Genetic and molecular regulation of experience-dependent structural plasticity

经验依赖性结构可塑性的遗传和分子调控

• 批准号: 10562121
• 负责人: Michael P Hart
• 金额: $ 39.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562121
• 关键词: Adhesions; Adult; Age; Aging; Behavior; Behavioral; Behavioral Assay; Brain; CRISPR/Cas technology; Caenorhabditis elegans; Cell Adhesion; Cell Adhesion Molecules; Complex; Defect; Development; Disease; Down Syndrome Cell Adhesion Molecule; Genes; Genetic; Health; Hermaphroditism; Injury; Knowledge; Learning; Life; Longevity; Measures; Modeling; Molecular; Morphology; Nematoda; Nervous System; Neurites; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Output; Pathogenesis; Process; Protein Isoforms; Proteins; Regulation; Resolution; Role; Signal Transduction; Signaling Molecule; Structural Models; Synapses; Synaptic plasticity; System; Testing; Therapeutic Intervention; Transgenic Organisms; age related; aging brain; brain health; emerging adult; experience; experimental study; gene conservation; gene interaction; gene network; insight; male; member; molecular targeted therapies; nervous system disorder; neuronal circuitry; neuropsychiatric disorder; new therapeutic target; novel; response; scaffold; sex; tool; transgene expression

PROJECT SUMMARY Structural plasticity of neuronal connections is crucial for the wiring and rewiring of neuronal circuits in response to experience during development and in adulthood. Defects in plasticity of neuronal connectivity underlie, exacerbate, or contribute to the pathogenesis of many neurodevelopmental, neuropsychiatric, and neurological disorders, including age-related decline. However, our understanding of the molecular control of structural plasticity across the lifespan and in different neuronal contexts is far from complete, in part due to the lack of an experimentally tractable system to study this complex process at this resolution. The well-defined nervous system of the nematode Caenorhabditis elegans is an ideal system to identify the genes and molecular mechanisms involved with direct comparison of multiple life stages. We propose to exploit a robust model of structural plasticity we discovered in C. elegans to identify and compare the genetic and molecular regulation of experience-dependent structural plasticity across development, adulthood, and aging at single neuron resolution. In Aim #1, we will use the power of C. elegans genetics to screen 20 conserved cell adhesion, scaffolding, and signaling molecules for roles in experience-dependent structural plasticity during both development and in early adulthood. Aim #2 will comprehensively characterize the impact of aging on a neuron, circuit, and behavior in both sexes, and directly measure any changes in the capacity for structural plasticity across adulthood and aging by inducing and inhibiting structural plasticity with opto- and chemo-genetic tools. We will identify the mechanisms that maintain or degrade the capacity for structural plasticity with age, providing novel characterization and understanding of structural plasticity across the lifespan. In Aim #3, we will leverage the model of experience-dependent structural plasticity in C. elegans to gain mechanistic insights into the role of multiple conserved and disease-associated cell adhesion molecules in the regulation of structural plasticity. Using a combination of transgenic rescue experiments and insertion of tags/tools into the endogenous CAM genes, we will define the cellular, molecular, and temporal mechanisms by which CAMs contribute to plasticity. The proposed experiments will directly contribute to our understanding of the mechanisms and conserved genes that regulate experience-dependent structural plasticity. thereby informing its role in brain health, disease, and aging, while potentially identifying novel molecular targets for therapeutic intervention.

项目概要 神经元连接的结构可塑性对于神经元的布线和重新布线至关重要 神经元回路对发育和成年期间的经历做出反应。缺陷于 神经元连接的可塑性是、加剧或促成许多疾病的发病机制 神经发育、神经精神和神经系统疾病，包括与年龄相关的衰退。 然而，我们对整个生命周期结构可塑性的分子控制的理解 并且在不同的神经元环境中还远未完成，部分原因是缺乏实验 在此分辨率下研究这个复杂过程的易处理系统。明确的神经系统 线虫秀丽隐杆线虫的基因和分子鉴定是一个理想的系统 涉及多个生命阶段直接比较的机制。我们建议利用 我们在秀丽隐杆线虫中发现了用于识别和比较的稳健结构可塑性模型 经验依赖性结构可塑性的遗传和分子调控 单神经元分辨率下的发育、成年和衰老。在目标 #1 中，我们将使用 线虫遗传学筛选 20 种保守细胞粘附、支架和信号传导的能力 分子在发育和发育过程中在依赖于经验的结构可塑性中发挥作用 成年早期。目标 #2 将全面描述衰老对神经元的影响， 电路和两性的行为，并直接测量结构能力的任何变化 通过利用光电和抑制结构可塑性诱导和抑制整个成年期和衰老过程中的可塑性 化学遗传学工具。我们将确定维持或降低能力的机制 结构可塑性随年龄的变化，提供新的表征和结构理解 整个生命周期的可塑性。在目标#3中，我们将利用依赖经验的模型 秀丽隐杆线虫的结构可塑性，以获得多重保守作用的机制见解 和疾病相关的细胞粘附分子在结构可塑性的调节中的作用。使用 转基因拯救实验和将标签/工具插入内源性的组合 CAM 基因，我们将定义 CAM 的细胞、分子和时间机制 有助于可塑性。所提出的实验将直接有助于我们的理解 调节经验依赖性结构可塑性的机制和保守基因。 从而了解其在大脑健康、疾病和衰老中的作用，同时有可能识别新的 治疗干预的分子靶点。