Postnatal Cajal-Retzius neurons as pacemakers of neocortical network activity

出生后 Cajal-Retzius 神经元作为新皮质网络活动的起搏器

• 批准号: 8641437
• 负责人: Carlos Portera-Cailliau
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641437
• 关键词: Adult; Apical; Apoptosis; Area; Autistic Disorder; Axon; Bipolar Disorder; Birth; Brain; Cajal-Retzius cells; Cell Death; Cells; Cerebral cortex; Cognition; Communication; Cre-LoxP; Creativeness; Defect; Dendrites; Dendritic Spines; Development; Disease; Electrophysiology (science); Emotions; Epilepsy; Exhibits; Fire - disasters; Foundations; Functional disorder; Future; Glycoproteins; Goals; Human; Image; Imagery; In Vitro; Interneurons; Label; Learning; Light; Memory; Methodology; Morphology; Mus; Neocortex; Neurons; Pacemakers; Play; Process; Property; Rhodopsin; Role; Schizophrenia; Slice; Staging; Synapses; Technology; Testing; Time; Viral Vector; Work; age group; brain cell; cell type; cohort; critical period; density; design; hippocampal pyramidal neuron; in vivo; mature animal; migration; neocortical; neuropsychiatry; optogenetics; postnatal; promoter; public health relevance; research study; two-photon

DESCRIPTION (provided by applicant): Neuropsychiatric disorders like schizophrenia, autism and bipolar disorder may be caused by changes in the maturation of connections between brain cells of the cerebral cortex during development. In mouse neocortex, we and others have shown that the 2nd postnatal week is a time when dendritic spines become stabilized, the density of synapses increases dramatically, and spontaneous activity becomes abruptly desynchronized. This is also a period when most Cajal-Retzius (CR) cells undergo cell death, although we recently showed that a small subset survives into adulthood. Although CR cells are well-known for their critical role in cortical lamination much less is known about their function as neurons. Indeed, considering that CR neurons are spontaneously active, fire synchronously, and make synapses with apical dendrites of pyramidal neurons, we envision that they might function as pacemakers of cortical network activity. Specifically, we propose to test the hypothesis that postnatal CR neurons can trigger synchronous activity in neocortex and that those that survive into adulthood continue to influence pyramidal neuron firing. Previous work in brain slices has been unable to demonstrate that CR neurons and pyramidal neurons are functionally connected probably because the integrity of axons and dendrites was disrupted. We intend to overcome this shortcoming by using in vivo two-photon Ca2+ imaging and electrophysiology to record from these cell types in the intact brain. We have identified a specific promoter for CR neurons that will allow us not only to specifically visualize these cells in Layer 1 but also to conditionaly express channel-rhodopsin using viral vectors and a Cre-Lox approach. In the first aim, we will examine morphological and electrophysiological properties of CR neurons at early postnatal vs. adult stages to determine whether surviving CR neurons in mature animals are distinct from those that are destined to die during early development. In the second aim, we intend to modulate the firing of cohorts of CR neurons with optogenetics while recording from their synaptic partners in deeper cortical layers. The goal is to test whether CR neurons can influence the firing of pyramidal neurons and contribute to the emergence of synchronous network activity in the developing neocortex. These experiments will lay the foundation for future studies exploring the mechanisms by which dysfunction of CR neurons could cause neuropsychiatric diseases.

描述（由申请人提供）：精神分裂症，自闭症和躁郁症等神经精神疾病可能是由于发育过程中大脑皮层脑细胞之间连接的成熟而导致的。在小鼠新皮层中，我们和其他人表明，第二周是树突状棘的稳定，突触的密度急剧增加，并且自发活性突然变得更同步。这也是大多数Cajal-Retzius（Cr）细胞发生细胞死亡的时期，尽管我们最近表明一个小子集生存到成年。尽管CR细胞以其在皮质层压中的关键作用而闻名，但对它们的神经元功能的了解却少得多。确实，考虑到CR神经元具有自发活性，同步发射，并与金字塔神经元的顶端树突制成突触，我们设想它们可能是皮质网络活动的起搏器。具体而言，我们建议检验以下假设：产后CR神经元可以触发新皮层中的同步活动，而生存到成年的人则继续影响金字塔神经元的射击。以前在脑切片中的工作无法证明CR神经元和锥体神经元在功能上连接，这可能是因为轴突和树突的完整性破坏了。我们打算通过使用体内两光子Ca2+成像和电生理学来克服这一缺点，以记录完整大脑中这些细胞类型的情况。我们已经确定了CR神经元的特定启动子，该启动子不仅可以使我们在第1层中专门可视化这些细胞，而且还可以使用病毒载体和CRE-LOX方法来表达cyseedaly表达通道 - 偶像蛋白。在第一个目的中，我们将检查早期和成人阶段的CR神经元的形态和电生理特性，以确定成熟动物中幸存的CR神经元是否与注定要在早期发育期间死亡的动物不同。在第二个目的中，我们打算调节具有光遗传学的CR神经元的发射，同时在其深层皮质层中记录其突触伴侣的射击。目的是测试CR神经元是否可以影响锥体神经元的发射，并有助于发育中的新皮层中同步网络活动的出现。这些实验将为将来的研究奠定基础，以探讨CR神经元功能障碍可能引起神经精神疾病的机制。