Spatiotemporal Dynamics of Noradrenergic Signaling in the Neocortex

新皮质去甲肾上腺素能信号传导的时空动态

• 批准号: 10537371
• 负责人: Clayton Barnes
• 金额: $ 4.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537371
• 关键词: Adaptive Behaviors; Adrenergic Agents; Adrenergic Receptor; Affinity; Agonist; Animals; Anxiety; Area; Arousal; Attention deficit hyperactivity disorder; Behavioral; Brain; Brain region; Cells; Cognition; Cognitive; Communication; Coupled; Coupling; Data; Disease; Dorsal; Electronic Medical Records and Genomics Network; Electrophysiology (science); Exhibits; Functional disorder; Goals; Health; Image; Individual; Infusion procedures; Kinetics; Mediating; Mental Depression; Mental disorders; Methodology; Neocortex; Neurodegenerative Disorders; Neuromodulator; Neurons; Norepinephrine; Pattern; Pharmacology; Photons; Play; Population; Post-Traumatic Stress Disorders; Property; Regulation; Resolution; Resources; Role; Sensory; Shapes; Signal Transduction; Silicon; Sleep Wake Cycle; Somatosensory Cortex; Source; Specificity; Stimulus; Structure; System; Techniques; Testing; Work; antagonist; area striata; cell type; combinatorial; density; extracellular; frontal lobe; insight; locus ceruleus structure; nervous system disorder; neuroregulation; noradrenergic; novel; receptor; relating to nervous system; spatiotemporal; tool; virtual

Project Summary: Noradrenaline is thought to mediate arousal and regulate the behavioral state of animals. In particular, noradrenaline bidirectionally modifies mnemonic and sensory encoding, prioritizing neural resources for imminent behavioral demands. Emerging evidence has suggested a capacity for spatially targeted noradrenergic release, yet the field has lacked tools with sufficient spatiotemporal resolution to resolve this possibility. Cell type specific sensitives to noradrenergic modulation underly the differing action of noradrenaline on mnemonic tuning in the frontal cortex and stimulus encoding in primary visual and somatosensory cortices. However, the study of isolated brain regions has precluded a holistic view of noradrenergic modulation across the cortex. Furthermore, how noradrenergic modulation of cortex-wide networks emerges from the level of single cells is virtually unexplored. Leveraging a recently developed technique from our lab to image the release of neuromodulators with high spatiotemporal resolution across the entirety of the dorsal-cortex, we have begun to characterize the spatiotemporal specificity of noradrenergic release and its relation to neural activity. Our preliminary data shows noradrenergic release is spatially homogenous and associated with distinct behavioral states. We further find the coupling of noradrenergic release to be spatiotemporally heterogenous, implicating noradrenaline in the engagement of distinct cortex-wide networks. To further pursue our preliminary data, we propose simultaneous application of several methodological approaches: 1 photon widefield “mesoscopic” dual channel imaging, local pharmacological infusions, and extracellular electrophysiological recordings with high density silicon probes. Our combinatorial approach will allow us to test the following hypothesis: (1) noradrenergic release is spatially homogenous but temporally heterogenous, with noradrenergic release associated with some behavioral states but not others. (2) Noradrenergic release is heterogeneously coupled with local neural activity through α2a receptors and prone to behavioral state dependent regulation. (3) Noradrenaline modulates the coupling of single cells to large-scale cortical networks in a state dependent manner. Our results will provide an unprecedented characterization of the spatiotemporal dynamics of noradrenergic modulation.

项目摘要： 去甲肾上腺素被认为可以介导唤醒并调节动物的行为状态。尤其， 去甲肾上腺素双向修改助记符和感官编码，优先考虑神经资源 迫在眉睫的行为要求。新兴的证据表明，具有空间靶向的诺肾上腺素的能力 释放，但是该领域缺乏具有足够时空分辨率的工具来解决这种可能性。细胞类型 在去甲肾上腺素对助记符调整的分化作用下，对去甲肾上腺素能调节的特定敏感性 在额叶皮质和刺激中，在一级视觉和体感皮层中编码。但是，研究 孤立的大脑区域排除了整个皮质中去甲肾上腺素能调节的整体视野。此外， 皮质范围网络的北肾上腺素能调节如何从单个单元的水平出现实际上是 未探索。利用我们实验室的最近开发的技术来形象神经调节剂的释放 在整个背皮层上，具有高时空分辨率，我们已经开始表征 去甲肾上腺素能释放的时空特异性及其与神经活动的关系。我们的初步数据显示 去肾上腺素能释放在空间上是同质的，并且与不同的行为状态相关。我们进一步找到 去甲肾上腺素能释放的耦合在空间上是异质的，在 参与不同皮质范围的网络。为了进一步提高我们的初步数据，我们提出同时提出的 几种方法学方法的应用：1个光子广场“介镜”双通道成像，本地 药理学输注和具有高密度硅问题的细胞外电生理记录。我们的 组合方法将使我们能够检验以下假设：（1）甲肾上腺素能释放是空间的 同质但暂时异质，与某些行为状态相关的去甲肾上腺素能释放 但没有其他人。 （2）去肾上腺素能通过α2a异质释放与局部神经活性相结合 接收者和容易受到行为状态依赖性法规。 （3）去甲肾上腺素调节单一的耦合 细胞以状态依赖性方式到大规模皮质网络。我们的结果将提供前所未有的 去甲肾上腺素能调节的空间时间动力学的表征。