Yan Chen1,2 · Jie Shao1  · Lu Zhang1  · Yuchuan Hong1  · Hao Yang3  · Shirui Jun1  · William Weijia Lu4  · Jie Tu1,6 · Guoxin Ni5  · Fan Yang1

1 The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China 

2 School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China 

3 State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 200433, China 

4 Faculty of Pharmaceutical Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China 

5 Department of Rehabilitation Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China 

6 SIAT‑HKUST Joint Laboratory for Brain Science, Chinese Academy of Sciences, Shenzhen 518055, China

Abstract

Chronic hypoxia at high altitudes disrupts emotional and metabolic homeostasis. However, the underlying mechanisms remain unclear. Using mice chronically exposed to 11.35% oxygen, we combined three-dimensional motion capture, anxiety-related behavioral tests, brain-wide c-Fos mapping, and metabolic cage recordings. Hypoxic mice showed anxiety-like behavior, altered posture, and spontaneous behavioral distribution, elevated oxygen consumption, carbon dioxide production, and energy expenditure, together with reduced feeding. c-Fos mapping implicated the limbic, prefrontal, hypothalamic, and nucleus accumbens shell (NAcSh) regions in hypoxic adaptation. Selective depolarization of NAcSh dopamine D1 receptor (D1R) neurons alleviated anxiety-like behavior and attenuated hypoxia-associated hypermetabolism while further shifting substrate utilization. Exercise preconditioning also reduced anxiety-like behavior and partially restored NAcSh D1R-related signaling. Together, these findings identify NAcSh D1R-related signaling as a key component of chronic hypoxia adaptation and show that activation of NAcSh D1R neurons is sufficient to attenuate the coupled anxiety-like and metabolic phenotypes.

Keywords

Chronic hypoxia; Anxiety-like behavior; Nucleus accumbens shell; Dopamine D1 receptor; Metabolic phenotyping; Three-dimensional motion capture; Exercise preconditioning

[Springerlink]