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Linking neuronal identity transcription factors to neural circuit establishment and maintenance

将神经元身份转录因子与神经回路的建立和维护联系起来

基本信息

批准号：
10386149
负责人：
Kristen M Lee
金额：
$ 6.98万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386149
关键词：
Address Adult Affect Aging Attention deficit hyperactivity disorder Axon Biological Assay Biological Metamorphosis Brain Caenorhabditis elegans Cell surface Cognition Complex Coupled Data Defect Dendrites Development Developmental Process Drosophila genus Drug abuse Embryo Esthesia Event Foundations Gene Expression Gilles de la Tourette syndrome Goals Hormones Individual Interneurons Larva Lead Learning Life Link Locomotion Maintenance Mammals Membrane Mental disorders Modeling Molecular Molecular Profiling Morphology Motor Movement Neuraxis Neurites Neurodevelopmental Disorder Neuronal Plasticity Neurons Neurotransmitters Outcome Phenotype Property Puberty RNA interference screen Risk Role Schizophrenia Shapes Sleep Specific qualifier value Synapses System Testing Therapeutic Walking Work autism spectrum disorder behavioral phenotyping experimental study fly homeodomain interest molecular marker neural circuit neural patterning neurogenesis neuromechanism optogenetics relating to nervous system response transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Neuronal identity is generated during development, with identity characterized by neuron-specific gene expression, axon/dendrite morphology, and connectivity. Homeodomain transcription factors (TFs) are required for establishing gene expression and neuronal morphology, but whether they are required for neuronal connectivity is unknown. Understanding the developmental processes generating neuronal identity in general, and connectivity in particular, is essential for understanding brain assembly and function. An attractive model is that homeodomain TFs – known to regulate neuronal molecular and morphological identity – also facilitate the expression of cell surface molecules that allow the formation of highly-specific neural connections. Connections between individual neurons contribute to neural circuits, which allow sensation, movement and cognition. Proper circuit function throughout life relies on continued circuit remodeling, both synaptically and structurally. Interestingly, homeodomain TFs are expressed in adult neurons, well after neuronal identity has been established. I hypothesize that the homeodomain TFs are required for neural circuit establishment and maintenance throughout life. To test this, I have performed a systematic screen for homeodomain TFs required for the function of a locomotor neural circuit in Drosophila, the Moonwalker Descending Neuron (MDN) and Pair1 circuit. I have identified 16 homeodomain TFs required for MDN or Pair1 optogenetic induced locomotion. In Aim 1, I will test how these 16 homeodomain TFs contribute to neuronal identity by assaying molecular identity, axon/dendrite morphology, and connectivity. My pilot experiments have already shown that the homeodomain TF Bicoid is required for connectivity but not molecular identity or morphology. In Aim 2, I will utilize how the MDN-Pair1 circuit is remodeled during Drosophila metamorphosis and persists in the adult fly. I will assay whether the TFs required for establishing MDN-Pair1 connectivity are also required for maintaining the MDN-Pair1 circuit throughout adulthood. My pilot data shows that Bicoid is also expressed in the adult Pair1 neurons. My overarching goal is to advance the understanding of how developmental mechanisms, specifically homeodomain TFs, establish circuits during development and maintain circuits after periods of plasticity/remodeling. Given that fly and mammalian neurogenesis share many conserved features, that homeodomain TFs are highly conserved between species, and that aberrant neural circuits have been implicated in neurodevelopmental and psychiatric disorders, we expect our results to be both translatable and therapeutically relevant.

项目总结/文摘