2. Academic Validation
  3. ATP release from the amygdala-prefrontal pathway regulates vulnerability to social stress in male mice

ATP release from the amygdala-prefrontal pathway regulates vulnerability to social stress in male mice

  • Mol Psychiatry. 2026 Mar 27. doi: 10.1038/s41380-026-03561-z.
Ding-Yu Wu # 1,  Jian-Lin Wu # 1,  Hao Chen # 1,  Rong Luo # 1,  Ying Kong 1,  Jian Hu 1,  Lang Huang 1,  Ji-Hong Liu 1,  Neng-Yuan Hu 1,  Meng-Ling Wang 1,  Shi-Yang Jin 1,  Xiao-Wen Li 1,  Jian-Ming Yang 1,  Zhao-Fa Wu 2,  Yu-Long Li 3,  Wei Lu 4,  Yi-Hua Chen 5,  Tian-Ming Gao 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China.
  • 2 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101, Beijing, China.
  • 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, 100871, Beijing, China.
  • 4 Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, Minister of Education (MOE) Frontiers Center for Brain Science, Fudan University, 200032, Shanghai, China.
  • 5 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China. [email protected].
  • 6 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41896365 DOI: 10.1038/s41380-026-03561-z
Abstract

Extracellular adenosine triphosphate (ATP) dysregulation has been implicated in the pathogenesis of major depressive disorder. However, the mechanisms underlying ATP deficiency in the medial prefrontal cortex (mPFC) under stress conditions remain unclear. Here, we found that only stress-susceptible mice exhibited deficiencies in both the basal ATP levels and reward task-evoked ATP release, and these deficits could be reversed by treatment with fluoxetine. We also observed specific downregulation of Slc17a9, a gene encoding the vesicular nucleotide transporter (VNUT), in the mPFC of stress-susceptible mice. Conditional knockout of Slc17a9 in neurons (n-cKO), but not in astrocytes was sufficient to induce depressive-like behaviors following subthreshold social defeat stress (SSDS), accompanied by decreased basal extracellular ATP levels and impaired reward-evoked ATP release in the mPFC. Similar deficits were reproduced by specific knockdown of Slc17a9 in BLAmPFC-projecting neurons. Notably, these behavioral deficits were reversed by microinjection of the nonhydrolyzable ATP analogs (ATPγS) into the mPFC. Furthermore, we demonstrated that the BLA-mPFC pathway bidirectionally regulated depressive-like behaviors via ATP release following SSDS. Overall, our study provides evidence that ATP release modulates susceptibility to social stress in a circuit-specific manner and highlights the essential role of stress-induced ATP deficiency in the pathogenesis of depression.

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