Behavioral barcoding in the cloud: Embracing data-intensive digital phenotyping in neuropharmacology
ABSTRACT For decades, studying the behavioral effects of individual drugs and genetic mutations has been at the heart of efforts to understand and treat nervous system disorders. High-throughput technologies adapted from other disciplines (e.g., high-throughput chemical screening, genomics) are changing the scale of data acquisition in behavioral neuroscience. Massive behavioral datasets are beginning to emerge, particularly from zebrafish labs, where behavioral assays can be performed rapidly and reproducibly in 96-well, high-throughput format. Mining these datasets and making comparisons across different assays are major challenges for the field. Here, we review behavioral barcoding, a process by which complex behavioral assays are reduced to a string of numeric features, facilitating analysis and comparison within and across datasets.
- SourceAvailable from: Alexander Y Payumo
[Show abstract] [Hide abstract]
- "Zebrafish have emerged as versatile models of vertebrate biology, due to their amenability to genetic and pharmacological manipulations, optical transparency during embryogenesis and larval development, and facile and economical husbandry –. They have been used extensively to investigate the molecular and cellular mechanisms that contribute to tissue patterning  and more recently have contributed to our understanding of tissue regeneration, tumorigenesis, metabolism, infectious disease, and behavior –. As the importance of teleost models in biomedical research continues to grow, transgenic lines that can provide real-time indicators of specific biological events will be increasingly valuable. "
ABSTRACT: The Hedgehog (Hh) pathway is essential for embryonic development and tissue regeneration, and its dysregulation can lead to birth defects and tumorigenesis. Understanding how this signaling mechanism contributes to these processes would benefit from an ability to visualize Hedgehog pathway activity in live organisms, in real time, and with single-cell resolution. We report here the generation of transgenic zebrafish lines that express nuclear-localized mCherry fluorescent protein in a Gli transcription factor-dependent manner. As demonstrated by chemical and genetic perturbations, these lines faithfully report Hedgehog pathway state in individual cells and with high detection sensitivity. They will be valuable tools for studying dynamic Gli-dependent processes in vertebrates and for identifying new chemical and genetic regulators of the Hh pathway.PLoS ONE 07/2014; 9(7):e103661. DOI:10.1371/journal.pone.0103661 · 3.23 Impact Factor
[Show abstract] [Hide abstract]
- "This may, in turn, decrease the risk for relapse and increase tobacco abstinence rates. With the advent of the validated behavioral screen described here, primed with initial drug evaluation data, the development of a high-throughput screening method for pharmacotherapeutic modifiers of nicotine and ethanol response is now warranted, and a number of studies have shown measuring larval locomotion is amenable to high throughput approaches , , . Moreover, exploiting this model to evaluate medications approved for human use by the FDA enables clinicians to study these medications in clinical trials without further preclinical safety testing. "
ABSTRACT: Cigarette smoking remains the most preventable cause of death and excess health care costs in the United States, and is a leading cause of death among alcoholics. Long-term tobacco abstinence rates are low, and pharmacotherapeutic options are limited. Repositioning medications approved by the U.S. Food and Drug Administration (FDA) may efficiently provide clinicians with new treatment options. We developed a drug-repositioning paradigm using larval zebrafish locomotion and established predictive clinical validity using FDA-approved smoking cessation therapeutics. We evaluated 39 physician-vetted medications for nicotine-induced locomotor activation blockade. We further evaluated candidate medications for altered ethanol response, as well as in combination with varenicline for nicotine-response attenuation. Six medications specifically inhibited the nicotine response. Among this set, apomorphine and topiramate blocked both nicotine and ethanol responses. Both positively interact with varenicline in the Bliss Independence test, indicating potential synergistic interactions suggesting these are candidates for translation into Phase II clinical trials for smoking cessation.PLoS ONE 03/2014; 9(3):e90467. DOI:10.1371/journal.pone.0090467 · 3.23 Impact Factor
[Show abstract] [Hide abstract]
- "Zebrafish are popular as a vertebrate model with which to perform compound screens [3,4] and increasingly used to model human neurological disease processes, such as epilepsy and neurodegeneration [5,6]. Therefore, it is important to understand whether and when the zebrafish BBB forms and compare its characteristics and function with that of mammals. "
ABSTRACT: Zebrafish are becoming increasingly popular as an organism in which to model human disease and to study the effects of small molecules on complex physiological and pathological processes. Since larvae are no more than a few millimetres in length, and can live in volumes as small as 100 microliters, they are particularly amenable to high-throughput and high content compound screening in 96 well plate format. There is a growing literature providing evidence that many compounds show similar pharmacological effects in zebrafish as they do in mammals, and in particular humans. However, a major question regarding their utility for small molecule screening for neurological conditions is whether a molecule will reach its target site within the central nervous system. Studies have shown that Claudin-5 and ZO-1, tight-junction proteins which are essential for blood-brain barrier (BBB) integrity in mammals, can be detected in some cerebral vessels in zebrafish from 3 days post-fertilisation (d.p.f.) onwards and this timing coincides with the retention of dyes, immunoreactive tracers and fluorescent markers within some but not all cerebral vessels. Whilst these findings demonstrate that features of a BBB are first present at 3 d.p.f., it is not clear how quickly the zebrafish BBB matures or how closely the barrier resembles that of mammals. Here, we have combined anatomical analysis by transmission electron microscopy, functional investigation using fluorescent markers and compound uptake using liquid chromatography/tandem mass spectrometry to demonstrate that maturation of the zebrafish BBB occurs between 3 d.p.f. and 10 d.p.f. and that this barrier shares both structural and functional similarities with that of mammals.PLoS ONE 10/2013; 8(10):e77548. DOI:10.1371/journal.pone.0077548 · 3.23 Impact Factor