Morphogenesis and Function of the Cerebral Cortex

大脑皮层的形态发生和功能

• 批准号: 7665609
• 负责人: FLORA M VACCARINO
• 金额: $ 39.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665609
• 关键词: Adolescence; Age; Alleles; Area; Astrocytes; Attention; Autistic Disorder; Birth; Cell Death; Cell Maturation; Cells; Cerebral cortex; Data; Development; Disease; Dominant-Negative Mutation; Drug Addiction; Electroporation; Embryo; Embryonic Development; Equilibrium; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Generations; Genes; Genetic Recombination; Gilles de la Tourette syndrome; Glial Fibrillary Acidic Protein; Goals; Growth Factor; Hyperactive behavior; Impulse Control Disorders; Interneurons; Knock-out; Knockout Mice; Lead; Lentivirus Vector; Life; Location; Measures; Medial; Morphogenesis; Mus; Mutant Strains Mice; Neocortex; Neuroglia; Neurons; Parvalbumins; Phenotype; Play; Potassium Channel; Prefrontal Cortex; Production; Property; Prosencephalon; Radial; Relative (related person); Reporter; Research; Role; Schizophrenia; Signal Transduction; Somatostatin; Specific qualifier value; Staging; Stem cells; Structure; Substance abuse problem; Surface; Symptoms; Synapses; Syndrome; Tamoxifen; Techniques; Testing; Time; Tissues; Transgenic Mice; Transplantation; Varicosity; Ventricular; Virus; Work; autism spectrum disorder; cell type; critical period; density; excitatory neuron; frontal lobe; hippocampal pyramidal neuron; in vivo; inhibitory neuron; interdisciplinary approach; morphometry; mouse model; mutant; nestin protein; neural circuit; neuroepithelium; neurogenesis; neuron development; neuropsychiatry; postnatal; prenatal; progenitor; programs; promoter; public health relevance; receptor; research study; response; stem; subventricular zone

DESCRIPTION (provided by applicant): Abnormal level of neuronal activity in the prefrontal cortex (PFC) and connected regions is thought to underlie the symptoms of serious neuropsychiatric syndromes, including schizophrenia, autism, Tourette's syndrome and substance abuse disorders. The long- term goal of our research program is to understand how the relative proportions of excitatory and inhibitory cortical neurons are regulated during pre- and post-natal development. Our previous studies have shown that Fibroblast Growth Factor (Fgf) signaling upregulates excitatory cortical neuron number, leading to volume expansion in prefrontal and temporal regions. Pilot data suggest that Fgf receptor 2 (Fgfr2) during embryogenesis increases the number of "intermediate" progenitors in the SVZ, which in turn is associated with pyramidal neuron genesis in PFC. In contrast, Fgf receptor1 (Fgfr1) is not involved in prenatal cortical development, but may increase the differentiation or survival of cortical parvalbumin+ and somatostatin+ inhibitory interneurons by an action in postnatal glial cells. In this competing continuation proposal, we hypothesize that Fgfr2 signaling in embryogenesis expands the surface area of PFC by stimulating the production of intermediate progenitors in the SVZ from radial glial cells. This will be tested in Specific Aim 1 by tracing the progeny of radial glial cells harboring a deletion of Fgfr2 alleles induced at specific stages of prenatal development. Also, general cortical morphogenesis will be compared amongst mice lacking Fgfr2 versus mice with a combined deletion of Fgfr1, Fgf2 and Fgf3. The effect of Fgf receptor stimulation and blockade upon identified radial glial cells will be also assessed by electroporating dominant negative and dominant active Fgf receptors driven by a specific radial glial promoter. In specific aim 2 and 3, we will assess whether Fgf signaling in glial cells indirectly promotes the survival or functional maturation of cortical inhibitory neurons expressing Parvalbumin (PV) and Somatostatin (ST) and the developmental time window for this action. In Aim 2, we will transplant GFP+ wild type interneurons into the postnatal cortex of Fgfr1 mutant mice to determine whether the Fgfr1 mutant cortex is less permissive for interneuron maturation. We will also assess intrinsic firing properties and synaptic integration into the cortical network of the transplanted and endogenous interneurons in Fgfr1 mutant mice. In specific aim 3, we will specifically inactivate Fgfr1 in GFAP+ cells by virus-induced or temporally regulated recombination of Fgfr1 at either prenatal or postnatal stages of development, and examine interneuron maturation and survival. Together, the experiments will elucidate how specific Fgf receptors may play specific roles in different epochs of life. PUBLIC HEALTH RELEVANCE Abnormalities in the development of the prefrontal cortex are thought to underlie the symptoms of schizophrenia, autism, attention deficit hyperactivity and drug addiction. This proposal investigates how growth factors of the FGF family establish the primary structure of the cerebral cortex by controlling the genesis of cortical projection neurons from SVZ precursors. The project also focuses on the role of glia in the maturation of inhibitory interneurons during postnatal development of the cerebral cortex. Both aspects may offer promising leads to correct or reverse the excitatory and inhibitory neuron imbalances that are present in the cerebral cortex of neuropsychiatric and impulse control disorders.

