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）：在大约50％的早产儿童中，发现了不集中，多动症，自闭症，情绪障碍，社交能力，癫痫和智力较低的能力。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播之间的不平衡。早产和相关并发症---缺氧，低血压和败血症 - can会影响GABA能中间神经元的产生并破坏神经元电路。因此，我们询问中间神经元如何在怀孕的下半年发展，以及早产如何破坏其产生，密度和分布。回答这些问题将决定早产儿童认知和行为障碍的基础。释放GABA的神经元构成了皮质抑制神经元的主要种群，并根据其产生的神经肽进行了分类。它们在人类和仅在啮齿动物中的GE中都产生到背侧室内室（SVZ）和腹侧SVZ（神经节杰出，GE）中。它们的形成受转录因子的调节，包括NKX2.1，DLX1/2，LHX6和MASH1。早产会影响中间神经元的发展。这是因为氧气水平调节了神经发生，早产会剥夺婴儿的宫内宫内环境以及胎盘激素和孕妇营养素。尽管如此，在怀孕的下半年尚未研究中间神经元的发展，也没有关于过早出生如何影响中间神经元的信息。因此，我们假设a）a）中间神经元及其前体在妊娠时代的密度，增殖和分布发生明显的发育变化，而b）早产会破坏其产生和分布。我们的方法是a）使用人体组织在妊娠晚期研究中间神经元的发育，b）使用人类样本和兔模型来评估早产对GABA能神经发生的影响。人类的研究是必须的，因为人类皮质比动物独特，更复杂。 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在人类胎儿和早产儿（20-40周）的背面SVZ和GE中。 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)相对于短期生存（26周妊娠 + <3d Old = 26周） - 同等的后年龄（妊娠年龄 +妊娠年龄 +产后年龄）b）B）兔模型：比较早产（E29，3 d off）和术语（E32，<2 H Old）的幼体年龄的同等年龄的幼体，用于人类作为人类参数的同等年龄。