The Challenge
Major open questions in the epilepsy field:
- The unpredictable nature of seizures is one of the things that patients find most challenging about living with epilepsy. What conditions are permissive for / protective against seizure onset?
- Seizures are typically brief (seconds to minutes) but many patients with epilepsy experience prolonged symptoms after seizures (hours to day), as well as chronic comorbidities in sleep, attention, mood, and cognition. What changes do seizures impose on neuronal networks?
Our lab’s mission is to answer these questions, with a focus on subcortical neuromodulatory networks. The long term goal of this work is to motivate more effective treatments to prevent or terminate seizures — and to limit the sequalae of those seizures — towards improved outcomes and quality of life for patients with epilepsy.
The Obstacles
Investigation of neuronal circuits in epilepsy has been limited by significant technical challenges: First, different neuron types are intermingled in the brain, such that it is difficult to selectively isolate an individual cell type experimentally. Second, epilepsy is a dynamic condition, with seizures emerging suddenly from baseline brain activity, such that static measurements may not be adequate to understand seizures. Third, spontaneous seizures are experimentally challenging to study, but chemically or electrically evoked seizures in wild-type animals may not recapitulate fundamental features of seizures in epilepsy.
Our Approach
We now have the tools to overcome these challenges. Pre-clinical models of epilepsy in which seizures can be induced with naturalistic stimuli, facilitating acute experiments during seizures, as well as enabling investigators to titrate the number of seizures in each animal. These models can be combined with Cre-driver lines, allowing genetic access to specific cell types. Within these defined cell types, we can selectively express molecular tools that allow us to dynamically measure (e.g., via 2-photon or fiber photometry calcium or neurotransmitter imaging) or manipulate (e.g., via optogenetics or chemogenetics) neuronal firing during seizures.
