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是介导唤醒和调节动物的行为状态。特别是， 去甲肾上腺素双向修改记忆和感觉编码，优先考虑神经资源， 迫在眉睫的行为需求。新出现的证据表明，空间靶向的去甲肾上腺素能受体的能力， 释放，但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 对去甲肾上腺素能调节的特殊敏感性是去甲肾上腺素对记忆调节的不同作用的基础 以及初级视觉和躯体感觉皮层的刺激编码。然而，研究 孤立的脑区排除了对整个皮层的去甲肾上腺素能调节的整体观点。此外，委员会认为， 去甲肾上腺素能调节皮层网络是如何从单细胞水平出现的， 未开发的利用我们实验室最近开发的技术来成像神经调质的释放 随着整个背侧皮层的高时空分辨率，我们已经开始描述 去甲肾上腺素能释放时空特异性及其与神经活动的关系我们的初步数据显示 去甲肾上腺素能释放在空间上是均匀的，并与不同的行为状态相关。我们进一步发现， 去甲肾上腺素能释放的偶联是时空异质性的，暗示去甲肾上腺素在 参与不同的皮层网络。为了进一步追求我们的初步数据，我们建议同时 几种方法的应用：1光子宽场“介观”双通道成像，局部 药理学输注和用高密度硅探针进行细胞外电生理学记录。我们 组合的方法将允许我们测试以下假设：（1）去甲肾上腺素能释放是空间的， 同质但时间异质，去甲肾上腺素能释放与某些行为状态相关 而不是其他人。(2)去甲肾上腺素能释放通过α2a与局部神经活动不均匀耦合 受体和倾向于行为状态依赖性调节。(3)去甲肾上腺素调节单个 细胞以状态依赖的方式连接到大规模的皮层网络。我们的研究结果将提供一个前所未有的 去甲肾上腺素能调节的时空动力学的表征。