GABAergic neurogenesis in humans and the effect of prematurity

人类 GABA 能神经发生和早产的影响

基本信息

批准号：
8769736
负责人：
PRAVEEN BALLABH
金额：
$ 24.15万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769736
关键词：
Affect Age Animals Anxiety Disorders Area Autistic Disorder Behavior Disorders Behavioral Biochemical Markers Brain Cerebral cortex Child Cognition Disorders Cognitive Complex Data Development Diagnosis Disease Dorsal Emotional Disturbance Environment Epilepsy Equilibrium Exhibits Fetus Gene Expression Generations Gestational Age Glutamates Growth Human Hyperactive behavior Hypotension Hypoxia Infant Intelligence Interneurons Learning Location Memory Mental disorders Modeling Molecular Genetics Morphology Motor Activity Neonatal Intensive Care Neurons Neuropeptides Nutrient Oryctolagus cuniculus Oxygen Parvalbumins Perception Placental Hormones Play Population Pregnancy Premature Birth Premature Infant Process Pyramidal Cells Rodent Role Sampling Sensory Sepsis Signal Transduction Somatostatin Staging Synapses Time Vasoactive Intestinal Peptide base calretinin density executive function gamma-Aminobutyric Acid hippocampal pyramidal neuron human tissue inattention inhibitory neuron insight neocortical nervous system disorder neurogenesis neuronal circuitry novel postnatal premature progenitor public health relevance pup research study social social skills subventricular zone transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Inattention, hyperactivity, autism, emotional disturbance, social incompetence, epilepsy, and lower intellectual abilities are found in about 50% of preterm-born children. These disorders are attributed to an imbalance between inhibitory GABAergic and excitatory glutamatergic transmission in neuronal circuits. Premature birth and associated complications---hypoxia, hypotension, and sepsis--can affect the generation of GABAergic interneurons and disrupt neuronal circuitry. Therefore, we ask how interneurons develop in the second half of pregnancy, and how prematurity disrupts their generation, density, and distribution. Answering these questions will determine the bases of cognitive and behavioral disorders in preterm-born children. Interneurons releasing GABA constitute the major population of cortical inhibitory neurons and are classified based on the neuropeptides they produce. They are generated into both dorsal subventricular zone (SVZ) and ventral SVZ (ganglionic eminence, GE) in humans and only in GE in rodents. Their formation is regulated by transcription factors including, Nkx2.1, Dlx1/2, Lhx6, and Mash1. Prematurity can impact the development of interneurons. This is because oxygen level regulates neurogenesis and preterm birth deprives the infants of the hypoxic intrauterine environment along with the placental hormones and maternal nutrients. Despite this, the development of interneurons has not been studied in the second half of pregnancy and there is no information on how premature birth affects interneurons. Therefore, we hypothesize that a) interneurons and their precursors undergo distinct developmental changes in their density, proliferation, and distribution with advance in gestational age and that b) prematurity disrupts their generation and distribution. Our approach is to a) use human tissues for studying interneuron development in late pregnancy and b) employ both human samples and a rabbit model to assess the effect of prematurity on GABAergic neurogenesis. Human studies are imperative as the human cortex is unique and more complex than animals. Aim #1: Generation of late-born interneurons (20-40 weeks): Evaluate a) the proliferation and density of subtypes of interneurons-GABA+, parvalbumin+, calretinin+, somatostatin+-and their precursors-Nkx2.1+, Dlx1/2+, Mash1+, and b) gene expression of transcription factors regulating GABAergic neurogenesis, Nkx2.1, Dlx1/2, Lhx6, Mash1, in the dorsal SVZ and GE of human fetuses & preterm infants (20-40 weeks). Aim #2: Effect of prematurity on GABAergic neurogenesis: A) HUMAN: Compare the density and proliferation of a) subtypes of interneurons, and b) their progenitors (Dlx1/2+, Nkx2.1+, and Mash1+) in the GE and dorsal SVZ between two sets of premature infants- long postnatal survival (24 week gestational age + 2 week old=26 weeks) vs. short postnatal survival (26 wk gestation + <3d old=26 weeks)--of equivalent postmenstrual age (gestational age + postnatal age) B) RABBIT model: To compare preterm (E29, 3 d old) and term (E32,<2 h old) pups of an equivalent postmenstrual age for parameters as in human experiments.

描述（由申请人提供）：约 50% 的早产儿存在注意力不集中、多动、自闭症、情绪障碍、社交能力低下、癫痫和智力低下等问题。这些疾病归因于神经元回路中抑制性 GABA 能和兴奋性谷氨酸能传递之间的不平衡。早产和相关并发症——缺氧、低血压和败血症——会影响 GABA 能中间神经元的生成并破坏神经元回路。因此，我们想知道中间神经元在妊娠后半期如何发育，以及早产如何扰乱它们的生成、密度和分布。回答这些问题将确定早产儿认知和行为障碍的基础。释放 GABA 的中间神经元构成了皮质抑制神经元的主要群体，并根据它们产生的神经肽进行分类。它们在人类中产生于背侧室下区 (SVZ) 和腹侧 SVZ（神经节隆起，GE），仅在啮齿类动物中产生于 GE。它们的形成受转录因子调节，包括 Nkx2.1、Dlx1/2、Lhx6 和 Mash1。早产会影响中间神经元的发育。这是因为氧气水平调节神经发生，早产剥夺了婴儿的缺氧宫内环境以及胎盘激素和母体营养。尽管如此，妊娠后半期中间神经元的发育尚未得到研究，也没有关于早产如何影响中间神经元的信息。因此，我们假设：a) 中间神经元及其前体随着胎龄的增长，在密度、增殖和分布方面经历明显的发育变化；b) 早产会破坏它们的生成和分布。我们的方法是 a) 使用人体组织研究妊娠晚期的中间神经元发育，b) 使用人体样本和兔子模型来评估早产对 GABA 能神经发生的影响。人类研究势在必行，因为人类皮质比动物更独特且更复杂。目标#1：晚生中间神经元的产生（20-40 周）：评估 a) 中间神经元亚型（GABA+、小清蛋白+、钙视网膜素+、生长抑素+）及其前体 -Nkx2.1+、Dlx1/2+ 的增殖和密度、Mash1+ 和 b) 调节 GABA 能神经发生的转录因子的基因表达、Nkx2.1、 Dlx1/2、Lhx6、Mash1，位于人类胎儿和早产儿（20-40 周）的背侧 SVZ 和 GE。目标 #2：早产对 GABA 能神经发生的影响：A) 人类：比较 GE 和 GABA 中 a) 中间神经元亚型和 b) 祖细胞（Dlx1/2+、Nkx2.1+ 和 Mash1+）的密度和增殖两组早产儿之间的背侧 SVZ - 长产后生存（24 周胎龄 + 2 周龄 = 26 周）与短出生后生存产后存活率（妊娠 26 周 + <3 日龄 = 26 周）--相当于经后年龄（胎龄 + 产后年龄） B) 兔模型：比较早产儿（E29，3 日龄）和足月儿（E32，<2 小时）老）幼犬的参数与人体实验中的经后年龄相当。