Ablation of Ventral Midbrain/Pons GABA Neurons Induces Mania-like Behaviors with Altered Sleep Homeostasis and Dopamine D2R-mediated Sleep Reduction

Takato Honda; Yohko Takata; Yoan Cherasse; Seiya Mizuno; Fumihiro Sugiyama; Satoru Takahashi; Hiromasa Funato; Masashi Yanagisawa; Michael Lazarus; Yo Oishi

doi:10.1016/j.isci.2020.101240

Ablation of Ventral Midbrain/Pons GABA Neurons Induces Mania-like Behaviors with Altered Sleep Homeostasis and Dopamine D₂R-mediated Sleep Reduction

iScience. 2020 Jun 26;23(6):101240. doi: 10.1016/j.isci.2020.101240. Epub 2020 Jun 4.

Authors

Affiliations

¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Electronic address: takatoh@mit.edu.
² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
³ Laboratory Animal Resource Center and Trans-border Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Laboratory Animal Resource Center and Trans-border Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
⁵ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Anatomy, Faculty of Medicine, Toho University, Ota, Tokyo 143-8540, Japan.
⁶ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Life Science Center for Survival Dynamics (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
⁷ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: lazarus.michael.ka@u.tsukuba.ac.jp.
⁸ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: oishi.yo.fu@u.tsukuba.ac.jp.

Abstract

Individuals with the neuropsychiatric disorder mania exhibit hyperactivity, elevated mood, and a decreased need for sleep. The brain areas and neuronal populations involved in mania-like behaviors, however, have not been elucidated. In this study, we found that ablating the ventral medial midbrain/pons (VMP) GABAergic neurons induced mania-like behaviors in mice, including hyperactivity, anti-depressive behaviors, reduced anxiety, increased risk-taking behaviors, distractibility, and an extremely shortened sleep time. Strikingly, these mice also showed no rebound sleep after sleep deprivation, suggesting abnormal sleep homeostatic regulation. Dopamine D₂ receptor deficiency largely abolished the sleep reduction induced by ablating the VMP GABAergic neurons without affecting the hyperactivity and anti-depressive behaviors. Our data demonstrate that VMP GABAergic neurons are involved in the expression of mania-like behaviors, which can be segregated to the short-sleep and other phenotypes on the basis of the dopamine D₂ receptors.

Keywords: Behavioral Neuroscience; Cellular Neuroscience; Neuroscience.