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？

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10680972
• 关键词: Adolescent; Adult; Adult Children; Affect; Animal Model; Animals; Attention; Automobile Driving; Awareness; Behavior; Behavioral; Blood; Brain; Breathing; Child; Chronic; Clinical; Cognitive; Cognitive deficits; Complex; Data; Dendritic Spines; Development; Developmental Delay Disorders; Diagnosis; Disease; Drops; Etiology; Exhibits; Experimental Models; Exposure to; FRAP1 gene; Female; Fetus; Foundations; Functional disorder; Future; Genetic; Health; High-Risk Pregnancy; Human; Hyperactivity; Hypoxia; Immune response; Impairment; Individual; Inflammation; Inflammatory; Interleukin-6; Learning; Life Experience; Link; Medial; Medical; Memory impairment; Modeling; Morbidity - disease rate; Mothers; Motivation; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Newborn Infant; Outcome; Oxygen; Paper; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Perinatal; Phenotype; Physicians; Placenta; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevalence; Rattus; Recurrence; Risk; Risk Factors; Rodent Model; Severities; Signal Transduction; Sleep; Sleep Apnea Syndromes; Social Development; Source; Stimulus; Suggestion; Synapses; Testing; Third Pregnancy Trimester; Time; Up-Regulation; Uterus; Vertebral column; Woman; Work; adverse outcome; autism spectrum disorder; behavioral impairment; behavioral phenotyping; comparative; compliance behavior; cytokine; density; early onset; experience; fetal; health of the mother; hippocampal pyramidal neuron; human model; immune activation; male; maternal serum; memory recognition; neural; neuropsychiatric disorder; neuropsychiatry; new therapeutic target; offspring; perinatal health; postnatal; pregnancy disorder; pregnant; prenatal; prevent; repetitive behavior; response; screening; sex; sexual dimorphism; social; social cognition; social deficits; transmission process; virtual

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 推动这一探索性R21（FOA PA-21-200）的基本假设是， 怀孕导致母体免疫激活（MIA），导致多种认知和社会缺陷， 在幼年期出现并持续到成年期。睡眠呼吸暂停的特点是反复发作的部分或 睡眠期间呼吸完全停止，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50万的女性未经治疗的睡眠 怀孕期间呼吸暂停，部分原因是筛查不足，或患者对睡眠呼吸暂停缺乏依从性 疗法虽然孕妇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已经受到重视，但对母亲SA对新生儿的影响知之甚少。 她后代的长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类似人类睡眠呼吸暂停的IH模式中。我们的发现表明， 在妊娠期间暴露于间歇性缺氧（GIH）的小鼠中， 内侧前额叶皮层和行为障碍，包括记忆和社交缺陷，表现在 青少年，并坚持到成年。引人注目的是，GIH诱导的行为缺陷在男性中更为突出， 而女性则只会受到轻微的影响（或根本不受影响）。尽管这些行为缺陷 单独代表与人类健康相关的几种神经精神障碍，增强的 皮质突触连接、行为功能障碍的早期发作和持续性以及比较 男性中表型的严重性提示可能与我们的发现有关。证据表明 怀孕期间MIA与后代患自闭症谱系障碍的风险增加有关。在这一提议中， 我们将开始检验孕妇在怀孕期间睡眠呼吸暂停会引起 母亲的免疫反应，这是一个关键的启动器，随后的神经元和行为障碍，在她的 后代IH在人类和动物模型中引起慢性炎症，并且是许多病理学的基础 睡眠呼吸暂停综合征的发病率。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那些相同。 我们的初步数据表明，GIH上调IL-17 a在GIH男性（而不是女性）胎盘和 母体血清，一种众所周知的细胞因子，在母亲暴露于 其他型号的MIA。因此，我们的数据表明，胃肠道出血可能是一个未被认识的触发MIA， 导致后代出现一系列缺陷，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-17 a是罪魁祸首。如果我们的假设 是正确的，我们的发现将是变革性的，并将告知医生和患者， 在怀孕期间进行早期和一致的SA筛查，以尽量减少对未出生婴儿的神经损伤。