Biology subjects

Collins, E.-M. S.

Publications and source records attributed to Collins, E.-M. S..

8 recordsLinked to original sources

bioRxiv2026

Modulation of planarian seizure-like activity via antiseizure medications

Acute chemical exposure to organophosphorus compounds (OPs) arising from terrorist attacks or accidental poisonings pose a serious threat to human health. Acetylcholinesterase inhibition due to acute OP exposure causes a cholinergic crisis, manifested as increased secretions, respiratory distress, loss of consciousness, seizures, and ultimately death if left untreated. Benzodiazepines, such as midazolam, are currently used to stop OP-induced seizures, but must be administered within minutes after exposure to be effective. This makes midazolam impractical for large-scale civilian emergencies. Thus, there is a need to identify novel antiseizure medications (ASMs) that are equally effective even when administered later. It has been challenging to identify such compounds with traditional mammalian testing; high throughput screening assays that can quickly and cost-effectively evaluate many candidates for their potential as an ASM are needed. Planarians are aquatic invertebrates that are suitable organismal models for OP neurotoxicity studies due to the conservation of OP targets and their ability to metabolize OPs. Here, we built on our prior work that introduced a computational image analysis pipeline to quantify planarian seizure-like activity (pSLA) in two planarian species (Dugesia japonica and Girardia dorotocephala). We previously used this approach to characterize pSLA following acute exposure (up to 30 minutes) to seizurogenic compounds. In the present study, we asked whether pSLA induced by the OP pesticide parathion, pentylenetetrazole, or NMDA could be rescued by co-exposure to four ASMs: midazolam, topiramate, MK-801, and carbamazepine. All tested ASMs were effective at reducing parathion-induced pSLA in one planarian species. However, ASM responses varied substantially across proconvulsants and planarian species. Defining the molecular mechanisms underlying pSLA will be essential for establishing planarians as a reliable model for ASM discovery.

pharmacology and toxicology↗

bioRxiv2025

Planarian behavioral screening is a useful invertebrate model for evaluating seizurogenic chemicals

Detecting adverse health effects of drugs and other chemicals early during chemical/drug development saves significant time and resources. Freshwater planarians are an emerging invertebrate model for rapid, cost-effective neurotoxicity screening. Because planarians exhibit seizure-like behavior when exposed to chemicals that cause seizures in mammals, such as N-methyl-D-aspartate (NMDA) and picrotoxin, they could be a useful first-tier model for seizure screening and thus reduce the need for slow and expensive mammalian tests. However, planarian seizure studies to date have been low-throughput and lacking the necessary standardization and automated analysis to make this model a viable screening solution. Here, we present results from medium-throughput behavioral testing conducted in 48-well plates using two popular models for planarian pharmacological and toxicological studies: Dugesia japonica and Girardia dorotocephala. Planarian behavior was scored using automated image analysis, measuring both translational behavior and body shape changes. We found that known seizurogenic compounds in mammals (NMDA, nicotine, picrotoxin, pilocarpine, and pentylenetetrazole (PTZ)) induced seizure-like behavior in both planarian species within 30 minutes of exposure. We also tested three pesticides (parathion, carbaryl, and permethrin). Parathion and carbaryl, but not permethrin, caused planarian seizure-like activity. While the planarian species responded similarly to most compounds, some compounds showed potency differences of 10-100-fold (pilocarpine and nicotine, respectively). G. dorotocephala planarians were generally more sensitive, but D. japonica planarians displayed more reproducible behaviors. By standardizing both experimental approach and analysis methods and making them available, this work can serve as a framework for future testing of chemicals for seizurogenic potential in planarians.

pharmacology and toxicology↗

bioRxiv2024

Distinguishing classes of neuroactive drugs based on computational physicochemical properties and experimental phenotypic profiling in planarians

