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，但癫痫相关性抑郁症（EAD）的机制尚不清楚。这种程度的了解对于设计治疗和预防EAD的新模式至关重要。我们之前的工作表明，由于癫痫持续状态（SE）而发生癫痫的动物会出现绝望和绝望的行为症状。这些动物表现出皮层和海马体中诱发血清素水平下降，但癫痫动物血清素水平下降的原因尚不清楚。从内侧前额叶皮层（mPFC）到RN的兴奋性投射在自上而下控制血清素释放中起着重要作用，激活该系统可以挽救抑郁相关行为。因此，我们假设这种前额叶输入在癫痫动物中减弱，光遗传方法可以通过增加剩余前额叶输入的兴奋驱动来使血清素水平正常化并治疗EAD。本研究的主要目的是探索光遗传刺激对血清素能RN的远程输入，作为一种新的治疗原理证明方法，有效管理EAD。我们将使用尖端的体内光遗传学技术、行为研究和电生理学来寻找远程投射在癫痫患者抑郁中的作用的证据。具体来说，我们将验证以下假设，即EAD的特征是mPFC进入RN的兴奋驱动减弱，以及mPFC-RN通路功能正常化对慢性癫痫和并发抑郁症的动物具有抗抑郁作用。

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.