Department of Psychiatry, Yale University, New Haven, Connecticut 06511.
Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06510.
eNeuro. 2024 May 28;11(5). doi: 10.1523/ENEURO.0252-23.2024. Print 2024 May.
Norepinephrine (NE), a neuromodulator released by locus ceruleus (LC) neurons throughout the cortex, influences arousal and learning through extrasynaptic vesicle exocytosis. While NE within cortical regions has been viewed as a homogenous field, recent studies have demonstrated heterogeneous axonal dynamics and advances in GPCR-based fluorescent sensors permit direct observation of the local dynamics of NE at cellular scale. To investigate how the spatiotemporal dynamics of NE release in the prefrontal cortex (PFC) affect neuronal firing, we employed in vivo two-photon imaging of layer 2/3 of the PFC in order to observe fine-scale neuronal calcium and NE dynamics concurrently. In this proof of principle study, we found that local and global NE fields can decouple from one another, providing a substrate for local NE spatiotemporal activity patterns. Optic flow analysis revealed putative release and reuptake events which can occur at the same location, albeit at different times, indicating the potential to create a heterogeneous NE field. Utilizing generalized linear models, we demonstrated that cellular Ca fluctuations are influenced by both the local and global NE field. However, during periods of local/global NE field decoupling, the local field drives cell firing dynamics rather than the global field. These findings underscore the significance of localized, phasic NE fluctuations for structuring cell firing, which may provide local neuromodulatory control of cortical activity.
去甲肾上腺素(NE)是一种由蓝斑核(LC)神经元在整个皮质中释放的神经调质,通过细胞外囊泡胞吐作用影响觉醒和学习。虽然皮质区域内的 NE 被视为同质场,但最近的研究表明,轴突具有异质动力学,基于 GPCR 的荧光传感器的进步允许在细胞尺度上直接观察 NE 的局部动力学。为了研究前额叶皮层(PFC)中 NE 释放的时空动力学如何影响神经元放电,我们采用了活体双光子成像技术,以同时观察皮层 2/3 层的细粒度神经元钙和 NE 动力学。在这项原理验证研究中,我们发现局部和全局 NE 场可以彼此解耦,为局部 NE 时空活动模式提供了基础。光流分析揭示了潜在的释放和再摄取事件,这些事件虽然发生在不同时间,但可以在同一位置发生,表明存在产生异质 NE 场的潜力。利用广义线性模型,我们证明细胞 Ca 波动受到局部和全局 NE 场的影响。然而,在局部/全局 NE 场解耦期间,局部场驱动细胞放电动力学,而不是全局场。这些发现强调了局部、相位 NE 波动对细胞放电结构的重要性,这可能为皮质活动提供局部神经调质控制。