Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle

Akiyo Natsubori; Shinobu Hirai; Soojin Kwon; Daisuke Ono; Fei Deng; Jinxia Wan; Momoka Miyazawa; Takashi Kojima; Haruo Okado; Akihiro Karashima; Yulong Li; Kenji F Tanaka; Makoto Honda

doi:10.1016/j.isci.2022.105830

Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle

iScience. 2023 Jan 5;26(1):105830. doi: 10.1016/j.isci.2022.105830. eCollection 2023 Jan 20.

Authors

Akiyo Natsubori¹, Shinobu Hirai¹, Soojin Kwon¹, Daisuke Ono^{2

3}, Fei Deng^{4

5}, Jinxia Wan^{4

5}, Momoka Miyazawa^{1

6}, Takashi Kojima¹, Haruo Okado¹, Akihiro Karashima⁷, Yulong Li^{4

5}, Kenji F Tanaka⁸, Makoto Honda¹

Affiliations

¹ Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
² Department of Neuroscience Ⅱ, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
³ Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
⁴ State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China.
⁵ PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China.
⁶ Faculty of Science Division Ⅱ, Tokyo University of Science, Shinjuku-ku, Tokyo 162-8601, Japan.
⁷ Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Sendai 982-8577, Japan.
⁸ Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.

Abstract

The central serotonergic system has multiple roles in animal physiology and behavior, including sleep-wake control. However, its function in controlling brain energy metabolism according to the state of animals remains undetermined. Through in vivo monitoring of energy metabolites and signaling, we demonstrated that optogenetic activation of raphe serotonergic neurons increased cortical neuronal intracellular concentration of ATP, an indispensable cellular energy molecule, which was suppressed by inhibiting neuronal uptake of lactate derived from astrocytes. Raphe serotonergic neuronal activation induced cortical astrocytic Ca²⁺ and cAMP surges and increased extracellular lactate concentrations, suggesting the facilitation of lactate release from astrocytes. Furthermore, chemogenetic inhibition of raphe serotonergic neurons partly attenuated the increase in cortical neuronal intracellular ATP levels as arousal increased in mice. Serotonergic neuronal activation promoted an increase in cortical neuronal intracellular ATP levels, partly mediated by the facilitation of the astrocyte-neuron lactate shuttle, contributing to state-dependent optimization of neuronal intracellular energy levels.

Keywords: Biological sciences; Neuroscience; molecular neuroscience.