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.

刻板的重复行为被认为是复杂任务执行的障碍， 包括社会行为和学习，是在哺乳动物和鱼类身上观察到的。暴露在压力下的动物- 相关环境经常表现出重复的行为。众所周知，慢性压力会改变人的 具有神经环路特性，升高血糖水平。相应地，低碳水化合物生酮饮食 减少障碍模型动物的重复行为。然而，存在着巨大的知识鸿沟 关于如何在其他自愿行为中特别选择重复行为；它是否基于 神经回路和/或代谢改变？自然遗传变异是促进增加还是减少 在重复行为水平上也知之甚少。因此，我们的中心假设是，在一个 与典型异质性相关的实验系统，营养酮症通过以下方式减少重复行为 修改选择行为模块的已知的多巴胺能和GABA能信号(例如， 重复行为、交配行为等)。为了为检验这一假设提供基础，该项目的 主要目的是确定基因共表达调控网络及其中枢基因，以减少 酮病时的重复行为。墨西哥硬骨鱼Astianax micianus将被战略选择 作为实验模型，由洞穴栖息鱼(穴居鱼)和表层栖息鱼(表层鱼)组成。 洞鱼表现出非社会性行为，并表现出1,839个共同的定向基因表达变化 出现在与重复行为有关的人类疾病中。这个项目的基本原理是基因和 具有自然主义异质性的环境对重复行为的影响很容易在我们的 动物平台，产生与酮病相关的神经元和细胞反应的基本知识 重复的行为。本申请中提出的研究是创新的，因为它将自然地使用 遗传和行为状况与精神病患者相似的异质群体 精神错乱。该项目还将借助一种新兴的聚类算法来整合组学数据， 拓扑数据分析(TDA)。TDA对噪声和稀疏数据集具有较强的鲁棒性，同时保留了个体 使用典型降维算法可能丢失的变化。这项研究具有重要意义，因为它 承诺为重复行为的营养可塑性的遗传基础提供第一个见解， 这将最重要地有助于未来理解由 营养干预。此外，从这个R01项目中获得的知识将应用于 在未来的小鼠系统中测试它是否具有翻译能力。这次试验的成功将支持一个保守的 在我们鱼类的不同种群之间，以及在鱼类和哺乳动物之间的通道，打开了 人类对这一知识的应用。