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

项目摘要/摘要 自闭症谱系障碍(ASD)和相关神经发育疾病的个体 表现出这些疾病的刻板的社会情感局限的不同表现。 突出的是，在处理和解释感觉输入方面的缺陷一直是 观察到的。基础研究提示抑制性中间神经元功能障碍在发病机制中的作用 以及选定的中间神经元亚型在协调感觉组织中的作用 处理大脑皮层区域。我们假设感觉输入到确定的抑制性亚型 早期发育阶段的中间神经元是招募基因程序所必需的 正确构图的感觉图的出现。为了检验这一假设，我们将 展示了一种分子定义的亚型浅层中间神经元的局部电路， 这是它们在感觉皮质组装中的协调作用的基础，使用 免疫组织化学和电生理分析。我们将展示感官剥夺 尽管这些中间神经元中高危ASD基因的遗传消融改变了它们的转录 以一种依赖于活动的方式制定计划。最后，我们将牵涉到感官敏感者 根据需要在这些中间神经元中表达一个新出现的亚型定义基因 足以推动它们在新生儿阶段锐化感觉图的作用，并 成年期随之而来的触觉感觉行为。这一建议是与知识分子共同提出的 三所院校研究界的支持和指导团队的指导 神经科学和精神病学的联系，将解决在理解 遗传性风险和异常活动依赖的感觉处理回路之间的交集 ASD症状学的出现。

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.