Shuang‑Shuang Cui1,2 · Zhuo‑Nan Yang1,2 · Jin Xiao3  · Jin‑Ping Qiao4  · Yue‑Ming Zhang1,2,5 · Ling‑Ge Shi1,2 · Hui‑Ru Cheng1,2 · Si‑Min Ding1,2 · Meng‑Yao Wang1,2 · Dong‑Mei Ji1,2 · Tao Zhang8,9 · Dan Liang1,2 · Peng Chen5  · Yun‑Xia Cao1,2,6,7 · Jiang‑Ning Zhou5  · Ya‑Jing Liu1,2,6,7

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 Anhui Provincial Key Laboratory of Reproductive Disorders and Obstetrics and Gynecology Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China 

7 Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230022, China 

8 Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China 

9 Chinese University of Hong Kong‑Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China

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; HTR7; mTOR signaling pathway; Mitochondrial dysfunction; Diminished ovarian reserve; HPO axis

[SpringerLink]