Sleep state-dependent mechanisms of seizure-induced death

 描述(申请人提供)：癫痫突发意外死亡(SUDEP)是难治性癫痫患者的主要死亡原因。大多数SUDEP病例发生在夜间，在睡眠中，但为什么会出现这种情况尚不清楚。有人提议，有一部分 这些病例可能是由于夜间缺乏足够的监督，以及癫痫发作后转播复苏努力所致。最近的证据表明，这并不是故事的全部。在睡眠期间发生的许多生理变化可能会使睡眠相对不能忍受癫痫发作的额外生理侮辱。癫痫所致损害 呼吸、心脏和觉醒机制都与SUDEP有关。所有这些都受到睡眠状态依赖的调节。大量证据表明，神经递质5-羟色胺信号的异常在SUDEP中很重要。5-羟色胺也以睡眠状态依赖的方式进行调节，参与呼吸、心脏活动、睡眠和觉醒的调节，并可以调节癫痫发作。这项提议的主要目标是了解睡眠中发生的癫痫发作是如何变得致命的。在追求这一目标的过程中，我们将检验有关5-羟色胺参与调节的首要假设。 惊厥致死的状态依赖性。在目标1中，我们将确定睡眠中发生的癫痫是如何调节呼吸功能的。在目标2中，我们将确定发生在睡眠中的癫痫是如何失调唤醒机制的。最后，在目标3中，我们将确定快速眼动睡眠是如何防止癫痫发作的。完成这些目标将使人们了解在睡眠中发生的癫痫发作如何可能是致命的，其中一些发现可以直接翻译给临床，以帮助识别SUDEP的风险人群和实施新的预防策略。这项工作还将为今后更深入地研究这些机制的项目奠定基础。

 DESCRIPTION (provided by applicant): Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. The majority of SUDEP cases occur at night, during sleep, but why this is the case in unclear. It has been proposed that a portion of these cases may be due to lack of adequate supervision during the nighttime and relayed resuscitation efforts following a seizure. Recent evidence suggests this is not the whole story. There are a number of physiologic changes that occur during sleep that may make sleep relatively intolerant to the additional physiologic insult of a seizure. Seizure-induced impairment of respiratory, cardiac and arousal mechanisms have all been implicated in SUDEP. All of these are subject to sleep state-dependent regulation. A large body of evidence suggests that abnormalities in signaling of the neurotransmitter serotonin are important in SUDEP. Serotonin is also regulated in a sleep state-dependent manner, and is involved in the regulation of breathing, cardiac activity, and sleep and wakefulness, and can modulate seizures. The primary goal of this proposal is to understand how seizures that occur during sleep become fatal. In pursuing this goal we will test the overarching hypothesis that serotonin is involved in regulating the state-dependence of seizure-induced death. In Aim 1 we will determine how seizures that occur during sleep dysregulate respiratory function. In Aim 2 we will determine how seizures that occur during sleep dysregulate arousal mechanisms. Finally, in Aim 3 we will determine how REM sleep is protective against seizures. Completion of these aims will provide an understanding of how seizures that occur during sleep could be fatal, and some of the findings could be directly translatable to the clinic to aid in identification of persons at risk for SUDEP and in implementation of novel prophylactic strategies. This work will additionally lay the groundwork for future projects delving deeper into these mechanisms.