Optogenetics has recently revolutionized the field of neuroscience. Not only does optogenetics have broad implications as a research tool for studying complex neural networks, but it also shows great potential to be used directly as a treatment for diseases like epilepsy. Indeed, the optogenetic approach has been recently used to halt seizure activity in various animal models. However, despite the progress made towards a future clinical application, the use of optogenetic techniques in vivo still faces many important challenges that need to be addressed.
Most of these challenges lie with the light source, which currently relies on using lasers or LEDs coupled to optical fibers implanted into the brain. Not only are these light sources impractical to use in long term in vivo settings (i.e. hardware dependency, limited tissue penetration), they also pose a significant safety risk (e.g. tissue scarring and infection).
The overall goal of this project is to address the current technical limitations of using optogenetics in vivo by utilizing bioluminescent proteins as an alternative light source for activating light-sensitive opsins. The proposed research will develop several optogenetic systems using bioluminescent proteins. These systems will then be studied in the context of controlling epileptic activity in in vitro and in vivo settings.
The proposed research would therefore not only provide an alternative means to activate opsins (adding to the versatility of the tool for neuroscience research), but would also provide a novel approach to controlling seizure activity seen in epilepsy.
One in 26 people will be diagnosed with epilepsy in their lifetime. Of these, nearly a third will be refractory to medical therapy, and many will not be candidates for surgical resection. Thus there is a need for novel targets and therapies, the former of which will require a greater understanding of neural networks involved in epilepsy, and the latter of which demands the development of novel techniques.
In humans, seizures are less frequent during REM sleep where theta oscillation – a 3-12Hz oscillatory rhythm in the hippocampal local field potential – is present. Animal models of epilepsy also have fewer seizures during spontaneous theta oscillation. Theta oscillation originates in the medial septum, a basal forebrain structure that projects to the hippocampus, the sight of origin for the most common form of intractable epilepsy. Generation of theta oscillation via the medial septum is thus an ideal target for intervention. However, of the three neuronal populations of the medial septum – cholinergic, GABAergic, and glutamatergic – it is unclear which is responsible for generating theta.
To gain greater insight into septohippocampal function, a novel tool with both spatial (cell-type specific) and temporal (millisecond time-scale) precision is needed. Optogenetics, a novel neuromodulation technique, which enables activation and inhibition of genetically-defined neurons, provides the mean to functionally dissect the septohippocampal axis and leverage the results for seizure therapy. We hypothesize that one of these medial septal subpopulations of neurons is responsible for the generation and modulation of hippocampal theta oscillations, and that optogenetic activation of these neurons can suppress hippocampal epileptic activity. To accomplish this, we are selectively activating and inhibiting these cell types and looking at the effects on normal and epileptic hippocampal neural activity.