描述（由申请人提供）：前额叶皮层（PFC）和连接区域中神经元活性的异常水平被认为是严重神经精神综合症的症状，包括精神分裂症，自闭症，Tourette，Tourette的综合征和药物滥用失调。我们研究计划的长期目标是了解兴奋性和抑制性皮质神经元的相对比例如何在产前和产后发育过程中调节。我们先前的研究表明，成纤维细胞生长因子（FGF）信号传导上调兴奋性皮质神经元数，从而导致前额叶和颞区域的体积膨胀。试验数据表明，胚胎发生过程中FGF受体2（FGFR2）增加了SVZ中“中间”祖细胞的数量，而SVZ中的“中间”祖细胞的数量与PFC中的金字塔神经元起源有关。相反，FGF受体1（FGFR1）不参与产前皮质发育，但可能会增加皮质白细胞蛋白蛋白+和生长抑素+抑制性神经元的分化或存活，并通过生成后胶质细胞的作用。在这个竞争性的延续建议中，我们假设胚胎发生中的FGFR2信号传导通过刺激从径向神经胶质细胞中刺激SVZ中的中间祖细胞的产生来扩大PFC的表面积。这将在特定的目标1中进行测试，通过追踪具有在产前发育的特定阶段诱导的FGFR2等位基因缺失的径向神经胶质细胞的后代。同样，在缺乏FGFR2的小鼠中，将比较一般的皮质形态发生，而FGFR1，FGF2和FGF3的综合缺失。 FGF受体刺激和阻断对识别的径向神经胶质细胞的影响也将通过电穿孔负极和显性活性FGF受体进行评估，该受体由特定的radial胶质神经胶质启动子驱动。在特定的目标2和3中，我们将评估神经胶质细胞中的FGF信号传导间接促进表达白蛋白（PV）的皮质抑制神经元的生存或功能成熟，以及Somatostatin（ST）以及此动作的发育时间窗口。在AIM 2中，我们将将GFP+野生型中间神经元移植到FGFR1突变小鼠的产后皮层中，以确定FGFR1突变体皮层是否不太允许间神经元成熟。我们还将评估内在的触发特性和突触整合到FGFR1突变小鼠中移植和内源性中间神经元的皮质网络中。在特定的目标3中，我们将通过病毒诱导的或在发育产后或产后的时间调节的FGFR1重组GFAP+细胞中的FGFR1在GFAP+细胞中灭活。总之，实验将阐明特定的FGF受体如何在不同时期的不同时期发挥特定作用。公共卫生相关性异常在前额叶皮层的发展中被认为是精神分裂症，自闭症，注意力缺陷多动和药物成瘾的症状的基础。该提案研究了FGF家族的生长因子如何通过控制SVZ前体的皮质投射神经元的起源来建立大脑皮层的主要结构。该项目还侧重于神经胶质在大脑皮层产后发育过程中抑制性中间神经元成熟的作用。这两个方面都可以提供有前途的潜在客户，可以纠正或扭转神经精神病和冲动控制障碍的大脑皮层中存在的兴奋性和抑制性神经元失衡。