Optical manipulation of local cerebral blood flow in the deep brain of freely moving mice

• Published in: Cell reports (Cambridge) 2021-07, Vol.36 (4), p.109427-109427, Article 109427
• Main Authors: Abe, Yoshifumi, Kwon, Soojin, Oishi, Mitsuhiro, Unekawa, Miyuki, Takata, Norio, Seki, Fumiko, Koyama, Ryuta, Abe, Manabu, Sakimura, Kenji, Masamoto, Kazuto, Tomita, Yutaka, Okano, Hideyuki, Mushiake, Hajime, Tanaka, Kenji F.
• Format: Article
• Language: English
• Subjects: Animals; Arterioles - metabolism; Behavior, Animal; Brain - blood supply; Capillaries - metabolism; cerebral blood flow; Cerebrovascular Circulation - physiology; channelrhodopsin 2; Channelrhodopsins - metabolism; Doppler; endothelial cell; Endothelial Cells - metabolism; fMRI; Mice; Mice, Inbred C57BL; Movement; multi-unit activity; Myocytes, Smooth Muscle - metabolism; neural firing; Neurons - metabolism; Optogenetics; photoactivated adenylyl cyclase; smooth muscle cell; Time Factors; Venules - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109427

An artificial tool for manipulating local cerebral blood flow (CBF) is necessary for understanding how CBF controls brain function. Here, we generate vascular optogenetic tools whereby smooth muscle cells and endothelial cells express optical actuators in the brain. The illumination of channelrhodopsin-2 (ChR2)-expressing mice induces a local reduction in CBF. Photoactivated adenylyl cyclase (PAC) is an optical protein that increases intracellular cyclic adenosine monophosphate (cAMP), and the illumination of PAC-expressing mice induces a local increase in CBF. We target the ventral striatum, determine the temporal kinetics of CBF change, and optimize the illumination intensity to confine the effects to the ventral striatum. We demonstrate the utility of this vascular optogenetic manipulation in freely and adaptively behaving mice and validate the task- and actuator-dependent behavioral readouts. The development of vascular optogenetic animal models will help accelerate research linking vasculature, circuits, and behavior to health and disease. [Display omitted] •The Pvalb promoter is active in arterial smooth muscle cells and endothelial cells•ChR2 and PAC are CBF-reducing and -increasing actuators, respectively•Understanding spatiotemporal CBF change is key to interpreting behavioral outcomes•Vascular optogenetics in awake animals facilitates behavioral neurovascular studies Abe et al. generate vascular optogenetic animal models and demonstrate the local cerebral blood flow (CBF) manipulation in freely moving animals. They provide detailed information about the spatiotemporal titration of optogenetics-mediated CBF changes and exemplify the behavior- and circuitry-level outcomes by defined vascular optogenetics.