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

基本信息

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
项目类别：
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

项目摘要

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.

斑马鱼中新兴社会行为的遗传和神经机制我们的目标是了解群体的新兴集体行为，例如在鱼类中进行教育和浅滩。我们的方法是剖析斑马鱼中的基本感觉运动转变，我们认为这是在解释新兴的社会互动中的基本作用。我们已经确定了两个简单且描述的反身行为：1）验光反射（OMR），鱼与整个田间运动刺激一起游泳， 2）对象唤起鱼的重新定位响应（OER），在该响应中，鱼转动或向移动物体转向移动的物体，具体取决于关于对象的大小和运动。我们在初步建模研究中显示了实施在这两个简单的“电动机原则”中，虚拟代理可以解释新兴社会的很大一部分成人鱼类的行为。将我们的研究集中在这两个简单反射上的令人信服的优势是它们在7天大的幼虫中强烈表达，该幼虫是一种详细且定量的行为分析相关的视觉运动转化以及其潜在神经回路的解剖。我们提案中的一个关键要素是我们已证明表现出微妙的突变斑马鱼的产生但是在成人阶段独特的社会行为表型。我们发现，即使在幼虫阶段，在强大的教育和浅滩行为开始之前，这些突变体已经揭示了行为在OMR和OER的背景下的表型，这些表型出发是可以预测的后来，成年人的教育和浅滩差异。我们的核心目标之一是解剖突变体中神经回路的特定变化，导致这些改变的行为改变表型。神经表型的某些这种变化可能表现在全球大脑结构的水平上，但许多可能会破坏微电路 - 在细胞身份的水平或突触连通性的水平上 - 基于胚胎中的简单行为和成年人的更复杂行为。值得注意的是，我们已经已经产生了逼真的电路模型，这些模型形成了有关神经网络的特定假设野生型动物中的OMR和OER，这些模型很容易调整以识别和限制突变动物中改变的特定潜在变量。这种调整后的模型是理想的先验以及要在大脑广泛的功能成像实验中测试的特定假设。最后，标识在解剖位置，神经元细胞命运和突触特异性将促进这些解剖学和物理变化与特定细胞命运的联系和分子途径。我们在描述和建模大脑广泛的神经回路方面的持续努力斑马鱼（在U19团队研究脑电路计划的框架内）将使我们能够缩小在突变体中的所有这些可观察到的神经表型中的哪个是负责的，有时与行为变化的基础的特定神经变化。