5.18万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425441
关键词：
Ablation Address Adult Affect Anatomy Animal Model Area Automobile Driving Behavior Behavior assessment Behavioral Characteristics Child Communities Dependence Development Developmental Process Discrimination Disease Electrophysiology (science)Electroporation Environmental Risk Factor Exhibits Eye Fiber Foundations Functional disorder Future Genes Genetic Genetic Diseases Genetic Risk Genetic Transcription Goals Impairment Incidence Interneurons Investigation Ligands Link Literature Maps Mediating Mentorship Molecular Molecular Target Morphology Mus N-Methyl-D-Aspartate Receptors Neonatal Neurons Neurosciences Pathogenesis Pattern Play Population Property Psychiatry Research Role Sensory Sensory Deprivation Somatosensory Cortex Stereotyping Symptoms Tactile Testing Texture Thalamic structure Vibrissae Viral Work autism spectrum disorder autistic axon growth barrel cortex cell type chemokine critical period experience gamma-Aminobutyric Acid high risk in utero individuals with autism spectrum disorder inhibitory neuron neuropsychiatry novel diagnostics novel therapeutics optogenetics postnatal programs recruit selective expression sensory cortex sensory input social deficits somatosensory symptomatology targeted treatment trait transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Individuals with Autism Spectrum Disorders (ASD) and related neurodevelopmental diseases exhibit diverse manifestations of the stereotyped socioemotional limitations of these conditions. Prominently, deficits in the processing and interpreting of sensory inputs are consistently observed. Foundational studies implicate inhibitory interneuron dysfunction in the pathogenesis of ASD as well as the role of select interneuron subtypes in coordinating organization of sensory processing cortical areas. We hypothesize that sensory input to defined subtypes of inhibitory interneurons at early developmental stages is necessary to recruit genetic programs mediating the emergence of correctly patterned sensory maps. To test this hypothesis, we will demonstrate the local circuitry of a molecularly-defined subtype of superficial interneurons, which underlies their coordinating role in sensory cortical assembly, using a combination of immunohistochemical and electrophysiologic profiling. We will show that sensory deprivation though genetic ablation of a high-risk ASD gene in these interneurons alters their transcriptional programs in an activity- dependent manner. Finally, we will implicate the sensory-sensitive expression of an emerging subtype-defining gene in these interneurons as necessary and sufficient for driving their role in sharpening sensory maps at neonatal stages and for consequent tactile sensing behavior in adulthood. This proposal, undertaken with the intellectual support of the Tri-Institutional research community and the guidance of a mentorship team at the nexus of neuroscience and psychiatry, will address a significant gap in understanding the intersection between genetic risk and aberrant activity-dependent sensory processing circuitry in the emergence of ASD symptomatology.

项目总结/摘要患有自闭症谱系障碍（ASD）和相关神经发育疾病的人表现出这些条件的定型社会情感限制的各种表现。突出的是，在处理和解释感官输入的缺陷是一致的，观察基础研究表明，抑制性中间神经元功能障碍与发病机制有关以及选择的中间神经元亚型在协调感觉组织中的作用处理皮层区域我们假设，对特定抑制亚型的感觉输入在早期发育阶段的中间神经元是必要的招募遗传程序介导正确模式化的感觉地图的出现。为了验证这个假设，我们将展示了表面中间神经元的分子定义亚型的局部回路，这是它们在感觉皮层组装中协调作用的基础，免疫组织化学和电生理分析。我们会证明感官剥夺尽管在这些中间神经元中基因切除高风险ASD基因改变了它们的转录水平，以活动依赖的方式进行编程。最后，我们将暗示感官敏感的人必要时在这些中间神经元中表达一种新出现的亚型定义基因，足以驱动它们在新生儿阶段锐化感觉地图的作用，成年后的触觉感知行为。这一建议，与知识分子进行三机构研究社区的支持和导师团队的指导，神经科学和精神病学的联系，将解决在理解遗传风险和异常活动依赖性感觉处理回路之间的交叉点， ASD症状的出现。