CDS&E: Modeling the Zebrafish Model Organism Toward Reducing, Refining, and Replacing Animal Experiments

斑马鱼正成为研究人类几种功能和功能失调生物过程的实验物种，包括调节情绪模式、学习过程以及个人和社会对酒精和药物滥用的反应的基本机制。然而，与啮齿类动物和灵长类动物一样，斑马鱼实验构成了一个复杂的当代伦理问题，要求探索替代测试方法，以减少受试者数量，在考虑动物福利的情况下完善实验设计，并可能用其他科学仪器代替活体动物。该奖项支持计算和数据科学与工程方面的基础研究，以帮助设计对斑马鱼行为的前所未有的“计算机”研究。建立一个经过实验验证的计算平台，以帮助减少实验所需的动物受试者数量，在不增加动物不适的情况下量化动物行为感兴趣的变量，并在动物实验之前进行试点试验。所有这些因素都将有助于减少动物的使用和痛苦。跨学科的正式和非正式教育活动将补充研究，并将为经济上处于不利地位的布鲁克林社区的贫困学生提供机会。本研究计划旨在推进动物行为的计算建模，以改善临床前研究中的动物福利。具体而言，该奖项将建立斑马鱼行为的计算建模框架，通过实验信息建模选择，通过严格的统计技术进行模型校准，并最终对新实验进行实验验证。该框架将以随机微分方程为基础，以便能够预测斑马鱼在二维和三维、幼虫和成虫、单个和群体、外部刺激和精神活性化合物作用下的运动。这种新颖的计算工具将用于评估以下方面的可行性：在模拟数据的基础上进行先验的功率分析，选择解释变量，在面对生物混杂时分析可重复性，以及在不需要实验的情况下推断实验结果。虽然这项研究将主要依赖于现有的实验数据，但将进行额外的实验来剖析显著的行为线索，并展示计算机实验的潜力。

Zebrafish are gaining momentum as laboratory species for the investigation of several functional and dysfunctional biological processes in humans, including the fundamental mechanisms modulating emotional patterns, learning processes, and individual and social response to alcohol and drugs of abuse. However, as with rodents and primates, experimentation with zebrafish constitutes a complicated and contemporary ethical issue that demands the exploration of alternative testing methods to reduce the number of subjects, refine the experimental designs with animal welfare in mind, and possibly replace live animals with other scientific instruments. This award supports fundamental research in computational and data-enabled science and engineering to aid the design of unprecedented "in silico" studies on zebrafish behavior. An experimentally-validated computational platform will be established to help decrease the number of animal subjects needed for experiments, quantify variables of interest in animal behavior without increasing animal discomfort, and perform pilot trials preceding animal experiments. All of these factors will contribute to a reduction in animal use and suffering. Interdisciplinary formal and informal education activities will complement the research and will provide opportunities to underprivileged students within economically-disadvantaged Brooklyn communities.This research program seeks to advance computational modeling of animal behavior towards improving animal welfare in preclinical research. Specifically, this award will establish a computational modeling framework of zebrafish behavior, through experimentally-informed modeling choices, model calibration via rigorous statistical techniques, and, ultimately, experimental validation against new experiments. The framework will be based on stochastic differential equations to enable the prediction of zebrafish locomotion in two and three dimensions, in larvae and adults, with a single individual and in groups, in the presence of external stimuli, and under the effect of psychoactive compounds. This novel computational tool will be used to assess the feasibility of: performing a priori power analysis on the basis of simulated data, selecting explanatory variables, analyzing the reproducibility in the face of biological confounds, and inferring experimental outcomes without the need for experiments. While the study will primarily rely on available experimental data, additional experiments will be conducted to dissect salient behavioral cues and demonstrate the potential of in silico experimentation.