Sleep state-dependent mechanisms of seizure-induced death

 描述（由申请人提供）：癫痫猝死（SUDEP）是难治性癫痫患者的主要死因。大多数SUDEP病例发生在晚上，在睡眠中，但为什么会这样尚不清楚。有人提议， 这些病例可能是由于夜间缺乏足够的监护和癫痫发作后的复苏努力。最近的证据表明，这不是故事的全部。在睡眠期间发生的许多生理变化可能使睡眠相对不耐受癫痫发作的额外生理损害。癫痫所致损害 呼吸、心脏和唤醒机制都与SUDEP有关。所有这些都受到睡眠状态依赖性调节。大量的证据表明，神经递质5-羟色胺的信号传导异常在SUDEP中很重要。5-羟色胺也以睡眠状态依赖性方式调节，并且参与呼吸、心脏活动以及睡眠和觉醒的调节，并且可以调节癫痫发作。这项提案的主要目标是了解在睡眠期间发生的癫痫发作是如何致命的。在追求这一目标，我们将测试总体假设，即血清素参与调节 死亡诱导的状态依赖性在目标1中，我们将确定在睡眠期间发生的癫痫发作如何失调呼吸功能。在目标2中，我们将确定在睡眠期间发生的癫痫发作如何失调唤醒机制。最后，在目标3中，我们将确定快速眼动睡眠如何防止癫痫发作。这些目标的完成将使人们了解睡眠期间发生的癫痫发作是如何致命的，其中一些发现可以直接转化为临床，以帮助识别SUDEP风险人群和实施新的预防策略。这项工作还将为今后深入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.