Nucleus Accumbens D1 Receptor Neurons Contribute to Emotional and Metabolic Adaptation to Chronic Hypoxia

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.