Genetic and neural mechanisms underlying emerging social behavior in zebrafish

斑马鱼新兴社会行为的遗传和神经机制

• 批准号: 10306905
• 负责人: Florian Engert
• 金额: $ 247万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306905
• 关键词: Address; Adult; Anatomy; Animal Model; Animals; Behavior; Behavioral; Behavioral Assay; Behavioral Genetics; Behavioral Model; Biological Assay; Biological Models; Brain; Brain imaging; Calcium; Cells; Characteristics; Complex; DISC1 gene; DNA Sequence Alteration; Diffusion; Dissection; Elements; Embryo; Environment; Exhibits; Fishes; Five-Year Plans; Functional Imaging; Generations; Genes; Genetic; Genetic Transcription; Goals; Hand; Head; Image; Individual; Infant; Larva; Link; Location; Membrane; Modeling; Modification; Molecular; Motion; Motor; Movement; Mutation; Neurons; Neurosciences; Pathway interactions; Performance; Phenotype; Physiological; Physiology; Play; Population; Reflex action; Role; Schizophrenia; Schools; Social Behavior; Social Interaction; Specificity; Stimulus; Structure; Study models; Swimming; Synapses; Testing; Time; Zebrafish; autism spectrum disorder; base; behavioral phenotyping; brain research; experimental study; mature animal; migration; mutant; neural circuit; neural network; neuromechanism; neurophysiology; neuropsychiatric disorder; optogenetics; patch clamp; programs; relating to nervous system; response; social; virtual; visual motor

Genetic and neural mechanisms underlying emerging social behavior in zebrafish Our goal is to understand emerging collective behaviors of groups, such as schooling and shoaling in fish. Our approach is to dissect basic sensorimotor transformations in the zebrafish, which we believe play a fundamental role in explaining emerging social interactions. We have identified two simple and well described reflexive behaviors: 1) the optomotor reflex (OMR), where fish swim along with whole field motion stimuli and 2) object evoked re-orienting responses (OER) where fish turn away or towards moving objects, depending on the object’s size and movement. We have shown in preliminary modeling studies that an implementation of these two simple “motor primitives” in virtual agents can explain a significant fraction of the emerging social behaviors in adult fish. A compelling advantage of focusing our studies on these two simple reflexes is that they are robustly expressed in 7 day old larvae, which facilitates a detailed and quantitative behavioral analysis of the related visuomotor transformation, as well as a dissection of their underlying neural circuitry. A critical element in our proposal is the generation of mutant zebrafish that we have shown to display subtle but distinctive social behavioral phenotypes at the adult stage. We found that, even in the larval stage, and prior to onset of robust schooling and shoaling behaviors, these mutants already reveal behavioral phenotypes in the context of the OMR and OER, and that these phenotypical deviations are predictive of the later emerging differences in schooling and shoaling in adults. One of our central goals is the dissection of the specific changes in neural circuitry in the mutants that are responsible for these altered behavioral phenotypes. Some such changes in neural phenotype may manifest at the level of global brain structures, but many are likely to disrupt micro-circuits - either at the level of cellular identities or synaptic connectivity - that underlie both simple behavior in the embryo and more complex behaviors in the adult. Notably, we already have generated realistic circuit models that form specific hypotheses about the neural networks underlying the OMR and OER in wild-type animals, and these models are readily adjusted to identify and constrain the specific latent variables that are changed in the mutant animals. Such adjusted models serve as ideal priors and specific hypotheses to be tested in brain wide functional imaging experiments. Lastly, the identification of detailed neural phenotypes in mutant animals in terms of anatomical location, neuronal cell fate and synaptic specificity will facilitate linkage of these anatomical and physiological changes to specific cell fates and molecular pathways. Our parallel ongoing efforts in describing and modelling brain wide neural circuits in zebrafish (within the framework of the U19 Team-Research BRAIN Circuits program) will allow us to narrow down which of all these observable neural phenotypes in the mutants are responsible and causally related to the specific neural changes that underlie the changes in behavior.

斑马鱼新出现的社会行为的遗传和神经机制 我们的目标是了解新出现的群体集体行为，例如鱼类的鱼群和浅滩。 我们的方法是剖析斑马鱼的基本感觉运动转换，我们认为这是一种 在解释新出现的社交互动方面的基本作用。我们已经确定了两个简单且描述得很好的 反射行为：1)视觉运动反射(OMR)，鱼随着整个领域的运动刺激和 2)鱼转身或朝向移动物体的物体引起的重定向反应(OER)，取决于 物体的大小和运动。我们已经在初步建模研究中表明，实施 在虚拟代理人中，这两个简单的“运动原语”可以很大程度上解释新兴的社会 成鱼的行为。将我们的研究重点放在这两个简单的反射上的一个引人注目的优势是 它们在7日龄的幼虫中强势表达，这有助于详细和定量的行为 分析相关的视觉运动转换，以及对其潜在神经回路的剖析。 我们计划中的一个关键因素是我们已经展示出的微妙的突变斑马鱼的产生 但在成年阶段有独特的社会行为表型。我们发现，即使在幼虫阶段， 在强健的学校教育和浅滩行为开始之前，这些突变体已经揭示了行为 OMR和OER背景下的表型，这些表型偏差可以预测 后来，成年人在教育和浅滩方面出现了差异。我们的中心目标之一是剖析 导致这些行为改变的突变体中神经回路的特定变化 表型。神经表型的一些变化可能表现在整体大脑结构的水平上，但 许多都可能扰乱微电路--无论是在细胞身份的层面还是在突触连接的层面-- 这既是胚胎简单行为的基础，也是成人复杂行为的基础。值得注意的是，我们已经 已经生成了现实的电路模型，形成了关于潜在神经网络的特定假设 野生型动物的OMR和OER，这些模型很容易调整以识别和约束 在突变动物中发生变化的特定潜在变量。这种调整后的模型可以作为理想的先验 以及需要在全脑功能成像实验中检验的具体假设。最后，身份识别 突变动物的详细神经表型在解剖位置，神经细胞命运和 突触的特异性将有助于将这些解剖和生理变化与特定的细胞命运联系起来 和分子途径。我们在描述和模拟大脑广泛的神经回路方面正在进行的平行努力 斑马鱼(在U19团队-研究大脑回路计划的框架内)将允许我们缩小 突变体中所有这些可观察到的神经表型中的哪一种负责和因果相关 特定的神经变化是行为变化的基础。