About

Robbert Creton is a Professor of Medical Science (Research) and a Professor of Pathology and Laboratory Medicine (Research) at Brown University. He received his B.S. in Biology in 1990 and his Ph.D. in Developmental Biology in 1994 from the University of Utrecht in the Netherlands. His post-doctoral training was in developmental physiology at the Marine Biological Laboratory in Woods Hole, Massachusetts. He was appointed as an investigator at Women & Infants Hospital of Rhode Island before joining Brown University in 2002. His research focuses on brain development and behavior using zebrafish as a model system, with particular interest in understanding mechanisms underlying visual impairment, developmental brain disorders, and neurodegenerative diseases such as Alzheimer’s. He is the director of the Leduc Bioimaging Facility, which provides high-resolution imaging equipment and training for life sciences research. His laboratory has developed automated imaging and behavioral analysis tools that are used to study neural and behavioral responses, including the effects of environmental toxicants and pharmacological agents on zebrafish development and behavior. His work aims to contribute to the understanding of biological mechanisms involved in neurodevelopment and neurodegeneration, and to facilitate the development of treatments for related human disorders.

Research topics

• Internal medicine
• Biology
• Medicine
• Cell biology
• Neuroscience
• Pharmacology
• Bioinformatics
• Psychology
• Genetics

Selected publications

• Target the Heart: a new axis of Alzheimer’s disease prevention

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-28

  preprintOpen accessSenior author

  ABSTRACT Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. Utilizing a neural network model, Z-LaP Tracker, we previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved drugs using Z-LaP Tracker revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. 14 of these drugs were heart medications, including angiotensin receptor blockers, beta-blockers, alpha-adrenergic receptor antagonists, and a statin. This suggests some heart medications may be effective in preventing or ameliorating Alzheimer’s disease pathology. Other studies have shown that many of these 14 drugs directly or indirectly inhibit the calcineurin-NFAT pathway, alike cyclosporine A. Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. This indicates that co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for Alzheimer’s disease and cardiovascular dysfunction, while mitigating side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer’s disease in many patients, physicians may be able to create a treatment regimen that simultaneously addresses both conditions. Our results suggest that cyclosporine A combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol are the most promising candidates for future exploration.

  PublisherDOI

• Target the Heart: A New Axis of Alzheimer’s Disease Prevention

  Journal of dementia and Alzheimer's disease · 2025-05-01

  articleOpen accessSenior author

  Background/Objective: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease. Methods: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. Results: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism. Conclusions: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.

  PublisherOA PDFDOI

• Drug repurposing for neurodegenerative diseases using Zebrafish behavioral profiles

  Biomedicine & Pharmacotherapy · 2024-01-06 · 16 citations

  articleOpen accessSenior author

  Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer's disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.

  PublisherDOI

• Combining supervised and unsupervised analyses to quantify behavioral phenotypes and validate therapeutic efficacy in a triple transgenic mouse model of Alzheimer's disease

  Biomedicine & Pharmacotherapy · 2024-12-01 · 2 citations

  articleOpen accessSenior author

  Behavioral testing is an essential tool for evaluating cognitive function and dysfunction in preclinical research models. This is of special importance in the study of neurological disorders such as Alzheimer’s disease. However, the reproducibility of classic behavioral assays is frequently compromised by interstudy variation, leading to ambiguous conclusions about the behavioral markers characterizing the disease. Here, we identify age- and genotype-driven differences between 3xTg-AD and non-transgenic control mice using a low-cost, highly customizable behavioral assay that requires little human intervention. Through behavioral phenotyping combining both supervised and unsupervised behavioral classification methods, we are able to validate the preventative effects of the immunosuppressant cyclosporine A in a rodent model of Alzheimer’s disease, as well as the partially ameliorating effects of candidate drugs nebivolol and cabozantinib. • Behavioral assays are an important tool to assess cognitive function in pre-clinical neurological disease models. • We combined supervised and unsupervised behavioral classification methods to quantify deficits in female 3xTg-AD mice. • Chronic treatment with cyclosporine, nebivolol, or cabozantinib mitigate behavioral and gait deficits in young and old mice.

  PublisherDOI

• Behavioral effects of visual stimuli in adult zebrafish using a novel eight-tank imaging system

  Frontiers in Behavioral Neuroscience · 2024-03-11 · 3 citations

  articleOpen accessSenior author

  Introduction: Animals respond to various environmental cues. Animal behavior is complex, and behavior analysis can greatly help to understand brain function. Most of the available behavioral imaging setups are expensive, provide limited options for customization, and allow for behavioral imaging of one animal at a time. Methods: The current study takes advantage of adult zebrafish as a model organism to study behavior in a novel behavioral setup allowing one to concurrently image 8 adult zebrafish. Results: Our results indicate that adult zebrafish show a unique behavioral profile in response to visual stimuli such as moving lines. In the presence of moving lines, the fish spent more time exploring the tank and spent more time toward the edges of the tanks. In addition, the fish moved and oriented themselves against the direction of the moving lines, indicating a negative optomotor response (OMR). With repeated exposure to moving lines, we observed a reduced optomotor response in adult zebrafish. Discussion: Our behavioral setup is relatively inexpensive, provides flexibility in the presentation of various animated visual stimuli, and offers improved throughput for analyzing behavior in adult zebrafish. This behavioral setup shows promising potential to quantify various behavioral measures and opens new avenues to understand complex behaviors.

