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

妊娠期睡眠呼吸暂停是否是一种以前未被认识到的母体免疫激活的原因，导致男性后代容易出现与疾病相关的神经功能障碍？

基本信息

批准号：
10680972
负责人：
Tracy L Baker
金额：
$ 22.66万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

项目摘要

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.

项目摘要驱动此探索性R21（FOA PA-21-200）的基本假设是在怀孕会导致母体免疫激活（MIA），导致多种认知和社会缺陷在少年阶段出现，并持续成年。睡眠呼吸暂停的特征是反复出现的部分或在睡眠期间完全停止呼吸，导致病理氧气的病理降低（间歇性缺氧； ih），通常每晚几百次。每年，超过一百万的妇女没有治疗睡眠怀孕期间呼吸暂停，部分原因是筛查不足或缺乏患者遵守睡眠呼吸暂停治疗。尽管怀孕期间母亲睡眠呼吸暂停对围产期健康的有害影响母亲和她的新生儿最近受到赞赏，对母亲SA的影响知之甚少她后代的持久健康。我们通过将怀孕的大鼠暴露于模仿人类睡眠呼吸暂停的IH模式。我们的发现表明后代在妊娠期间暴露于间歇性缺氧（GIH）表现出明显的神经元脊柱密度升高内侧前额叶皮层和行为障碍，包括表现出的记忆和社会缺陷少年，一直持续到成年。令人惊讶的是，GIH引起的行为缺陷在男性中更为突出后代，而女性仅受到略有影响（或不影响）。虽然揭示的行为缺陷单独代表与人类健康相关的几种神经精神疾病，增强的结合皮质突触连通性，行为功能障碍的早期发作和持久性以及比较男性表型的严重程度表明我们的发现可能与自闭症相关。证据表明怀孕期间的MIA与自闭症谱系障碍的后代风险增加有关。在此提案中，我们将开始检验以下假设，即怀孕期间母亲的睡眠呼吸暂停会诱导激活孕产妇免疫反应是随后的神经元和行为障碍的关键引发者后代。 IH引起人类和动物模型的慢性炎症，这是许多病理的基础与非怀孕个体的睡眠呼吸暂停相关。有趣的是，许多细胞因子因睡眠而增加呼吸暂停与MIA模型中与后代神经功能障碍相关的呼吸暂停相同。我们的初步数据表明，GIH上调了GIH雄性（但不是女性）胎盘中的IL-17A，在孕产妇血清，一种众所周知的细胞因子到其他MIA模型。因此，我们的数据表明，GIH可能是MIA的一个未被发现的触发因素导致后代的赤字星座，类似于行为和突触异常患有自闭症谱系障碍的人。他们还指出IL-17A是罪魁祸首。如果我们的假设是正确的，我们的发现将是有变革性的，并且会告知医生和患者在怀孕期间对SA进行早期和一致的筛查，以最大程度地减少对未出生婴儿的神经损害。