Spatiotemporal Dynamics of Noradrenergic Signaling in the Neocortex

项目总结： 去甲肾上腺素被认为是调节唤醒和调节动物行为状态的物质。特别是， 去甲肾上腺素双向改变记忆和感觉编码，优先考虑神经资源 迫在眉睫的行为要求新出现的证据表明，空间靶向去甲肾上腺素能 然而，该领域缺乏具有足够时空分辨率的工具来解决这一可能性。单元格类型 去甲肾上腺素对助记调谐的不同作用下对去甲肾上腺素能调制的特异性敏感性 额叶皮质和初级视觉和躯体感觉皮质的刺激编码。然而，对其的研究 孤立的大脑区域排除了对整个皮质去甲肾上腺素能调制的整体看法。此外， 去甲肾上腺素能对整个皮层网络的调制是如何从单细胞水平出现的 未被开发的。利用我们实验室最近开发的一项技术来成像神经调节剂的释放 随着整个背侧皮质的高时空分辨率，我们已经开始描述 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 去甲肾上腺素的释放在空间上是同质性的，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在时空上是异质性的，暗示去甲肾上腺素在 参与不同的大脑皮层网络。为了进一步研究我们的初步数据，我们建议同时 几种方法学方法的应用：1光子宽视野“介观”双通道成像，局部 药物输注，以及高密度硅探针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)去甲肾上腺素的释放在空间上是 同质性但在时间上异质性，去甲肾上腺素释放与某些行为状态有关 但不是其他人。(2)去甲肾上腺素能释放通过α2a与局部神经活动异质性偶联 受体和易受行为状态依赖的调节。(3)去甲肾上腺素调节单细胞的偶联。 细胞以一种状态依赖的方式连接到大规模的皮质网络。我们的结果将提供前所未有的 去甲肾上腺素能调制的时空动力学特征。

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.