Acute intoxication with organophosphorus (OP) pesticides is a significant public health concern and long-term neurological effects are not well understood. A major obstacle to progress towards reproducible, rigorous preclinical research in the long-term effects of OP- induced status epilepticus is that current experimental approaches often require prohibitively time and labor-intensive 24/7 video-EEG monitoring and inherently subjective scoring of seizures by human observers (like the widely used Racine scale). While algorithms for automated seizure detection in EEG are improving, the critically important behavioral manifestations of acquired epilepsy and assessment of its cognitive comorbidities remain poorly quantified. Our parent grant focuses on developing an objective, high-throughput technique to characterize epileptic phenotypes using a new method called motion sequencing (MoSeq) and apply it to automated anti-epileptic drugs (AED) screening. The central idea of MoSeq rests on the discovery that complex animal behaviors are structured in stereotyped modules (?syllables?) at sub-second timescales that are arranged according to specific rules (?grammar?) that can be detected without observer bias by artificial intelligence (AI)-assisted 3D video analysis. In this administrative supplement project, we propose to employ and refine MoSeq to address key challenges in research into the development of new medical countermeasures (MCM) against nerve agents and OP pesticides. This includes testing if it is possible to objectively study the long-term effects of OP intoxication and evaluate MCMs at scale by determine epilepsy-specific behavioral modules and associated transition probabilities in mice after acute OP exposure. In addition, given that neuroinflammation is likely to play a key role in OP-induced persistent neuronal circuit disturbance, we will test if microglial depletion can rescue the OP-induced chronic changes in behavioral syllables and transition probabilities. Together, the aims in this administrative supplement will both benefit from and contribute to our parent grant?s goal to develop a reliable, sharable tool for the research community to study seizures and cognitive comorbidities of epilepsy.

Public Health Relevance

There is an urgent need for medical countermeasures (MCMs) against nerve agents and organophosphorus (OP) pesticides. The project will leverage from our recent technical breakthroughs in artificial intelligence (AI)-assisted analysis of 3-dimensional video data of mouse behavior to test if it is possible to objectively study the long-term effects of OP intoxication and evaluate MCMs at scale. If successful, this innovative approach is expected to have a significant and sustained impact on preclinical research by enabling objective, automated, inexpensive, reproducible assessment of epileptic phenotypes in experimental animals after acute OP intoxication to aid the testing of anti-seizure drugs and other novel therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Whittemore, Vicky R
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Stanford University
Schools of Medicine
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