Corticothalamic circuits drive voluntary physical exercise-mediated relief of surgery-induced negative emotions in mice

Surgery-induced negative emotions (SINE), such as fear and anxiety, are common clinically and hinder postoperative recovery. Although physical exercise is known to modulate various affective disorders, the underlying mechanisms by which voluntary physical exercise alleviates SINE remain unclear. Here we show that emotional stress promotes conditioned defensive expression and anxiety-like behaviors following fear conditioning-paired exploratory laparotomy in mice, whereas preoperative voluntary running wheel exercise significantly decreases these SINE-related behaviors.

In exercised male mice, emotional stress enhances the primary motor cortex glutamatergic neuronal (M1Glu) activity while suppressing posterior thalamic complex glutamatergic neurons (POGlu) via zona incerta GABAergic (ZIGABA) inputs through a dominant inhibitory M1Glu → ZIGABA→POGlu circuit, thereby alleviating SINE behaviors. In addition, raised norepinephrine release in the M1 triggered by emotional stress drives the activity of this circuit to attenuate SINE behaviors. This study identifies a voluntary physical exercise-activated, NE-mediated corticothalamic circuit linking motor activity to emotional processing in male mice, expanding the application of physical exercise and pinpointing therapeutic targets for clinical treatments of post-surgical mental disorders.

This work was supported by the National Natural Science Foundation of China (grants 82401441 to X.S.; 82471285 and 82101301 to Y.M.; 82422022 and U22A20305 to Y. J.); the Natural Science Foundation of Anhui Province (grants 2308085Y24 to Y.M.; 2508085JX005 to Y. These authors contributed equally: Ziqing He, Xiangjie Song, Ying Shi, Jing Zhou, Yuping Wang.

Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China Ziqing He, Ying Shi, Qingwei Wei, Dijia Wang, Liying Zhu, Lijian Chen, Yu Mao & Guanghong Xu Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China Core Facility Centre for Life Science, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China Department of Thyroid Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China Department of Thyroid Surgery, Anhui Provincial Cancer Hospital, Hefei, China Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China The Second Clinical Medical College, Anhui Medical University, Hefei, China The First Clinical Medical College, Anhui Medical University, Hefei, China Department of Pain Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China Department of Physiology, Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, School of Basic Medical Sciences, Anhui Medical University, Hefei, China Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China Correspondence to Zhi Zhang, Yan Jin, Yu Mao or Guanghong Xu. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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