Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?
副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险?
基本信息
- 批准号:10254240
- 负责人:
- 金额:$ 63.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-04 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdultAffectApneaAreaArousalAutomobile DrivingAutoreceptorsBindingBirthBrainBrain StemBreathingCell CountCellsCharacteristicsChildhoodChronicDataDevelopmentDiseaseDorsalEngineeringEnzymesEpidemiologyExhibitsExposure toFailureFunctional disorderGATA3 geneGenesHarvestHeterogeneityHumanHypoxiaImpairmentIn SituIn Situ HybridizationInfantInterruptionInvestigationLabelLinkLocationMethodsMolecularMorphologyMusNeonatalNeuronal PlasticityNeuronsNeurotransmittersNewborn AnimalsNewborn InfantPerinatalPhenotypePlayPopulationPregnancyProcessProspective StudiesRattusRecoveryReflex actionResolutionRespiratory CenterRiskRisk FactorsRodent ModelRoleSerotonergic SystemSerotoninShapesSignal TransductionStressStructureSudden infant death syndromeSystemTPH2TestingTissuesTranscriptbrain tissuecell typecohortcomparativedesigner receptors exclusively activated by designer drugsexperiencefunctional plasticitygestational hypoxiahindbrainhypoglossal nucleusimmunocytochemistryinsightmind controlmolecular phenotypemolecular subtypesneonatenerve supplyneuroadaptationnormoxianovelphenotypic biomarkerpostnatalpostneonatal mortalityprenatalprenatal exposureprenatal risk factorpreventive interventionpupraphe nucleirespiratoryresponsereuptakesingle-cell RNA sequencingsocial defeatstress managementstressortherapeutic targettranscription factortranscriptomics
项目摘要
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.
项目摘要:一个强大的自动复苏反射(AR)是至关重要的新生儿从出生存活。的
过渡到独立呼吸和适应呼吸中断,呼吸暂停,这是常见的,
新生儿和婴儿需要协调的心肺反应以恢复。5-羟色胺(5-
HT,血清素)和产生它的脑干中缝细胞,称为Pet 1神经元,组织和驱动
在新生动物和人类中成功的AR。不成功的AR被认为是导致
婴儿猝死综合征(SIDS),其中大脑5-HTergic系统的改变已被发现。
在约一半的人类SIDS病例中描述,包括不同形态的5-HT神经元数量增加
(更小,更简单,可能不成熟),自身受体5-HT 1A结合缺陷,以及5-HT 1A水平降低,
HT和色氨酸羟化酶2(TPH 2,5-HT的限速生物合成酶)。我们提出
在小鼠中揭示这种SIDS脑5-HTergic表型的各个方面是如何在产前发育的。我们
最近的两项研究结果为这种方法提供了信息。首先,中缝核中的Pet 1+神经元表达高水平的5-HT,
已经鉴定了一些身份基因(例如Ddc、Vmat 2、Gata 3、Pet 1),它们的大小较小,具有适度水平的
自身受体5-HT 1A显著表达很少或不表达TPH 2和5-HT。我们称这些新细胞为帕拉-5-
HTergic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-HT神经元。第二个是发现神经递质转换,一种非规范的形式,
神经元对压力的可塑性。最近的数据支持其在塑造5-HTergic中的作用
神经元系统,其中应激源可以驱动一些5-HT旁神经元产生5-HT作为适应性神经元。
反应初步结果表明帕拉-HT神经元密集地起源于菱形节(r)4,
选择性地支配呼吸和唤醒中心,妊娠期暴露于间歇性缺氧
导致出生后TPH 2+细胞数量增加,5-HT水平尚不确定。我们建议
帕拉-羟色胺神经元是一个可塑的群体,当受到产前刺激时,
缺氧可使新生儿产生5-HT,作为支持AR的代偿机制。我们假设
为了应对产前缺氧这一SIDS的主要危险因素,帕拉-HT神经元自适应地
转化产生5-HT以纠正阻碍AR的5-HT能信号传导失衡,
换句话说,转型不充分在小岛屿发展中国家发挥着关键作用。我们将通过暴露来测试这一点
小鼠间歇性缺氧或常氧在怀孕期间,表征细胞和分子表型
和查询神经递质转化(目标1);进一步,我们将确定急性激活的影响
或抑制这些小鼠中AR上的这些r4-帕拉-5-HT神经元(目的2),我们将检查表型
人SIDS和对照脑组织中的帕拉-5-HT神经元的标记物(目的3)。这部小说,功能上
定义,帕拉5-HT细胞类型和可塑性可能是高度相关的新生儿的生存能力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Susan M. Dymecki其他文献
Development of an in vitro electroporation assay in the mouse to manipulate gene expression in the lower rhombic lip
- DOI:
10.1016/j.ydbio.2010.05.299 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Rebecca L. Landsberg;Susan M. Dymecki;Patrick Holland - 通讯作者:
Patrick Holland
Susan M. Dymecki的其他文献
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{{ truncateString('Susan M. Dymecki', 18)}}的其他基金
Early life stress and differential effects on the molecular maturation of specific subtypes of brain serotonin neurons
早期生活压力和对大脑血清素神经元特定亚型分子成熟的不同影响
- 批准号:
10725411 - 财政年份:2023
- 资助金额:
$ 63.98万 - 项目类别:
State-dependent and branch-specific neurotransmitter usage in a serotonergic/glutamatergic neural circuit regulating adaptation to seasonal photoperiod
状态依赖性和分支特异性神经递质在血清素能/谷氨酸能神经回路中的使用调节对季节性光周期的适应
- 批准号:
10666427 - 财政年份:2022
- 资助金额:
$ 63.98万 - 项目类别:
State-dependent and branch-specific neurotransmitter usage in a serotonergic/glutamatergic neural circuit regulating adaptation to seasonal photoperiod
状态依赖性和分支特异性神经递质在血清素能/谷氨酸能神经回路中的使用调节对季节性光周期的适应
- 批准号:
10451908 - 财政年份:2022
- 资助金额:
$ 63.98万 - 项目类别:
Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?
副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险?
- 批准号:
10460532 - 财政年份:2020
- 资助金额:
$ 63.98万 - 项目类别:
Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?
副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险?
- 批准号:
10672925 - 财政年份:2020
- 资助金额:
$ 63.98万 - 项目类别:
Gene expression underlying serotonin axon regrowth in the adult mammalian brain
成年哺乳动物大脑中血清素轴突再生的基因表达
- 批准号:
9765426 - 财政年份:2018
- 资助金额:
$ 63.98万 - 项目类别:
Function-specific serotonergic neurons, discrete brain targets, and addiction
功能特异性血清素能神经元、离散大脑目标和成瘾
- 批准号:
8828655 - 财政年份:2014
- 资助金额:
$ 63.98万 - 项目类别:
Developmental gene networks of 5HT neurons in addiction, aggression, and anxiety
成瘾、攻击性和焦虑中 5HT 神经元的发育基因网络
- 批准号:
8836993 - 财政年份:2014
- 资助金额:
$ 63.98万 - 项目类别:
Developmental gene networks of 5HT neurons in addiction, aggression, and anxiety
成瘾、攻击性和焦虑中 5HT 神经元的发育基因网络
- 批准号:
8628623 - 财政年份:2014
- 资助金额:
$ 63.98万 - 项目类别:
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