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.

项目概要： 去甲肾上腺素被认为可以介导兴奋并调节动物的行为状态。 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 新出现的证据表明，空间定向去甲肾上腺素能的能力。 发布，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。 对去甲肾上腺素能调节的特定敏感性是去甲肾上腺素对记忆调节的不同作用的基础 然而，额叶皮层的刺激编码和初级视觉皮层和体感皮层的刺激编码。 孤立的大脑区域阻碍了对整个皮质去甲肾上腺素能调节的整体观察。 皮层范围网络的去甲肾上腺素能调节如何从单细胞水平产生实际上是 利用我们实验室最近开发的技术来成像神经调节剂的释放。 通过整个背皮质的高时空分辨率，我们已经开始表征 我们的初步数据显示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。 我们进一步发现去甲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。 去甲肾上腺素能释放的耦合在时空上是异质的，暗示去甲肾上腺素在 为了进一步研究我们的初步数据，我们同时提出。 多种方法学方法的应用： 1 光子宽场“介观”双通道成像、局部 使用我们的高密度硅探针进行药理输注和细胞外电生理记录。 组合方法将使我们能够检验以下假设：（1）去甲肾上腺素能释放在空间上 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 (2) 去甲肾上腺素能释放通过 α2a 与局部神经活动异质耦合。 (3) 去甲肾上腺素调节单个 我们的研究结果将提供前所未有的研究结果。 去甲肾上腺素能调节的时空动力学特征。