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

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.