Mental illnesses put a tremendous burden on afflicted individuals and society. Identification of novel drugs to treat such conditions is intrinsically challenging due to the complexity of neuropsychiatric diseases and the need for a systems-level understanding that goes beyond single molecule-target interactions. Thus far, drug discovery approaches focused on target-based in silico or in vitro high-throughput screening (HTS) have had limited success because they cannot capture pathway interactions or predict how a compound will affect the whole organism. Organismal behavioral testing is needed to fill the gap, but mammalian studies are too time-consuming and cost-prohibitive for the early stages of drug discovery. Behavioral HTS in small organisms promises to address this need and complement in silico and in vitro HTS to improve the discovery of novel neuroactive compounds. Here, we used cheminformatics and HTS in the freshwater planarian Dugesia japonica - an invertebrate system used for neurotoxicant HTS - to evaluate the extent to which complementary insight could be gained from the two data streams. In this pilot study, our goal was to classify 19 neuroactive compounds into their functional categories: antipsychotics, anxiolytics, and antidepressants. Drug classification was performed with the same computational methods, using either physicochemical descriptors or planarian behavioral profiling. As it was not obvious a priori which classification method was most suited to this task, we compared the performance of four classification approaches. We used principal coordinate analysis or uniform manifold approximation and projection, each coupled with linear discriminant analysis, and two types of machine learning models -artificial neural net ensembles and support vector machines. Classification based on physicochemical properties had comparable accuracy to classification based on planarian profiling, especially with the machine learning models that all had accuracies of 90-100%. Planarian behavioral HTS correctly identified drugs with multiple therapeutic uses, thus yielding additional information compared to cheminformatics. Given that planarian behavioral HTS is an inexpensive true 3R (refine, reduce, replace) alternative to vertebrate testing and requires zero a priori knowledge about a chemical, it is a promising experimental system to complement in silico HTS to identify new drug candidates. Author summaryIdentifying drugs to treat neuropsychiatric diseases is difficult because the complexity of the human brain remains incompletely understood. Pathway interactions and compensatory mechanisms make it challenging to identify new compounds using computational models and cell-based assays that evaluate potential interactions with specific protein targets. Despite major efforts, neither of these approaches alone nor in combination have been particularly successful in identifying novel neuroactive drugs. Here, we test the hypothesis that rapid behavioral screening using an aquatic invertebrate flatworm, the planarian Dugesia japonica, augments the information obtained from computational models based on the physical and chemical properties of neuroactive drugs. Using 19 drugs classified by the vendor as antipsychotics, antidepressants, or anxiolytics, we found that planarian screening could correctly classify most of the drugs based on behavior alone. For compounds known to have multiple therapeutic uses, planarian phenotyping correctly identified the "off-label" class, thereby uncovering effects that were not predicted using the physicochemical properties of the drug alone. This pilot study is the first to show that behavioral phenotyping in a flatworm can be used to classify neuroactive drugs.

pharmacology and toxicology↗

bioRxiv2020

Dugesia japonica is the best suited of three planarian species for high-throughput toxicology screening

High-throughput screening (HTS) using new approach methods is revolutionizing toxicology. Asexual freshwater planarians are a promising invertebrate model for neurotoxicity HTS because their diverse behaviors can be used as quantitative readouts of neuronal function. Currently, three planarian species are commonly used in toxicology research: Dugesia japonica, Schmidtea mediterranea, and Girardia tigrina. However, only D. japonica has been demonstrated to be suitable for HTS. Here, we assess the two other species for HTS suitability by direct comparison with D. japonica. Through quantitative assessments of morphology and multiple behaviors, we assayed the effects of 4 common solvents (DMSO, ethanol, methanol, ethyl acetate) and a negative control (sorbitol) on neurodevelopment. Each chemical was screened blind at 5 concentrations at two time points over a twelve-day period. We obtained two main results: First, G. tigrina and S. mediterranea planarians showed significantly reduced movement compared to D. japonica under HTS conditions, due to decreased health over time and lack of movement under red lighting, respectively. This made it difficult to obtain meaningful readouts from these species. Second, we observed species differences in sensitivity to the solvents, suggesting that care must be taken when extrapolating chemical effects across planarian species. Overall, our data show that D. japonica is best suited for behavioral HTS given the limitations of the other species. Standardizing which planarian species is used in neurotoxicity screening will facilitate data comparisons across research groups and accelerate the application of this promising invertebrate system for first-tier chemical HTS, helping streamline toxicology testing.

pharmacology and toxicology↗

bioRxiv2019

Linalool acts as a fast and reversible anesthetic in Hydra

The ability to make transgenic Hydra lines has opened the door for quantitative in vivo studies of Hydra regeneration and physiology. These studies commonly include excision, grafting and transplantation experiments along with high-resolution imaging of live animals, which can be challenging due to the animals response to touch and light stimuli. While various anesthetics have been used in Hydra studies over the years, they tend to be toxic over the course of a few hours or their long-term effects on animal health have not been studied. Here we show that the monoterpenoid linalool is a useful anesthetic for Hydra. Linalool is easy to use, non-toxic, fast acting, and reversible. It has no detectable long-term effects on cell viability or cell proliferation. We demonstrate that the same animal can be immobilized in linalool multiple times at intervals of several hours for repeated imaging over 2-3 days. This uniquely allows for in vivo imaging of dynamic processes such as head regeneration. We further directly compare linalool to currently used anesthetics and show its superior performance. Because linalool, which is frequently utilized in perfumes and cosmetic products, is also non-hazardous to humans, it will be a useful tool for Hydra research in both research and teaching contexts.

