Piriform cortex: sequential developmental events

梨状皮层：顺序发育事件

• 批准号: 10442245
• 负责人: Charles A Greer
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442245
• 关键词: Address; Adult; Afferent Neurons; Anterior; Architecture; Attention; Axon; Brain; Cells; Cilia; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complex; Contralateral; Data; Development; Didelphidae; Electroporation; Epithelial; Event; FOXP2 gene; Foundations; Ganglia; Genetic; Goals; Interneurons; Ipsilateral; Knock-out; Knowledge; Lateral; Lens development; Ligand Binding; Maps; Methods; Molecular; Molecular Genetics; Mus; Neocortex; Neuroglia; Neurons; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory Pathways; Olfactory tract; Play; Property; Radial; Rattus; Recurrence; Resolution; Role; SOX5 gene; Seminal; Smell Perception; Specificity; Structure; Study models; Surface; Synapses; Testing; TimeLine; Work; anterior commissure; association cortex; connectome; course development; exhaustion; hippocampal pyramidal neuron; in utero; innovation; insight; migration; neocortical; nerve supply; neural circuit; neuroblast; neurogenesis; novel; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; piriform cortex; receptor; segregation; sensory system; spatiotemporal; tool; transcription factor

Project Summary – Abstract The perception of odors begins in the olfactory epithelium when odorant ligands bind to molecular receptors expressed on the cilia of the olfactory sensory neurons, each of which expresses only 1 of ~1200 candidate receptors. As the sensory neuron axons exit the epithelium they progress over the surface of the olfactory bulb and all of the axons coming from neurons expressing the same odorant receptor converge into only 2/3 glomeruli/olfactory bulb. However, the convergence and discrete circuitry of the olfactory bulb is not apparent in piriform cortex (PCX), at least grossly. Afferent projections to piriform appear divergent and broadly distributed. Moreover, in contrast to the more widely studied neocortex, the 3-layer piriform paleocortex does not exhibit a definitive columnar structure, leaving open the question of whether principles learned from neocortex can be applied to understanding piriform. Most of what we know of the neuronal and synaptic organization of piriform has come from early studies of rat and opossum, that while important did not benefit from contemporary genetic and molecular tools. The mouse, which has emerged as the dominant mammalian model for studies of the olfactory epithelium and bulb, has benefited immeasurably from these new tools. However, there are few examples of the application of contemporary genetic and molecular methods to studies of mouse piriform cortex. We remain woefully ignorant of the most fundamental features of mouse piriform cortex When do synapses first appear in mouse PCX and when do they achieve laminar segregation? What is the organization of the ipsi- and contralateral association axons that likely contribute to the cortical coding of odors in ensembles of neurons? What are the molecular mechanisms/transcription factors underlying the fate and specificity of PCX neurons/structure? To begin addressing these significant gaps in our knowledge we are proposing 3 specific aims: Aim 1 addresses the emergence of synaptic circuits in PCX and tests the hypothesis that it occurs in a spatio-temporal format that distinguishes the laminar specificity of circuits. Aim 2 addresses the PCX associational connectome, both ipsilateral and contralateral via the anterior commissure. Aim 3 tests the spatiotemporal expression of transcription factors (TFs) that we hypothesize are important in establishing PCX pyramidal neuron identity and contributions to the association axon network in PCX. Selective TFs will be knocked out using CRISPR to determine their role at a more granular level. Collectively these innovative studies will provide new insight into the mechanisms regulating the organization of PCX and the foundations of odor coding in PCX.

项目摘要-摘要 当气味配体结合到分子上时，气味的感知开始于嗅上皮。 在嗅觉感觉神经元的纤毛上表达的受体，每个受体仅表达约1200个中的1个。 候选受体当感觉神经元轴突离开上皮时，它们在细胞表面上前进。 嗅球和所有来自神经元的轴突表达相同的气味受体 仅会聚成2/3肾小球/嗅球。然而，收敛和离散电路的 嗅球在梨状皮质（PCX）中不明显，至少大体上不明显。梨状传入投射 呈发散状分布广泛。此外，与更广泛研究的新皮层相反， 3-梨状古皮质层没有表现出明确的柱状结构，留下了开放的问题， 从新皮层学到的原理是否可以应用于理解梨状核。的大部分发明 对梨状核的神经元和突触组织的了解来自于对大鼠和负鼠的早期研究， 虽然很重要，但没有从当代遗传和分子工具中受益。老鼠， 已经成为研究嗅上皮和嗅球的主要哺乳动物模型， 从这些新工具中受益匪浅。然而，很少有应用 现代遗传学和分子生物学方法对小鼠梨状皮质的研究。我们仍然可悲地 不了解小鼠梨状皮质最基本的特征， 小鼠PCX和它们何时实现分层分离？什么是IPSI的组织-和 对侧关联轴突，可能有助于皮质编码的气味在合奏 神经元？什么是潜在的命运和特异性的分子机制/转录因子 PCX神经元/结构？为了开始解决我们知识中的这些重大差距，我们提出3 具体目标：目标1解决了PCX中突触回路的出现，并测试了以下假设： 它以区分电路的层特异性的时空格式发生。目标2地址 PCX联合连接体，同侧和对侧均通过前连合。目标3 测试转录因子（TF）的时空表达，我们假设这些转录因子在 建立PCX锥体神经元身份以及对PCX中联合轴突网络的贡献。 将使用CRISPR敲除选择性TF，以在更细粒度的水平上确定它们的作用。 总的来说，这些创新的研究将为调节细胞凋亡的机制提供新的见解。 PCX的组织和PCX气味编码的基础。