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、自闭症和双相情感障碍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成熟度的变化引起的。在小鼠新皮质中，我们和其他人已经证明，出生后第二周是树突棘变得稳定的时期，突触的密度急剧增加，自发活动突然变得不同步。这也是大多数 Cajal-Retzius (CR) 细胞经历细胞死亡的时期，尽管我们最近表明一小部分细胞可以存活到成年。尽管 CR 细胞因其在皮质层压中的关键作用而闻名，但对其作为神经元的功能却知之甚少。事实上，考虑到 CR 神经元是自发活动的、同步放电的，并与锥体神经元的顶端树突形成突触，我们设想它们可能充当皮质网络活动的起搏器。具体来说，我们建议测试以下假设：出生后 CR 神经元可以触发新皮质的同步活动，并且那些存活到成年的神经元继续影响锥体神经元放电。先前的脑切片研究无法证明 CR 神经元和锥体神经元在功能上相连，可能是因为轴突和树突的完整性被破坏了。我们打算通过使用体内双光子 Ca2+ 成像和电生理学来记录完整大脑中的这些细胞类型，从而克服这一缺点。我们已经确定了 CR 神经元的特定启动子，它不仅使我们能够在第 1 层中特异性地可视化这些细胞，而且还能够使用病毒载体和 Cre-Lox 方法有条件地表达通道视紫红质。第一个目标是，我们将检查出生后早期和成年阶段 CR 神经元的形态和电生理特性，以确定成熟动物中存活的 CR 神经元是否与那些在早期发育过程中注定死亡的神经元不同。在第二个目标中，我们打算利用光遗传学来调节 CR 神经元群的放电，同时记录其在更深皮质层中的突触伙伴。目的是测试 CR 神经元是否可以影响锥体神经元的放电并有助于发育中的新皮质中同步网络活动的出现。这些实验将为未来探索CR神经元功能障碍导致神经精神疾病的机制奠定基础。