pharmacology and toxicology↗

bioRxiv2019

Mouth Function Determines The Shape Oscillation Pattern In Regenerating Hydra Tissue Spheres

Hydra is a small freshwater polyp capable of regeneration from small tissue pieces and from aggregates of cells. During regeneration, a hollow bilayered sphere is formed that undergoes osmotically driven shape oscillations of inflation and rupture. These oscillations are necessary for successful regeneration. Eventually, the oscillating sphere breaks rotational symmetry along the future head-foot axis of the animal. Notably, the shape oscillations show an abrupt shift from large amplitude, long period oscillations to small amplitude, short period oscillations. It has been widely accepted that this shift in oscillation pattern is linked to symmetry breaking and axis formation. However, recent work showed that regenerating tissue pieces inherit the parent animals body axis and thus are asymmetric from the beginning. Thus, there is no mechanistic explanation for the observed shift in oscillation pattern and no clear understanding of its significance for Hydra regeneration. Using in vivo manipulation and imaging, we quantified the shape oscillation dynamics and dissected the timing and triggers of the pattern shift. Our experiments demonstrate that the shift in the shape oscillation pattern in regenerating Hydra tissue pieces is caused by the formation of a functional mouth, thereby linking morphological readouts to physiologically relevant events during regeneration. This study shows the power of using modern experimental techniques to revisit old questions in pattern formation and development.

biophysics↗

bioRxiv2019

Screening for neurotoxic potential of 15 flame retardants using freshwater planarians

Asexual freshwater planarians are an attractive invertebrate model for high-throughput neurotoxicity screening, because they possess multiple quantifiable behaviors to assess distinct neuronal functions. Planarians uniquely allow direct comparisons between developing and adult animals to distinguish developmentally selective effects from general neurotoxicity. In this study, we used our automated planarian screening platform to compare the neurotoxicity of 15 flame retardants (FRs), consisting of representative phased-out brominated (BFRs) and replacement organophosphorus FRs (OPFRs). OPFRs have emerged as a proposed safer alternative to BFRs; however, limited information is available on their health effects. We found 11 of the 15 FRs (3/6 BFRs, 7/8 OPFRs, and Firemaster 550) caused adverse effects in both adult and developing planarians with similar nominal lowest-effect-levels for BFRs and OPFRs. This suggests that replacement OPFRs are comparably neurotoxic to the phased-out compounds. BFRs were primarily systemically toxic, whereas OPFRs, except Tris(2-chloroethyl) phosphate, shared a behavioral phenotype in response to noxious heat at sublethal concentrations, indicating specific neurotoxic effects. By directly comparing effects on adult and developing planarians, we further found that one BFR (3,3,5,5-Tetrabromobisphenol A) caused a developmental selective defect. Together, these results demonstrate that our planarian screening platform yields high content data resulting from assaying various behavioral and morphological endpoints, allowing us to distinguish selective neurotoxic effects and effects specific to the developing nervous system. Ten of these 11 bioactive FRs were previously found to be bioactive in other models, including cell culture and alternative animal models (nematodes and zebrafish). This level of concordance across different platforms emphasizes the urgent need for further evaluation of OPFRs in mammalian systems.

pharmacology and toxicology↗

bioRxiv2017

Forces driving cell sorting in Hydra

Cell sorting, whereby a heterogeneous cell mixture organizes into distinct tissues, is a fundamental patterning process in development. So far, most studies of cell sorting have relied either on 2-dimensional cellular aggregates, in vitro situations that do not have a direct counterpart in vivo, or were focused on the properties of single cells. Here, we report the first multiscale experimental study on 3-dimensional regenerating Hydra aggregates, capable of reforming a full animal. By quantifying the kinematics of single cell and whole aggregate behaviors, we show that no differences in cell motility exist among cell types and that sorting dynamics follow a power law. Moreover, we measure the physical properties of separated tissues and determine their viscosities and surface tensions. Based on our experimental results and numerical simulations, we conclude that tissue interfacial tensions are sufficient to explain Hydra cell sorting. Doing so, we illustrate DArcy Thompsons central idea that biological organization can be understood through physical principles, an idea which is currently re-shaping the field of developmental biology.\n\nSummary statementHydra regenerates after dissociation into single cells. We show how physical mechanisms can explain the first step of regeneration, whereby ectodermal and endodermal cells sort out to form distinct tissue layers.

biophysics↗