Is gestational sleep apnea a previously unrecognized cause of maternal immune activation that predisposes male offspring to disease-relevant neural dysfunction?

项目总结 驱动这一探索性R21(FOA PA-21-200)的基本假设是，在 怀孕导致母体免疫激活(MIA)，导致多种认知和社交缺陷， 出现在青少年阶段，并持续到成年。睡眠呼吸暂停的特征是反复发作的部分性或 睡眠时完全停止呼吸，导致血氧水平病理性下降(间歇性 缺氧；IH)，通常每晚数百次。每年有超过50万的女性有未经治疗的睡眠 妊娠期呼吸暂停，部分原因是筛查不充分，或患者对睡眠呼吸暂停缺乏依从性 心理治疗。尽管孕期母亲睡眠呼吸暂停对围产期健康的不利影响 母亲和她的新生儿最近变得很受欢迎，对母亲SA对 她后代的持久健康。我们开发了一种妊娠期睡眠呼吸暂停的实验模型 将怀孕的大鼠暴露在一种模仿人类睡眠呼吸暂停的IH模式中。我们的发现表明，后代 妊娠期间歇性低氧(GIH)组大鼠脊髓神经元密度显著增加 内侧前额叶皮质和行为障碍，包括记忆和社交缺陷，表现在 青春期，并坚持到成年期。值得注意的是，GIH导致的行为缺陷在男性中更为突出 而雌性只受轻微影响(或根本不受影响)。尽管暴露出来的行为缺陷 分别代表了几种与人类健康相关的神经精神障碍，增强的 皮质突触连接、行为功能障碍的早期发生和持续，以及比较 男性表型的严重性表明可能与我们的发现相关的自闭症。有证据表明， 怀孕期间的MIA与后代患自闭症谱系障碍的风险增加有关。在这份提案中， 我们将开始检验这一假说，即孕妇在怀孕期间发生睡眠呼吸暂停会导致 母体免疫反应是HER继发的神经元和行为损害的关键启动者 后代。肝炎会在人类和动物模型中引起慢性炎症，它是大部分病理的基础。 与非妊娠个体的睡眠呼吸暂停有关。有趣的是，许多细胞因子会因睡眠而增加 在MIA模型中，呼吸暂停与与后代神经功能障碍有关的呼吸暂停是相同的。 我们的初步数据表明，GIH上调IL-17a在GIH男性(但不是女性)胎盘和 母亲血清，一种众所周知的细胞因子，可协调接触过的母亲的后代的自闭症样行为 其他型号的MIA。因此，我们的数据表明，GIH可能是MIA的一个未被识别的触发因素 导致后代出现一系列缺陷，类似于大鼠的行为和突触异常 患有自闭症谱系障碍的人类。他们还指出，IL-17a是罪魁祸首。如果我们的假设 如果我们的发现是正确的，我们的发现将是革命性的，并将告知医生和患者 在怀孕期间进行早期和持续的SA筛查，以最大限度地减少对未出生婴儿的神经损害。

PROJECT SUMMARY The fundamental hypothesis driving this exploratory R21 (FOA PA-21-200) is that maternal sleep apnea during pregnancy causes maternal immune activation (MIA), resulting in multiple cognitive and social deficits that emerge in juvenile stages and persist into adulthood. Sleep apnea is characterized by recurrent partial or complete cessation of breathing during sleep that causes pathologic drops in blood oxygen levels (intermittent hypoxia; IH), often hundreds of times each night. Each year, over half a million women have untreated sleep apnea during pregnancy, in part due to insufficient screening, or a lack of patient compliance to sleep apnea therapy. Although detrimental effects of maternal sleep apnea during pregnancy on the perinatal health of the mother and her newborn have recently become appreciated, little is known about the impact of maternal SA on the long-lasting health of her offspring. We developed an experimental model of sleep apnea in pregnancy by exposing pregnant rats to a pattern of IH that mimics sleep apnea in humans. Our findings indicate that offspring exposed to intermittent hypoxia during gestation (GIH) exhibit significant increases in neuronal spine density in the medial prefrontal cortex, and behavioral impairments, including memory and social deficits that manifest in juveniles, and persist into adulthood. Strikingly, GIH-induced behavioral deficits are more prominent in male offspring whereas females are only slightly (or not at all) affected. Although the revealed behavioral deficits individually typify several neuropsychiatric disorders of relevance to human health, the combination of enhanced cortical synaptic connectivity, the early onset and persistence of behavioral dysfunction, and the comparative severity of phenotypes in males suggests a possible autism-relevancy to our findings. Evidence indicates that MIA during pregnancy is associated with increased offspring risk of autism spectrum disorder. In this proposal, we will begin to test the hypothesis that maternal sleep apnea during pregnancy induces activation of the maternal immune response that is a key initiator of the ensuing neuronal and behavioral impairments in her offspring. IH causes chronic inflammation in humans and animal models, and it underlies much of the pathology associated with sleep apnea in non-pregnant individuals. Intriguingly, many of the cytokines increased by sleep apnea are the same as those associated with offspring neurological dysfunction in models of MIA. Our preliminary data indicate that GIH upregulates IL-17a in the GIH male (but not female) placenta and in maternal serum, a cytokine well known to orchestrate autism-like behaviors in offspring of mothers exposed to other models of MIA. Our data therefore suggest that GIH may be an unrecognized trigger for MIA that leads to a constellation of deficits in offspring that resemble behavioral and synaptic abnormalities in humans with autism spectrum disorder. They also point to IL-17a as the culprit. If our hypotheses are correct, our findings would be transformative and would inform physicians and patients alike to perform early and consistent screening for SA in pregnancy to minimize neural damage to the unborn baby.