Optogenetic treatment of epilepsyassociated

描述(由申请人提供)：相当大比例的癫痫患者患有抑郁症，但癫痫相关抑郁(EAD)的机制尚不清楚。这样的认识水平对于设计治疗和预防EAD的新模式至关重要。我们以前的工作表明，由于癫痫持续状态(SE)而发展成癫痫的动物会发展出绝望和绝望的行为症状。这些动物表现出皮层和海马区诱发的5-羟色胺水平降低，但癫痫动物5-羟色胺水平降低的原因仍不清楚。从内侧前额叶皮质(MPFC)到RN的兴奋性投射在5-羟色胺释放的自上而下控制中起着至关重要的作用，激活这一系统可以挽救抑郁相关行为。因此，我们假设癫痫动物的前额叶输入被削弱，可以使用光遗传学方法增加剩余前额叶输入的兴奋性驱动，以正常化5-羟色胺水平和治疗EAD。这项建议的主要目的是探索对5-羟色胺能RN的远程输入的光遗传刺激，作为有效治疗EAD的一种新的治疗原则证明方法。我们将使用先进的体内光遗传技术、行为研究和电生理学来寻找长程投射在癫痫抑郁中的作用的聚合证据。具体地说，我们将检验这样一种假设，即EAD的特征是从mPFC到RN的兴奋性驱动减弱，并且mPFC-RN通路的功能正常化在慢性癫痫和并发抑郁的动物中发挥抗抑郁作用。

DESCRIPTION (provided by applicant): A substantial proportion of individuals with epilepsy suffer from depression but the mechanisms underlying epilepsy-associated depression (EAD) are not understood. Such a level of understanding is essential for designing new modalities for the treatment and prevention of EAD. Our previous work showed that animals that develop epilepsy as result of status epilepticus (SE) develop behavioral symptoms of despair and hopelessness. These animals show decreased evoked serotonin levels in cortex and hippocampus but the cause of decreased serotonin levels in epileptic animals is still not understood. The excitatory projection from the medial prefrontal cortex (mPFC) to the RN plays an essential role in the top-down control of serotonin release, and activating this system can rescue depression-related behaviors. We therefore hypothesize that this prefrontal input is weakened in animals with epilepsy and that optogenetic methods can be used increase excitatory drive from the remaining prefrontal inputs to normalize serotonin levels and treat EAD. The main goal of this proposal is to explore optogenetic stimulation of long-range inputs into serotonergic RN as a novel therapeutic proof-of-principle approach for effective management of EAD. We will use cutting edge in-vivo optogenetic techniques, behavioral studies, and electrophysiology to find convergent evidence for the role of long-range projections in depression in epilepsy. Specifically we will test the hypothesis that EAD is characterized by the diminished excitatory drive from mPFC into the RN and that normalizing the function of the mPFC-RN pathway exerts antidepressant effects in animals with chronic epilepsy and concurrent depression.