Cellular and Neural Network Mechanism of Transcranial Electric Stimulation

揭示神经刺激技术的机制是大脑倡议（RFA-NS-20-006）的一个重要目标。经颅电刺激（TES）是一种非侵入性神经调节技术，通过在大脑中产生弱电场，对癫痫控制、行为和认知产生广泛影响。这些弱电场如何与神经活动有效地相互作用仍然是一个悬而未决的问题，TES的作用机制仍然是未知的。我们的实验室最近发现，ephaptic耦合（非突触神经耦合电场）在神经募集中起着重要作用，并可能解释TES诱导的效果。我们建议测试的假设，ephaptic耦合是TES的作用机制。本论文将结合体外新型电压成像技术和转基因小鼠的光遗传学刺激以及体内电生理实验，研究肝突触耦合与三种已知的TES诱发效应之间的联系，具体目的如下：1）研究肝突触耦合在TES诱发的发作间期棘波传播速度调制中的作用。2)确定在TES-induced癫痫发作抑制中，肝纤维化偶联的作用。3)研究突触耦合在TES诱导的神经振荡效应中的作用。如果成功的话，这一提议将为TES诱导的效应提供一个新的视角，揭示TES的作用机制，并为开发这种非突触治疗方式的效率更高的改进TES方案打开大门。

Unveiling mechanisms of neural stimulation technologies is an important goal of the Brain Initiative (RFA-NS-20-006). Transcranial electric stimulation (TES) is a non-invasive neuromodulation technique to provide wide-range effects on seizure control, behaviors, and cognition by generating weak electric fields in the brain. It is still an open question of how these weak electric fields can interact effectively with neural activity, and the mechanism of action of TES is still unknown. Our laboratory has recently found that ephaptic coupling (non-synaptic neural coupling by electric fields) plays a significant role in neural recruitment and could possibly explain the TES-induced effects. We propose to test the hypothesis that ephaptic coupling is the mechanism of action of TES. With the combination of in-vitro novel voltage imaging techniques and optogenetic stimulation in the transgenic mice and in-vivo electrophysiological experiments, we will study the links between the ephaptic coupling and three known TES-induced effects in the following independent specific aims: 1) Investigate the role of ephaptic coupling in TES-induced propagation speed modulation of interictal spikes. 2) Determine the role of ephaptic coupling in TES-induced seizure suppression. 3) Study the role of ephaptic coupling in TES-induced effects on neural oscillations. This proposal, if successful, will provide a novel insight into TES-induced effects, reveal the mechanism of action of TES, and open the door to the development of improved TES protocols with improved efficiency for this non-synaptic therapeutic modality.