  PublisherOA PDFDOI

• Combining supervised and unsupervised analyses to quantify behavioral phenotypes and validate therapeutic efficacy in a triple transgenic mouse model of Alzheimer’s disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-08

  preprintOpen accessSenior author

  Behavioral testing is an essential tool for evaluating cognitive function and dysfunction in preclinical research models. This is of special importance in the study of neurological disorders such as Alzheimer's disease. However, the reproducibility of classic behavioral assays is frequently compromised by interstudy variation, leading to ambiguous conclusions about the behavioral markers characterizing the disease. Here, we identify age- and genotype-driven differences between 3xTg-AD and non-transgenic control mice using a low-cost, highly customizable behavioral assay that requires little human intervention. Through behavioral phenotyping combining both supervised and unsupervised behavioral classification methods, we are able to validate the preventative effects of the immunosuppressant cyclosporine A in a rodent model of Alzheimer's disease, as well as the partially ameliorating effects of candidate drugs nebivolol and cabozantinib.

  PublisherOA PDFDOI

• An 8-cage imaging system for automated analyses of mouse behavior

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-02-04

  preprintOpen accessSenior authorCorresponding

  Abstract The analysis of mouse behavior is used in biomedical research to study brain function in health and disease. Well-established rapid assays allow for high-throughput analyses of behavior but have several drawbacks, including measurements of daytime behaviors in a nocturnal animal, effects of animal handling, and the lack of an acclimation period in the testing apparatus. We developed a novel 8-cage imaging system, with animated visual stimuli, for automated analyses of mouse behavior in 22-hour overnight recordings. Software for image analysis was developed in two open-source programs, ImageJ and DeepLabCut. The imaging system was used to measure multiple behaviors, including acclimation to the novel cage environment, day and nighttime activity, stretch-attend postures, location in various cage areas, and habituation to animated visual stimuli. These behaviors were summarized in behavioral profiles, which may be used in further studies to examine treatments for neural disorders.

  PublisherOA PDFDOI

• Zebrafish Larvae Position Tracker (Z-LaP Tracker): a high-throughput deep-learning behavioral approach for the identification of calcineurin pathway-modulating drugs using zebrafish larvae

  Scientific Reports · 2023-02-23 · 26 citations

  articleOpen accessSenior author

  Brain function studies greatly depend on quantification and analysis of behavior. While behavior can be imaged efficiently, the quantification of specific aspects of behavior is labor-intensive and may introduce individual biases. Recent advances in deep learning and artificial intelligence-based tools have made it possible to precisely track individual features of freely moving animals in diverse environments without any markers. In the current study, we developed Zebrafish Larvae Position Tracker (Z-LaP Tracker), a modification of the markerless position estimation software DeepLabCut, to quantify zebrafish larval behavior in a high-throughput 384-well setting. We utilized the high-contrast features of our model animal, zebrafish larvae, including the eyes and the yolk for our behavioral analysis. Using this experimental setup, we quantified relevant behaviors with similar accuracy to the analysis performed by humans. The changes in behavior were organized in behavioral profiles, which were examined by K-means and hierarchical cluster analysis. Calcineurin inhibitors exhibited a distinct behavioral profile characterized by increased activity, acoustic hyperexcitability, reduced visually guided behaviors, and reduced habituation to acoustic stimuli. The developed methodologies were used to identify 'CsA-type' drugs that might be promising candidates for the prevention and treatment of neurological disorders.

  PublisherOA PDFDOI

• An 8-cage imaging system for automated analyses of mouse behavior

  Scientific Reports · 2023-05-19 · 8 citations

  articleOpen accessSenior author

  The analysis of mouse behavior is used in biomedical research to study brain function in health and disease. Well-established rapid assays allow for high-throughput analyses of behavior but have several drawbacks, including measurements of daytime behaviors in nocturnal animals, effects of animal handling, and the lack of an acclimation period in the testing apparatus. We developed a novel 8-cage imaging system, with animated visual stimuli, for automated analyses of mouse behavior in 22-h overnight recordings. Software for image analysis was developed in two open-source programs, ImageJ and DeepLabCut. The imaging system was tested using 4-5 month-old female wild-type mice and 3xTg-AD mice, a widely-used model to study Alzheimer's disease (AD). The overnight recordings provided measurements of multiple behaviors including acclimation to the novel cage environment, day and nighttime activity, stretch-attend postures, location in various cage areas, and habituation to animated visual stimuli. The behavioral profiles were different in wild-type and 3xTg-AD mice. AD-model mice displayed reduced acclimation to the novel cage environment, were hyperactive during the first hour of darkness, and spent less time at home in comparison to wild-type mice. We propose that the imaging system may be used to study various neurological and neurodegenerative disorders, including Alzheimer's disease.

  PublisherOA PDFDOI

• Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-09-13

  preprintOpen accessSenior author

  Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer's disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.

  PublisherOA PDFDOI

Recent grants

• Calcium Signaling in the Developing Zebrafish Brain

  NSF · $344k · 2004–2007

• Automated analyses of behavior in response to visual stimuli

  NIH · $1.4M · 2015–2021

• Emerging imaging technologies for automated analyses of calcineurin-dependent brain function

  NIH · $1.3M · 2020–2025

• Brain defects induced by embryonic exposure to modulators of calcium signaling

  NIH · $1.2M · 2010–2016

• Emerging imaging technologies for automated analyses of calcineurin-dependent brain function

  NIH · $295k · 2020–2024

Frequent coauthors

• Ruth M. Colwill

  John Brown University

  52 shared

• Jill A. Kreiling

  Brown University

  45 shared

• Peter J. Mohler

  The Ohio State University

  36 shared

• Andrew L. Miller

  iThemba Laboratory

  36 shared

• E. Karplus

  Science Wares (United States)

  36 shared

• Carole L. Browne

  36 shared

• Robert E. Palazzo

  36 shared

• Thaís Del Rosario Hernández

  Brown University

  33 shared

Education

• B.S., Biology

  University of Utrecht

  1990

• Ph.D., Developmental Biology

  University of Utrecht

  1994