No abstract

Arousal from sleep in response to CO is a critical protective phenomenon. Dysregulation of CO-induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO-induced arousal is unknown. Because CO is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo- and mechano-sensors is required for CO-induced arousal. However, populations of neurons that are not involved in the regulation of breathing are also chemosensitive. Among these are serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) that comprise a component of the ascending arousal system. We hypothesized that direct stimulation of these neurons with CO could cause arousal from sleep independently of enhancing breathing. Dialysis of CO-rich acidified solution into DRN, but not medullary raphe responsible for modulating breathing, caused arousal from sleep. Arousal was lost in mice with a genetic absence of 5-HT neurons, and with acute pharmacological or optogenetic inactivation of DRN 5-HT neurons. Here we demonstrate that CO can cause arousal from sleep directly, without requiring enhancement of breathing, and that chemosensitive 5-HT neurons in the DRN critically mediate this arousal. Better understanding mechanisms underlying this protective reflex may lead to interventions to reduce disease-associated morbidity and mortality. Although CO-induced arousal is critical to a number of diseases, the specific mechanism is not well understood. We previously demonstrated that serotonin (5-HT) neurons are important for CO-induced arousal, as mice without 5-HT neurons do not arouse to CO Many have interpreted this to mean that medullary 5-HT neurons that regulate breathing are important in this arousal mechanism. Here we found that direct application of CO-rich aCSF to the dorsal raphe nucleus, but not the medullary raphe, causes arousal from sleep, and that this arousal was lost with genetic ablation or acute inhibition of 5-HT neurons. We propose that 5-HT neurons in the dorsal raphe nucleus can be activated directly by CO to cause arousal independently of respiratory activation.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in patients with refractory epilepsy. Convergent lines of evidence suggest that SUDEP occurs due to seizure induced perturbation of respiratory, cardiac, and electrocerebral function as well as potential predisposing factors. It is consistently observed that SUDEP happens more during the night and the early hours of the morning. The aim of this review is to discuss evidence from patient cases, clinical studies, and animal research which is pertinent to the nocturnality of SUDEP. There are a number of factors which might contribute to the nighttime predilection of SUDEP. These factors fall into four categories: influences of (1) being unwitnessed, (2) lying prone in bed, (3) sleep-wake state, and (4) circadian rhythms. During the night, seizures are more likely to be unwitnessed; therefore, it is less likely that another person would be able to administer a lifesaving intervention. Patients are more likely to be prone on a bed following a nocturnal seizure. Being prone in the accouterments of a bed during the postictal period might impair breathing and increase SUDEP risk. Sleep typically happens at night and seizures which emerge from sleep might be more dangerous. Lastly, there are circadian changes to physiology during the night which might facilitate SUDEP. These possible explanations for the nocturnality of SUDEP are not mutually exclusive. The increased rate of SUDEP during the night is likely multifactorial involving both situational factors, such as being without a witness and prone, and physiological changes due to the influence of sleep and circadian rhythms. Understanding the causal elements in the nocturnality of SUDEP may be critical to the development of effective preventive countermeasures.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Although specific mechanisms underlying SUDEP are not well understood, evidence suggests most SUDEP occurs due to seizure-induced respiratory arrest. SUDEP also tends to happen at night. Although this may be due to circumstances in which humans find themselves at night, such as being alone without supervision or sleeping prone, or to independent influences of sleep state, there are a number of reasons why the night (i.e., circadian influences) could be an independent risk factor for SUDEP. We explored this possibility. Adult male WT mice were instrumented for EEG, EMG, and EKG recording and subjected to maximal electroshock (MES) seizures during wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep during the nighttime/dark phase. These data were compared with data collected following seizures induced during the daytime/light phase. Seizures induced during the nighttime were similar in severity and duration to those induced during the daytime; however, seizures induced during the nighttime were associated with a lesser degree of respiratory dysregulation and postictal EEG suppression. Seizures induced during REM sleep during the nighttime were universally fatal, as is seen when seizures are induced during REM during the daytime. Taken together, these data implicate a role for time of day in influencing the physiological consequences of seizures that may contribute to seizure-induced death. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP frequently occurs during the night, which has been attributed to an effect of sleep. We have shown that sleep state does indeed influence survival following a seizure. That SUDEP occurs during the night could also implicate a circadian influence. In this study we found that time of day independently affects the physiological consequences of seizures.

Summary Objective Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Although the mechanisms for SUDEP are incompletely understood, seizure‐induced respiratory arrest (S‐IRA) has been strongly and consistently implicated. A body of evidence indicates that serotonin (5‐HT), a modulator of breathing, plays a critical role in SUDEP. Because the 5‐HT and norepinephrine (NE) systems interact in many biologic processes and NE is known to modulate breathing and seizures, we hypothesized that NE may play a role in S‐IRA and SUDEP. Methods We examined the effects of pharmacologic manipulation of 5‐HT and NE on S‐IRA and death following maximal electroshock (MES)–induced seizures in adult wild‐type (WT) mice, genetically 5‐HT neuron–deficient (Lmx1bf/f/p) mice, and chemically NE neuron–deficient mice. Mice were treated with pharmacologic agents targeting the serotonergic and noradrenergic systems and subjected to seizure induction via MES while breathing was measured via whole‐body plethysmography. Results S‐IRA and death was reduced in WT mice with NE reuptake inhibitors (NRIs), reboxetine and atomoxetine, selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the dual 5‐HT/NE reuptake inhibitor (SNRI), duloxetine. S‐IRA and death was also reduced in Lmx1bf/f/p mice with reboxetine and fluoxetine. The protective effects of the reuptake inhibitors were prevented by the α1 antagonist, prazosin. Citalopram did not reduce S‐IRA and death in NE neuron–deficient mice. Significance These data suggest that 5‐HT and NE critically interact in the modulation of breathing following a seizure and potentially inform preventive strategies for SUDEP.