Roshgadol Jacob I, Chouinard Julie A, Majumder Shouvik, Scott Erin C, Borges Katharine, Hagihara Kenta M, Mancini Nino, Steveson Tanner, Kamath Tarun, Lodder Bart, MacLennan Bryan J, Dalangin Rochelin, Tjahjono Nikki, Pal Akash, Soares-Cunha Carina, Melugin Patrick R, Marley Aaron, Mahe Karan, Kurima Kiyoto, Takahashi Sakiko, Nosaka Dvyne, Murakami Kazuma, Colgan Lesley A, Freitas Peter T, Chaudhuri Rishidev, Siciliano Cody A, Rodrigues Ana João, Gradinaru Viviana, Von Zastrow Mark, Podgorski Kaspar, Sabatini Bernardo L, Bidaye Salil S, Hanks Timothy D, Ji Na, Wickens Jeffery R, Inagaki Hidehiko K, Tian Lin
Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA.
Biomedical Engineering Graduate Group, University of California Davis, Davis, CA, USA.
Res Sq. 2025 Aug 20:rs.3.rs-7313638. doi: 10.21203/rs.3.rs-7313638/v1.
Dopaminergic neurons modulate movement, motivation, and learning by dynamically regulating dopamine release across distributed neural circuits. However, existing genetically encoded dopamine sensors lack the sensitivity and resolution to capture the full amplitude and temporal complexity of dopamine signaling, limiting insight into its functions across behavioral contexts. Here, we present dLight3.8, a fluorescence-intensity and lifetime-based sensor with a substantially expanded dynamic range compared to existing dopamine sensors, enabling transformative detection and differentiation of dopamine release across brain regions and behaviors. Specifically, the enhanced sensitivity of dLight3.8 permits robust, single-trial recording of dopamine release spanning a wide concentration range in response to electrical, optogenetic, and behavioral stimuli, in multiple species and circuits. Using dLight3.8, we uncover a region-specific, gradual shift in dopamine encoding across motor learning, from tracking lick timing to signaling reward prediction. Our findings demonstrate that dLigth3.8 provides quantitatively reliable, highly sensitive measurements of graded dopamine release, which is essential for elucidating diverse roles of dopamine signaling in shaping animal behavior.
多巴胺能神经元通过动态调节分布于整个神经回路中的多巴胺释放来调节运动、动机和学习。然而，现有的基因编码多巴胺传感器缺乏足够的灵敏度和分辨率来捕捉多巴胺信号的完整幅度和时间复杂性，限制了我们对其在各种行为背景下功能的深入了解。在此，我们展示了dLight3.8，这是一种基于荧光强度和寿命的传感器，与现有的多巴胺传感器相比，其动态范围大幅扩展，能够对大脑区域和行为中的多巴胺释放进行变革性的检测和区分。具体而言，dLight3.8增强的灵敏度允许在多种物种和神经回路中，对电刺激、光遗传学刺激和行为刺激做出反应时，在很宽的浓度范围内对多巴胺释放进行稳健的单试次记录。使用dLight3.8，我们发现了在运动学习过程中多巴胺编码存在区域特异性的逐渐转变，从跟踪舔舐时间到发出奖励预测信号。我们的研究结果表明，dLigth3.8能够对分级多巴胺释放进行定量可靠、高度灵敏的测量，这对于阐明多巴胺信号在塑造动物行为中的多种作用至关重要。
