The Role of Cajal-Retzius Neurons in Postnatal Cortical Circuit Assembly

Cajal-Retzius 神经元在产后皮质回路组装中的作用

• 批准号: 8105527
• 负责人: Carlos Portera-Cailliau
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105527
• 关键词: Ablation; Address; Adult; Affect; Allatostatin; Apical; Apoptosis; Area; Autistic Disorder; Axon; Bipolar Disorder; Brain; Cajal-Retzius cells; Calcium; Cell Death; Cells; Chemical Synapse; Cognition; Creativeness; Data; Defect; Dendrites; Dendritic Spines; Development; Diphtheria Toxin; Disease; Electrical Synapse; Electrophysiology (science); Emotional Disturbance; Emotions; Ensure; Epilepsy; Excision; Filopodia; Fire - disasters; Green Fluorescent Proteins; Growth; Image; Impairment; Individual; Knowledge; Lasers; Lead; Learning; Length; Memory; Mental Retardation; Microscopy; Morphogenesis; Mus; Neocortex; Neurons; Photons; Play; Property; Pyramidal Cells; Role; Schizophrenia; Structure; Synapses; Techniques; Technology; Testing; Time; Transfection; Transgenic Mice; Vertebral column; Viral; Work; calcium indicator; cell motility; density; design; hippocampal pyramidal neuron; improved; in vivo; innovation; killings; migration; neocortical; neuropsychiatry; novel; postnatal; promoter; recombinase; research study; synaptogenesis; two-photon

DESCRIPTION (provided by applicant): To better understand the mechanisms of intellectual impairment and emotional disturbances in individuals with schizophrenia, bipolar disorder, mental retardation or autism, it is essential to first study how cortical circuits are assembled during normal brain development. Cajal-Retzius (CR) neurons have long been implicated in cortical development and are thought to play a role in several of these disorders. The best documented function of CR neurons is in orchestrating neuronal migration and cortical lamination. This is achieved through their secretion of reelin, though other reelin-producing cells in the cortex could also play a role. Interestingly, CR neurons show spontaneous correlated activity in the postnatal neocortex and are known to make both chemical and electrical synapses with apical dendritic spines of developing pyramidal neurons. Therefore, it is conceivable that CR neurons could play a role in synaptogenesis by pyramidal neuron dendrites and in the emergence of spontaneous oscillations in cortical neurons. We want to test this hypothesis using in vivo 2-photon imaging of the structure and function of immature cortical circuits. Specifically, we will image CR and pyramidal neurons expressing the green fluorescent protein (GFP) in different lines of transgenic mice, as well as cortical neurons loaded with fluorescent calcium indicators to detect neuronal firing. We have identified a line of transgenic mice (Ebf2-GFP) in which GFP is expressed in virtually all CR neurons. In addition, we obtained a line of mice (Ebf2:GFPiCre) that expresses the Cre recombinase in the same cells. Using state-of- the-art 2-photon microscopy, we intend to selectively kill CR neurons, or genetically silence their activity using optogenetics and Cre-Lox technologies, and then examine the repercussions of such targeted perturbations of CR neurons on neocortical development. We will investigate whether CR ablation/silencing affects the maturation of apical dendrites and spines of pyramidal neurons and/or the spontaneous activity of networks of pyramidal neurons. These studies address fundamental questions about cortical development. The experiments are designed to fill knowledge gaps about CR neurons and identify novel roles for these cells in cortical circuit assembly. These data should resolve longstanding controversies about their function that arose from methodological shortcomings of prior studies. Our work will also generate new ideas about how subtle defects in cortical circuits might contribute to several neuropsychiatric disorders and thereby help to find improved treatments for these devastating diseases. PUBLIC HEALTH RELEVANCE: The proposed studies will investigate how brain circuits are assembled during development in areas important for emotion, cognition and creativity, as well as for learning and memory. The experiments are designed to generate new ideas about how subtle alterations in brain wiring could result in devastating neuropsychiatric disorders such as schizophrenia, autism, mental retardation or bipolar disorder.

描述（由申请人提供）：为了更好地了解精神分裂症，躁郁症，智力低下或自闭症患者的智力障碍和情绪障碍的机制，首先研究如何在正常大脑发育过程中如何组装皮质回路是至关重要的。 Cajal-Retzius（CR）神经元长期以来一直与皮质发育有关，并被认为在其中几种疾病中起作用。 CR神经元的最佳记录功能是在精心策划神经元迁移和皮质层压层。这是通过对reelin的分泌来实现的，尽管皮质中的其他产生的细胞也可以发挥作用。有趣的是，CR神经元在产后新皮层中显示出自发的相关活性，并且已知可以与发展中的锥体神经元的顶端树突状刺一起化学和电突触。因此，可以想象CR神经元可以在锥体神经元树突和皮质神经元中自发振荡的出现中发挥作用。我们希望使用未成熟皮质回路的结构和功能的体内2光子成像检验这一假设。具体而言，我们将在不同的转基因小鼠中表达表达绿色荧光蛋白（GFP）的CR和锥体神经元，以及带有荧光钙指示剂的皮质神经元，以检测神经元触发。我们已经确定了一系列的转基因小鼠（EBF2-GFP），其中GFP几乎在所有CR神经元中表达。此外，我们获得了一系列小鼠（EBF2：GFPICRE），该系列在同一细胞中表达CRE重组酶。使用最先进的2光子显微镜，我们打算选择性地杀死CR神经元，或使用光遗传学和CRE-LOX技术从遗传上沉默它们的活性，然后检查CR神经元对新皮质发展的靶向扰动的影响。我们将研究CR消融/沉默是否影响锥体神经元的顶端树突和刺和/或锥体神经元网络的自发活性的成熟。这些研究涉及有关皮质发展的基本问题。该实验旨在填补有关CR神经元的知识空白，并确定这些细胞在皮质电路组装中的新作用。这些数据应解决有关其功能的长期争议，这是从先前研究的方法论缺点引起的。我们的工作还将产生有关皮质回路中微妙的缺陷如何有助于几种神经精神疾病的新想法，从而有助于为这些毁灭性疾病找到改进的治疗方法。 公共卫生相关性：拟议的研究将调查如何在对情感，认知和创造力以及学习和记忆力的重要领域开发过程中如何组装脑电路。该实验旨在产生有关大脑接线的微妙变化如何导致神经精神疾病（例如精神分裂症，自闭症，心理障碍或双相情感障碍）的新想法。