Optogenetics provides a powerful tool with which to not only observe but also manipulate neuronal activity, due to the possibility it provides to spatially and temporally target subpopulations of neurons. Recently, the first reports have emerged of the co-expression of excitatory and silencing opsins within the same neuron population, providing the opportunity to control the balance of excitation and inhibition within neural circuits. However, this approach is currently limited by interactions between co-expressed opsins, which are suggested to be nonlinear. Correspondingly, this nonlinearity complicates the proposal of stimulation protocols for modulating neural activity. Thus although optogenetics progresses towards the use of co-activated opsins to modulate neural activity, the mechanisms underlying their interaction have not been studied. In this project, I propose to address the functional implications of this deficit by studying the co-activation of excitatory and silencing opsins from the level of single neurons, to their dual activation in networks. I will do this by combining two parallel approaches. Firstly, I will use experimental in vitro and in vivo models to study the effects of co-activated opsins in isolated neurons and networks respectively. Secondly, based on an underlying biophysical model of opsins, I will examine computer models of co-activated opsins in single cells and in a multiscale model of a cortical circuit. By combining findings from experimental and theoretical models, I will increase our understanding of the possibilities of co-activated opsins, whilst simultaneously providing suitable experimental and theoretical models with which to further explore the balance of excitation and inhibition in cortical networks. This research will be of great immediate benefit to optogenetics, and help define the future direction of this technique as an effective tool with which to study the role of excitation and inhibition within neural circuits.
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