Approximately 20-40% of patients with epilepsy have refractory seizures unresponsive to pharmacotherapy. There is therefore a need to develop alternative treatments for this large population of people who are at higher risk of developing epilepsy-related disabilities. Optogenetics - which provides a powerful approach to excite and/or inhibit neural activity in a cell-type specific manner - possesses great potential to limit or abolish the spread of the pathological neural activity underlying epileptic seizures. Despite this therapeutic potential, the use of optogenetics faces many technical challenges that limit its usefulness and translatability to the clinical setting. In this proposal, we present a hihly innovative solution to these problems by combining the use of optogenetics with bioluminescent reporters. Calcium-sensitive luciferases are a kind of bioluminescent reporter that has been successfully used for imaging neural activity in vivo. These luciferases respond to depolarization-associated calcium influx by emitting light that is compatible with the absorption spectrum of various inhibitory light-sensitive ion channels. We propose to use these reporters to create what we term an autonomous biologic controller capable of driving optogenetic feedback to control pathological activity. In our proposed model, calcium-sensitive luciferases would report neural activity in the form of light, inhibitory opsins would be activated by the emitted liht, and propagation of activity would be inhibited as the cell is hyperpolarized by the opsin. This autonomous, biological feedback of epileptic activity provides a novel solution to the technical limitations of optogenetics by eliminating the need for an external light source and offering a means for autonomous closed-loop feedback control. We suggest that this research is highly innovative and has the potential of accelerating the use of optogenetics as a tool to develop new therapies for epilepsy.

Public Health Relevance

Approximately 20-40% of people with epilepsy do not respond to medicinal therapy. Although surgery and electrical stimulation have shown some success in treating these patients, alternative therapies are needed. This proposal aims to use bioluminescence and optogenetics in the treatment and understanding of epilepsy, and offer a solution to the latter's technical limitations by creating a means of autonomous, biological closed- loop feedback control.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZNS1 (32))
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Fureman, Brandy E
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Emory University
Schools of Medicine
United States
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Tung, Jack K; Shiu, Fu Hung; Ding, Kevin et al. (2018) Chemically activated luminopsins allow optogenetic inhibition of distributed nodes in an epileptic network for non-invasive and multi-site suppression of seizure activity. Neurobiol Dis 109:1-10
Jaiswal, Poonam B; Tung, Jack K; Gross, Robert E et al. (2017) Motoneuron activity is required for enhancements in functional recovery after peripheral nerve injury in exercised female mice. J Neurosci Res :
Berglund, Ken; Tung, Jack K; Higashikubo, Bryan et al. (2016) Combined Optogenetic and Chemogenetic Control of Neurons. Methods Mol Biol 1408:207-25
Tung, Jack K; Berglund, Ken; Gutekunst, Claire-Anne et al. (2016) Bioluminescence imaging in live cells and animals. Neurophotonics 3:025001
Tung, Jack K; Berglund, Ken; Gross, Robert E (2016) Optogenetic Approaches for Controlling Seizure Activity. Brain Stimul 9:801-810
Smart, Otis Lkuwamy; Tiruvadi, Vineet Ravi; Mayberg, Helen S (2015) Multimodal approaches to define network oscillations in depression. Biol Psychiatry 77:1061-70
Tung, Jack K; Gutekunst, Claire-Anne; Gross, Robert E (2015) Inhibitory luminopsins: genetically-encoded bioluminescent opsins for versatile, scalable, and hardware-independent optogenetic inhibition. Sci Rep 5:14366
Fairley, Jacqueline A; Georgoulas, George; Smart, Otis L et al. (2014) Wavelet analysis for detection of phasic electromyographic activity in sleep: influence of mother wavelet and dimensionality reduction. Comput Biol Med 48:77-84