Maternal Stress During Pregnancy Induces Higher Anxiety-Like Behavior in Male Mice Offspring Under Acute Stress by Upregulating CRF/CRFR1 and Driving Time-Specific Activation of the MHb-IPN Circuit
Yujie Wang1 · Jiajia Zhao1 · Yueyang Wang3 · Zhixin Du2 · Li Wang1 · Zibo Ma1 · Siyang Sun4 · Xinyang Qu5 · Xiaohan Geng6 · Jiaming Yan1 · Liping Yang1 · Junlin Hou1
1 School of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
2 The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450046, China
3 School of Orthopedics and Traumatology, Henan University of Chinese Medicine, Zhengzhou 450046, China
4 The Second Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou 450002, China
5 School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
6 Postgraduate School, Medical School of Chinese People’s Liberation Army, Senior Department of Traditional Chinese Medicine, The Sixth Medical Center of PLA General Hospital, Beijing 100853, China
Abstract
This study reveals that maternal stress during pregnancy (MSDP) increases anxiety susceptibility in male offspring through Corticotropin-Releasing Factor Receptor 1 (CRFR1)-mediated time-specific hyperactivation of medial habenula (MHb) cholinergic projections to the interpeduncular nucleus (IPN). Male MSDP offspring exhibited heightened anxiety-like behaviors following 30 minutes of acute restraint stress (ARS). In vivo calcium imaging showed excessive activation of MHb ChAT-IPN projections specifically during the late phase (25–30 min) of ARS in MSDP offspring. Chemogenetic and optogenetic manipulations confirmed that this time-specific circuit hyperactivation drives anxiety susceptibility. Mechanistically, MSDP upregulated CRF/CRFR1 in the MHb. Pharmacological experiments demonstrated that CRFR1 activation directly enhances circuit activity. CRFR1 overexpression recapitulated MSDP phenotypes by increasing circuit activity and anxiety, while CRFR1 antagonism reversed both circuit hyperactivation and anxiety behaviors. Chemogenetic circuit inhibition blocked CRFR1 overexpression-induced anxiety, confirming that CRFR1 drives anxiety through this pathway.
Keywords
Prenatal stress; Anxiety; Acute stress; CRF/ CRFR1; MHb-IPN
