Mechanical Regulation Underlies Effects of Exercise on Serotonin-Induced Signaling in the Prefrontal Cortex Neurons.

Youngjae Ryu,Keisuke Sawada,Tetsuro Tago,Jun Toyohara,Michiru Makuuchi,Naoyoshi Sakitani,Daisuke Yoshino,Toru Ogata,Yasuhiro Sawada,Takenobu Inoue,Yuki Yoshikawa,Hirokazu Hirai,Masashi Watanave,Jun Suzurikawa,Takamasa Sakai,Naoki Fujita,Motoshi Nagao,Masahiro Shirakawa ,Akira Takashima ,Toshiro Maekawa ,Sachiko Murase

doi:10.1016/j.isci.2020.100874

Abstract

SummaryMechanical forces are known to be involved in various biological processes. However, it remains unclear whether brain functions are mechanically regulated under physiological conditions. Here, we demonstrate that treadmill running and passive head motion (PHM), both of which produce mechanical impact on the head, have similar effects on the hallucinogenic 5-hydroxytryptamine (5-HT) receptor subtype 2A (5-HT2A) signaling in the prefrontal cortex (PFC) of rodents. PHM generates interstitial fluid movement that is estimated to exert shear stress of a few pascals on cells in the PFC. Fluid shear stress of a relevant magnitude on cultured neuronal cells induces ligand-independent internalization of 5-HT2A receptor, which is observed in mouse PFC neurons after treadmill running or PHM. Furthermore, inhibition of interstitial fluid movement by introducing polyethylene glycol hydrogel eliminates the effect of PHM on 5-HT2A receptor signaling in the PFC. Our findings indicate that neuronal cell function can be physiologically regulated by mechanical forces in the brain.

Highlights

As the phrase ‘‘Exercise is Medicine’’ indicates physical exercise has been widely recognized to be effective in maintaining homeostasis of various tissues and organs
Because the activity of 5-HT2A receptor is modulated by its internalization, either ligand dependently or ligand independently (Bhattacharyya et al, 2002), we hypothesized that 5-HT2A receptor signaling in the brain might be mechanically regulated by the receptor internalization. Both Treadmill Running and Passive Head Motion Alleviate 5-HT Receptor Signaling in the Brain We first examined whether treadmill running at a modest velocity (10 m/min for mice and 20 m/min for rats), a typical experimental intervention to test effects of physical exercise in rodents (Kim et al, 2010; Li et al, 2013), modulated 5-HT2A receptor signaling in the brain
We found that a week of treadmill running of mice (10 m/min, 30 min per day; see Figure 1A) significantly decreased head-twitch response (HTR) (Figures 1B and 1C), representing a suppressive effect of exercise on 5-HT2A receptor activation in the prefrontal cortex (PFC) neurons

Summary

Introduction

As the phrase ‘‘Exercise is Medicine’’ indicates physical exercise has been widely recognized to be effective in maintaining homeostasis of various tissues and organs. Molecular mechanisms underlying these positive effects of physical exercise on brain functions are poorly understood. Several factors released from musculoskeletal organs, which include irisin, brain-derived neurotropic factor, and osteocalcin, are associated with the nervous system (Oury et al, 2013; Wrann, 2015), it is enigmatic whether these factors underlie the benefit of exercise with regard to brain functions. Because of this lack of adequate understanding, it is difficult to develop a scientific evidence-based guideline for exercise as a therapeutic/preventative intervention for brain-related disorders

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