Morphogenesis and Function of the Cerebral Cortex

大脑皮层的形态发生和功能

• 批准号: 8044720
• 负责人: FLORA M VACCARINO
• 金额: $ 40.96万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044720
• 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; Health; 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; 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）和相连区域的神经元活动水平异常被认为是严重神经精神综合征症状的基础，包括精神分裂症、自闭症、抽动秽语综合征和药物滥用障碍。我们研究计划的长期目标是了解兴奋性和抑制性皮层神经元的相对比例在出生前和出生后的发育过程中是如何调节的。我们以前的研究表明，成纤维细胞生长因子（Fgf）信号上调兴奋性皮层神经元的数量，导致额前区和颞叶区的体积扩张。飞行员的数据表明，成纤维细胞生长因子受体2（Fgfr 2）在胚胎发育过程中的SVZ，这反过来又与锥体神经元的发生在PFC中的“中间”祖细胞的数量增加。相反，成纤维细胞生长因子受体1（Fgfr 1）是不参与产前皮质发育，但可能会增加皮质小白蛋白+和生长抑素+抑制性中间神经元的分化或生存的行动在出生后的胶质细胞。在这种竞争性的延续建议，我们假设，Fgfr 2信号在胚胎发生扩大表面积的PFC刺激生产的中间祖细胞的SVZ从放射状胶质细胞。这将在特定目标1中通过追踪在产前发育的特定阶段诱导的具有Fgfr 2等位基因缺失的放射状神经胶质细胞的后代来进行测试。此外，将在缺乏Fgfr 2的小鼠与具有Fgfr 1、Fgf 2和Fgf 3的组合缺失的小鼠之间比较一般皮质形态发生。还将通过电穿孔由特定放射状神经胶质启动子驱动的显性负性和显性活性Fgf受体来评估Fgf受体刺激和阻断对鉴定的放射状神经胶质细胞的影响。在具体目标2和3中，我们将评估胶质细胞中的FGF信号传导是否间接促进表达小清蛋白（PV）和生长抑素（ST）的皮质抑制性神经元的存活或功能成熟，以及这种作用的发育时间窗。在目标2中，我们将GFP+野生型中间神经元移植到Fgfr 1突变小鼠的出生后皮质中，以确定Fgfr 1突变皮质是否不太允许中间神经元成熟。我们还将评估内在的放电特性和突触整合到Fgfr 1突变小鼠的移植和内源性中间神经元的皮质网络中。在具体目标3中，我们将通过病毒诱导或在出生前或出生后发育阶段暂时调节Fgfr 1的重组，特异性地在GFAP+细胞中抑制Fgfr 1，并检查中间神经元的成熟和存活。总之，这些实验将阐明特定的FGF受体如何在生命的不同时期发挥特定的作用。前额叶皮层发育异常被认为是精神分裂症、自闭症、注意力缺陷多动和吸毒成瘾的基础。该提案调查了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发生来建立大脑皮质的初级结构。该项目还关注神经胶质细胞在大脑皮层出生后发育过程中抑制性中间神经元成熟中的作用。这两个方面都可能提供有希望的线索，以纠正或逆转存在于神经精神和冲动控制障碍的大脑皮层中的兴奋性和抑制性神经元失衡。