Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?

项目概述：强大的自苏醒反射(AR)对新生儿的出生存活率至关重要。这个 过渡到独立呼吸和适应呼吸中断，呼吸暂停，这在 新生儿和婴儿，需要协调的心肺反应才能康复。5-羟色胺 羟色胺)和产生它的脑干中缝细胞，称为Pet1神经元，组织和驱动 在新生动物和人类身上成功地进行了AR。不成功的应收账款被认为是 婴儿猝死综合征(SID)，其中大脑5-羟色胺能系统的变化 在约一半的人类小儿麻痹症病例中描述，包括不同形态的5-羟色胺神经元数量增加 (更小，更简单，可能不成熟)，自身受体5-HT1a结合不足，5-HT1a水平降低 羟色胺和色氨酸羟化酶2(TPH2，5-羟色胺的生物合成限速酶)。我们建议 研究揭示了这种小岛屿发展中国家大脑5-羟色胺能表型的某些方面是如何在产前发育的。我们的 最近的两个发现告诉了我们这一方法。首先，中缝内Pet1+神经元表达高水平的5-羟色胺 识别基因(如DDC、VMAT2、GATA3、Pet1)已被鉴定，大小较小，具有中等水平的 自身受体5-HT1a几乎或不表达TPH2和5-羟色胺。我们称这些新细胞为Par5-5- H能神经元，表明它们部分共享的分子表型、共享的位置和发育 出现5-羟色胺神经元。第二个是神经递质转换的发现，这是一种非规范的 神经元对应激源的反应发生的可塑性。最近的数据支持它在塑造5-HTeric中的作用 神经系统，在那里应激源可能驱动一些准-5-羟色胺神经元产生5-羟色胺作为适应性 回应。初步研究结果表明，从菱形核(R)4派生的类-5-羟色胺神经元密度较高， 选择性地支配呼吸和唤醒中心，以及孕期暴露在间歇性低氧中 结果出生后TPH2+细胞数量增加，但5-羟色胺水平尚不确定。我们建议 类5-羟色胺神经元是一个柔韧的群体，当产前受到 缺氧使新生儿产生5-羟色胺作为支持AR的代偿机制。我们假设 为了应对婴儿猝死综合征的主要危险因素产前缺氧，某些类5-羟色胺神经元自适应地 转化为产生5-羟色胺，以纠正5-羟色胺能信号失衡，从而阻碍AR和， 或者，不充分的转型在小岛屿发展中国家中起着关键作用。我们将通过曝光来测试这一点 小鼠在妊娠期间对间歇性低氧或常氧的反应，细胞和分子表型的特征 和询问神经递质转化(目标1)；进一步，我们将确定急性激活的效果 或抑制这些小鼠的R4-对-5-羟色胺神经元(目标2)，我们将检测表型 人类小儿麻痹症和对照脑组织中对5-羟色胺神经元的标记(目标3)。这部小说，从功能上讲 明确的对位5-羟色胺细胞类型和可塑性可能与新生儿存活率高度相关。

Project Summary: A robust autoresuscitatory reflex (AR) is critical to newborn survival from birth. The transition to independent breathing and accommodation of breathing interruptions, apneas, that are common in neonates and infants, requires a coordinated cardiorespiratory response for recovery. 5-hydroxytryptamine (5- HT, serotonin) and the brainstem raphe cells that produce it, referred to as Pet1 neurons, organize and drive successful AR in newborn animals and humans. Unsuccessful AR is understood to be a major contributor to the sudden infant death syndrome (SIDS), where alterations in the brain 5-HTergic system have been described in ~half of human SIDS cases, including increased number of 5-HT neurons of differing morphology (smaller, simpler, perhaps immature), deficiencies in autoreceptor 5-HT1A binding, and decreased levels of 5- HT and tryptophan hydroxylase 2 (TPH2, the rate-limiting biosynthetic enzyme for 5-HT). We propose investigations to reveal in mice how aspects of this SIDS brain 5-HTergic phenotype develop prenatally. Our approach is informed by two recent findings. First, Pet1+ neurons in the raphe expressing high levels of 5-HT identity genes (e.g. Ddc, Vmat2, Gata3, Pet1) have been identified, smaller in size, with modest levels of autoreceptor 5-HT1A yet remarkably expressing little or no TPH2 and 5-HT. We call these novel cells para-5- HTergic neurons, signifying their partially shared molecular phenotype, shared location, and developmental emergence with 5-HT neurons. Second is the discovery of neurotransmitter switching, a noncanonical form of neuronal plasticity that occurs in response to stressors. Recent data support its role in shaping the 5-HTergic neuronal system, where stressors may drive some para-5-HT neurons to produce 5-HT as an adaptive response. Preliminary findings reveal that para-5-HT neurons derived from rhombomere (r) 4 densely and selectively innervate respiratory and arousal centers, and that gestational exposure to intermittent hypoxia results in an increased number of TPH2+ cells postnatally with as yet uncertain 5-HT levels. We propose that para-5-HT neurons are a pliant population that may be transformed when challenged prenatally by hypoxia to produce 5-HT in newborns as a compensatory mechanism to support AR. We hypothesize that in response to the major SIDS risk factor of prenatal hypoxia, certain para-5-HT neurons adaptively transform to produce 5-HT to rectify a 5-HTergic signaling imbalance that hinders the AR and, alternatively, that an insufficient transformation plays a critical role in SIDS. We will test this by exposing mice to intermittent hypoxia or normoxia during gestation, characterizing cellular and molecular phenotypes and querying neurotransmitter transformation (Aim 1); further, we will determine the effect of acute activation or inhibition of these r4-para-5-HT neurons on the AR in these mice (Aim 2), and we will examine phenotypic markers of para-5-HT neurons in human SIDS and control brain tissue (Aim 3). This novel, functionally defined, para-5-HT cell type and plasticity may be highly relevant to newborn viability.