Gene Coexpression Network Regulating Repetitive Behavior under Nutritional Change.

营养变化下调节重复行为的基因共表达网络。

• 批准号: 10737180
• 负责人: Motoko Iwashita
• 金额: $ 40.35万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737180
• 关键词: Address; Algorithmic Analysis; Algorithms; Animal Genetics; Animal Model; Animals; Behavior; Behavioral; Biological Models; Blood Glucose; Brain; CRISPR/Cas technology; Carbohydrates; Chronic stress; Complex; Corpus striatum structure; Data; Data Analyses; Data Set; Development; Dietary Intervention; Dimensions; Disease; Disease model; Environment; Environmental Impact; Exhibits; Experimental Models; Exposure to; Fishes; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genomics; Goals; Heterogeneity; Human; Immediate-Early Genes; Inbred Mouse; Involuntary Movements; Ketone Bodies; Ketoses; Ketosis; Knowledge; Mammals; Maps; Mental disorders; Metabolic; Methods; Mexican; Modeling; Modernization; Molecular; Morphology; Mus; Nervous System Physiology; Neural Pathways; Neurons; Nutritional; Output; Pathway interactions; Patients; Periodicity; Physiological; Population; Population Heterogeneity; Property; Quantitative Trait Loci; Recording of previous events; Reducing diet; Regulator Genes; Research; Sensory; Serum; Signal Transduction; Social Behavior; Standard Model; Stereotyping; Stress; Surface; System; Techniques; Technology; Testing; Variant; Visualization; Wild Animals; behavior prediction; distraction; effective therapy; individual variation; innovation; insight; ketogenic diet; mating behavior; metabolomics; model organism; multidimensional data; neural; neuromechanism; null mutation; nutrition; open data; programs; repetitive behavior; response; social learning; success; teleost fish; transcriptome; transcriptomics

Stereotypic repetitive behaviors, which are thought to be an obstacle to complex task execution, including social behaviors and learning, are observed in mammalians and fish. Animals exposed to stress- associated environment frequently exhibit repetitive behaviors. Chronic stress is known to change the neurocircuit property and increase the blood glucose level. Accordingly, the low-carbohydrate ketogenic diet reduced repetitive behaviors in disorder model animals. However, there is a significant knowledge gap regarding how repetitive behaviors are particularly selected among other voluntary behaviors; is it based on neurocircuit and/or metabolic changes? Whether natural genetic variations promote an increase or decrease in repetitive behavior level is also poorly understood. Consequently, our central hypothesis is that, in an experimental system relevant to typical heterogeneity, nutritional ketosis reduces repetitive behavior by modifying the known dopaminergic and GABAergic signaling that choose the behavior modules (e.g., repetitive behavior, mating behavior, etc.). To provide the foundation to test this hypothesis, this project’s main objective is to identify the gene coexpression regulatory network and its hub genes that reduce repetitive behavior under ketosis. The Mexican teleost fish Astyanax mexicanus will be strategically chosen as an experimental model, which consists of cave-dwelling (cavefish) and surface-dwelling fish (surface fish). The cavefish display asocial behaviors and exhibit 1,839 of the shared directional gene expression changes seen in human disorders related to repetitive behavior. This project’s rationale is that the genetic and environmental impacts on repetitive behavior with the naturalistic heterogeneity are easy to study on our animal platform, yielding the basic knowledge for neuronal and cellular responses to ketosis associated with repetitive behavior. The research proposed in this application is innovative because it will use naturally heterogeneous populations whose genetic and behavioral conditions are similar to patients with psychiatric disorders. This project will also integrate omics data with the aid of an emerging clustering algorithm, topological data analysis (TDA). TDA is robust for noisy and sparse datasets while retaining individual variations that may be lost using typical dimension-reduction algorithms. This study is significant because it promises to provide the first insights into the genetic basis of the nutritional plasticity of repetitive behavior, which will foremost contribute to the future understanding of the neural and cellular responses governed by nutritional interventions. Furthermore, the knowledge derived from this R01 project will be applied to the murine system in the future to test if it is translational. The success of this test will support a conserved pathway among heterogeneous populations in our fish, and between fish and mammals, opening the door to human application of this knowledge.

刻板印象的重复行为，被认为是复杂任务执行的障碍， 在哺乳动物和鱼类中观察到包括社会行为和学习。暴露于压力的动物 相关的环境经常暴露重复行为。已知慢性压力会改变 神经电路特性并增加血糖水平。彼此之间的低碳水化合物饮食 疾病模型动物中的重复行为降低。但是，存在很大的知识差距 关于如何在其他自愿行为中特别选择重复行为；是基于 神经循环和/或代谢变化？自然遗传变异是促进还是减少 在重复的行为水平上也很少理解。因此，我们的中心假设是 与典型异质性相关的实验系统，营养酮症降低了重复行为 修改选择行为模块的已知多巴胺能和GABA能信号（例如， 重复行为，交配行为等）。为了检验这一假设的基础，该项目的 主要目的是确定基因共表达调节网络及其中心基因，以减少 酮症下的重复行为。墨西哥的Teleost鱼Astyanax Mexicanus将被战略选择 作为一个实验模型，由洞穴栖息（洞穴）和表面鱼（表面鱼）组成。 山洞鱼表现出无向行为，并展示共享定向基因表达的1,839个变化 在与重复行为有关的人类疾病中可见。这个项目的理由是遗传和 与自然主义异质性对重复行为的环境影响很容易研究我们 动物平台，对与酮症有关的神经元和细胞反应的基本知识与 重复行为。本应用程序中提出的研究具有创新性，因为它会自然使用 异质种群的遗传和行为状况与精神病患者相似 疾病。该项目还将借助新兴聚类算法集成OMICS数据， 拓扑数据分析（TDA）。 TDA在保留个人的同时，对于噪声和稀疏数据集很强 使用典型的尺寸减少算法可能会丢失的变化。这项研究很重要，因为它 有望提供对重复行为营养可塑性的遗传基础的首次见解， 最重要的有助于未来对受神经和细胞反应的理解 营养干预措施。此外，该R01项目得出的知识将应用于 将来的鼠系统要测试是否翻译。该测试的成功将支持保守的 我们鱼类中异质种群以及鱼类和哺乳动物之间的途径，打开了通往的大门 人类对此知识的应用。