MSLife

Treatment for multiple sclerosis (MS) focuses on managing its symptoms (e.g., depression, fatigue, poor sleep quality), varying with specific symptoms experienced. Thus, for optimal treatment, there arises the need to track these symptoms. Towards this goal, there is great interest in finding their relevant phenotypes. Prior research suggests links between activities of daily living (ADLs) and MS symptoms; therefore, we hypothesize that the behavioral phenotype (revealed through ADLs) is closely related to MS symptoms. Traditional approaches to finding behavioral phenotypes which rely on human observation or controlled clinical settings are burdensome and cannot account for all genuine ADLs. Here, we present MSLife, an end-to-end, burden-free approach to digital behavioral phenotyping of MS symptoms in the wild using wearables and graph-based statistical analysis. MSLife is built upon (1) low-cost, unobtrusive wearables (i.e., smartwatches) that can track and quantify ADLs among MS patients in the wild; (2) graph-based statistical analysis that can model the relationships between quantified ADLs (i.e., digital behavioral phenotype) and MS symptoms. We design, implement, and deploy MSLife with 30 MS patients across a one-week home-based IRB-approved clinical pilot study. We use the GENEActiv smartwatch to monitor ADLs and clinical behavioral instruments to collect MS symptoms. Then we develop a graph-based statistical analysis framework to model phenotyping relationships between ADLs and MS symptoms, incorporating confounding demographic factors. We discover 102 significant phenotyping relationships (e.g., later rise times are related to increased levels of depression, history of caffeine consumption is associated with lower fatigue levels, higher relative levels of moderate physical activity are linked with decreased sleep quality). We validate their healthcare implications, using them to track MS symptoms in retrospective analysis. To our best knowledge, this is one of the first practices to digital behavioral phenotyping of MS symptoms in the wild.

Behavioral phenotyping of Zip8 393T-KI mice for in vivo study of schizophrenia pathogenesis

Genetic studies have informed on the genetic landscape of schizophrenia, and the next challenge is to link the genetic associations to mechanistic studies. A common single nucleotide polymorphism in the zinc and manganese transporter ZIP8 (rs13107325; ZIP8 A391T) is a top candidate to prioritize for functional studies because it is a missense mutation that results in hypomorphic protein function. With this goal, we have established a mouse model (Zip8 393T-knock-in (KI)), and here, we report the results of brain necropsy and initial behavioral phenotyping experiments in the KI mice using open field testing, elevated plus maze, Y-maze, and trace fear conditioning. Overall, male, homozygous KI mice may exhibit subtle defects in cognition and spatial learning, otherwise the baseline testing supports minimal behavioral differences between wild-type and Zip8 393T-KI mice. There were no genotype-specific alterations of gross or microscopic neuroanatomy. These experiments are important to establish the baseline characteristics of the Zip8 393T-KI mice that may be perturbed in animal models of schizophrenia and position the Zip8 393T-KI mouse as an important model for translational studies of schizophrenia pathogenesis.

Deep Behavioral Phenotyping of Mouse Autism Models using Open-Field Behavior

Autism is noted for both its genotypic and phenotypic diversity. Repetitive action, resistance to environmental change, and motor disruptions vary from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we use advances in computer vision and deep learning to develop a framework for characterizing mouse behavior on multiple time scales using a single popular behavioral assay, the open field test. We observed male and female C57BL/6J mice to develop a dynamic baseline of adaptive behavior over multiple days. We then examined two rodent models of autism, a cerebellum-specific model, L7-Tsc1, and a whole-brain knockout model, Cntnap2. Both Cntnap2 knockout and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure-to-adapt took the form of maintained ambling, turning, and locomotion, and an overall decrease in grooming. Adaptation in Cntnap2 knockout mice more broadly resembled that of wild-type. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics.

A Customizable Low-Cost System for Massively Parallel Zebrafish Behavioral Phenotyping

High-throughput behavioral phenotyping is critical to genetic or chemical screening approaches. Zebrafish larvae are amenable to high-throughput behavioral screening because of their rapid development, small size, and conserved vertebrate brain architecture. Existing commercial behavioral phenotyping systems are expensive and not easily modified for new assays. Here, we describe a modular, highly adaptable, and low-cost system. Along with detailed assembly and operation instructions, we provide data acquisition software and a robust, parallel analysis pipeline. We validate our approach by analyzing stimulus response profiles in larval zebrafish, confirming prepulse inhibition phenotypes of two previously isolated mutants, and highlighting best practices for growing larvae prior to behavioral testing. Our new design thus allows rapid construction and streamlined operation of many large-scale behavioral setups with minimal resources and fabrication expertise, with broad applications to other aquatic organisms.