Vittani Marta, Herlo Rasmus, Wang Xiaowen, Christensen Michala Daniela Bach, Vo Camilla Trang, Mishima Tsuneko, Kusk Peter, Konno Ayumu, Hirai Hirokazu, Tsuboi Takashi, Kitaguchi Tetsuya, Kjaerby Celia, Asiminas Antonis, Yokoyama Tatsushi, Sakamoto Masayuki, Nedergaard Maiken, Hirase Hajime
Center for Translational Neuromedicine, Faculty of Health and Life Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
Neurotechnology Center, Department of Biological Sciences, Columbia University, New York, NY 10027.
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2422069122. doi: 10.1073/pnas.2422069122. Epub 2025 Jul 1.
Local neural activation drives regional increase of cerebral blood flow (CBF), in a phenomenon known as functional hyperemia. Astrocytes, which enwrap cerebral blood vessels and respond to neuronal activity through their G protein-coupled receptors (GPCRs), play a vital role in brain energy metabolism. Although astrocytic calcium (Ca) signaling has been widely studied in relation to neurovascular coupling, the role of cyclic adenosine monophosphate (cAMP), another key second messenger of GPCRs, on CBF has not been established. In this study, we explored the effects of optogenetically induced astrocytic cAMP elevation on CBF. We engineered adeno-associated viral vectors (AAVs) to express a bacterial photoactivated adenylyl cyclase in astrocytes, which triggers an increase in cAMP upon blue light stimulation. Opto-stimulation also elevated astrocytic Ca, albeit with a delayed onset under mild stimulation. In vivo imaging of anesthetized and awake wild-type mice through a thinned skull preparation revealed that optogenetically induced astrocytic cAMP elevation led to pronounced arteriole dilation, with a latency of 1.8 s and maximal dilation reached within 10 s in the awake state and slower response under anesthesia. Mild opto-stimulation causing sensory-level cAMP elevations was sufficient to induce arteriole dilation. This effect was preserved in IP receptor type 2-knockout (IPR2) mice, indicating a mechanism independent of GPCR-induced intracellular Ca elevations. These findings highlight astrocytic cAMP as a key modulator of cerebral vasodilation, contributing to our understanding of local CBF regulation. This study opens broad avenues for understanding astrocyte-mediated control of CBF and its implications in neurological diseases characterized by dysregulated blood flow.
局部神经激活驱动脑血流量（CBF）的区域性增加，这一现象被称为功能性充血。星形胶质细胞包裹着脑血管，并通过其G蛋白偶联受体（GPCRs）对神经元活动做出反应，在脑能量代谢中起着至关重要的作用。尽管星形胶质细胞钙（Ca）信号传导已被广泛研究与神经血管耦合相关，但环磷酸腺苷（cAMP）作为GPCRs的另一种关键第二信使，对CBF的作用尚未明确。在本研究中，我们探讨了光遗传学诱导的星形胶质细胞cAMP升高对CBF的影响。我们设计了腺相关病毒载体（AAVs），使其在星形胶质细胞中表达一种细菌光激活腺苷酸环化酶，该酶在蓝光刺激下会引发cAMP增加。光刺激也会升高星形胶质细胞的Ca，尽管在轻度刺激下其起始延迟。通过薄颅骨制备对麻醉和清醒的野生型小鼠进行体内成像显示，光遗传学诱导的星形胶质细胞cAMP升高导致明显的小动脉扩张，在清醒状态下潜伏期为1.8秒，最大扩张在10秒内达到，而在麻醉状态下反应较慢。引起感觉水平cAMP升高的轻度光刺激足以诱导小动脉扩张。这种效应在IP受体2型敲除（IPR2）小鼠中得以保留，表明其机制独立于GPCR诱导的细胞内Ca升高。这些发现突出了星形胶质细胞cAMP作为脑血管舒张的关键调节因子，有助于我们理解局部CBF调节。这项研究为理解星形胶质细胞介导的CBF控制及其在以血流失调为特征的神经系统疾病中的意义开辟了广阔的途径。
