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，但癫痫相关抑郁症（EAD）的潜在机制尚不清楚。这种理解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，癫痫持续状态（SE）导致癫痫的动物会出现绝望和绝望的行为症状。这些动物显示皮质和海马中诱发的5-羟色胺水平降低，但癫痫动物中5-羟色胺水平降低的原因仍不清楚。从内侧前额叶皮层（mPFC）到RN的兴奋性投射在自上而下控制5-羟色胺释放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，我们假设这种前额输入在癫痫动物中减弱，并且可以使用光遗传学方法增加来自剩余前额输入的兴奋性驱动，以使5-羟色胺水平正常化并治疗EAD。该提案的主要目标是探索将长距离输入光遗传学刺激到EAD能RN中，作为有效管理EAD的新的治疗原理验证方法。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长程投射在癫痫抑郁症中作用的会聚证据。具体来说，我们将测试的假设，EAD的特点是减少兴奋性驱动从mPFC到RN和正常化的mPFC-RN通路的功能发挥抗抑郁作用的动物慢性癫痫和并发抑郁症。

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.