Project 3: Normalization of Neural Excitability

Project 3: Normalization of Neural Excitability

Project 3 is leveraging a well established model of acute diisopropylflurophosphate (DFP) intoxication (a surrogate for OP nerve agents) to evaluate spontaneous recurring seizures (SRS), neural excitability, cognitive behaviors and histopathologic outcomes. Clinical and experimental evidence shows that current standard of care for acute OP intoxication (atropine, oxime, and benzodiazepine) does not sufficiently protect against persistent neuropathology or prevent development of spontaneous seizures and cognitive deficits in survivors. Project 3 is testing the hypothesis that changes in 1) neural activity (oscillations) will precede the development of SRS and scale the severity of neuropathy, chronic SRS, and behavioral dysfunction, and 2) modulating neural activity starting hours or days after acute DFP intoxication will normalize oscillations and reduce SRS, and improve cognitive behavior. Seizures induced by nerve agents are the result of abnormal brain activity, and restoring normal brain activity with select therapeutics may lower the risk of negative outcomes.

Project 3 aims to:

1. Determine if changes in oscillatory activity detected using depth recordings of field potentials precede SRS and behavioral deficits and if the degree of oscillatory change correlates with injury severity.
2. Evaluate if modulations of hyperexcitability reduce SRS intensity and frequency, neurodegeneration and severity of neuroinflammation.
3. Establish if modulation of hyperexcitability following acute OP intoxication drives oscillations and improves performance over a range of behavioral domains.