Brain Serotonin Deficiency Impairs Ovarian Reserve Function via the Hypothalamic-Pituitary-Ovarian Axis

  • Neurosci Bull. 2026 May 25. doi: 10.1007/s12264-026-01636-z.
Shuang-Shuang Cui  #  1  2 ,  Zhuo-Nan Yang  #  1  2 ,  Jin Xiao  #  3 ,  Jin-Ping Qiao  #  4 ,  Yue-Ming Zhang  1  2  5 ,  Ling-Ge Shi  1  2 ,  Hui-Ru Cheng  1  2 ,  Si-Min Ding  1  2 ,  Meng-Yao Wang  1  2 ,  Dong-Mei Ji  1  2 ,  Tao Zhang  6  7 ,  Dan Liang  1  2 ,  Peng Chen  8 ,  Yun-Xia Cao  9  10  11  12 ,  Jiang-Ning Zhou  13 ,  Ya-Jing Liu  14  15  16  17
Affiliations
  • 1. Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 2. Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education of China, Hefei, 230022, China.
  • 3. Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 4. Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 5. Institute of Brain Science, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 6. Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 7. Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 8. Institute of Brain Science, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. [email protected].
  • 9. Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. [email protected].
  • 10. Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education of China, Hefei, 230022, China. [email protected].
  • 11. Anhui Provincial Key Laboratory of Reproductive Disorders and Obstetrics and Gynecology Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. [email protected].
  • 12. Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, 230022, China. [email protected].
  • 13. Institute of Brain Science, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. [email protected].
  • 14. Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. [email protected].
  • 15. Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education of China, Hefei, 230022, China. [email protected].
  • 16. Anhui Provincial Key Laboratory of Reproductive Disorders and Obstetrics and Gynecology Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. [email protected].
  • 17. Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, 230022, China. [email protected].
  • # Contributed equally.
PMID: 42184065 DOI: 10.1007/s12264-026-01636-z
Abstract

Brain-derived serotonin (5-HT) is a key neurotransmitter that regulates diverse central and peripheral physiological processes, including endocrine function, mood, and circadian rhythms. Patients with anxiety and depression often exhibit reduced brain 5-HT levels, which contribute significantly to female infertility. However, the role of brain-derived 5-HT in maintaining ovarian reserve function remains unclear. We generated brain-specific Tph2 conditional knockout (Tph2-CKO) mice lacking 5-HT and observed reduced follicle numbers and anti-Müllerian hormone (AMH) levels, indicating diminished ovarian reserve (DOR). Mechanistically, Brain-derived 5-HT deficiency suppressed ovarian mTOR signaling, triggering excessive Autophagy, mitochondrial dysfunction, and Apoptosis. In the hypothalamus, reduced central 5-HT levels downregulated 5-HT Receptor 7 (HTR7)-cAMP/PKA signaling, disrupted circadian rhythms, and decreased gonadotropin-releasing hormone (GnRH) expression, impairing hypothalamic-pituitary-ovarian (HPO) axis function. Ovarian follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) levels decreased, ultimately leading to DOR. Thus, 5-HT deficiency in the dorsal raphe nucleus disrupts the HPO axis via HTR7, leading to DOR.

Keywords
5-HT; Diminished ovarian reserve; HPO axis; HTR7; Mitochondrial dysfunction; mTOR signaling pathway.
Products