Chudoba Rachel, Dabrowska Joanna
Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, School of Graduate and Postdoctoral Studies, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, School of Graduate and Postdoctoral Studies, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
Biol Psychiatry. 2025 Jul 28. doi: 10.1016/j.biopsych.2025.07.017.
The prevalence of post-traumatic stress disorder (PTSD) and anxiety disorders is higher in women than men. The severity of hallmark symptoms including hypervigilance and fear reactivity to unpredictable threats varies with sex and reproductive cycle, but the underlying mechanisms remain unclear. Here, we investigated corticotropin-releasing factor (CRF) neurons in the dorsolateral bed nucleus of the stria terminalis (BNST) as a potential nexus for the influence of biological sex and reproductive cycle on fear- and anxiety-related behaviors.
125 male and 156 cycle-monitored female CRF-Cre rats were used. BNST-CRF neuron excitability and synaptic activity was recorded with slice electrophysiology. Chemogenetic manipulations of BNST-CRF neurons were performed before elevated-plus maze, predator odor exposure, shock-induced startle sensitization, and anxiety-potentiated startle (APS) following unpredictable fear conditioning.
BNST-CRF neurons in females exhibit higher excitability (cycle-independent) and lower sensitivity to excitatory synaptic inputs (proestrus and diestrus) compared to males. BNST-CRF neuron inhibition reduces open-arm time in estrous females but not males. In the APS, BNST-CRF neuron inhibition attenuates short-term startle potentiation in males, whereas it causes persistent APS in diestrus females. Notably, chemogenetic activation of BNST-CRF neuron reduces APS in diestrus females.
Unpredictable fear conditioning elicits sex- and estrous phase-specific APS, differentially regulated by BNST-CRF neurons. Persistent APS in females align with hormonal phases marked by low levels of reproductive hormones, mirroring human PTSD findings. Widely used in human studies, APS may bridge animal and human research, supporting biomarker development and more effective pharmacotherapies.
创伤后应激障碍（PTSD）和焦虑症在女性中的患病率高于男性。包括过度警觉和对不可预测威胁的恐惧反应性在内的标志性症状的严重程度随性别和生殖周期而变化，但其潜在机制仍不清楚。在此，我们研究终纹床核背外侧（BNST）中的促肾上腺皮质激素释放因子（CRF）神经元，作为生物性别和生殖周期对恐惧和焦虑相关行为影响的潜在联系点。
使用125只雄性和156只经周期监测的雌性CRF-Cre大鼠。用切片电生理学记录BNST-CRF神经元的兴奋性和突触活动。在不可预测恐惧条件作用后的高架十字迷宫、捕食者气味暴露、电击诱发的惊吓致敏和焦虑增强惊吓（APS）之前，对BNST-CRF神经元进行化学遗传学操作。
与雄性相比，雌性BNST-CRF神经元表现出更高的兴奋性（与周期无关）和对兴奋性突触输入更低的敏感性（发情前期和动情间期）。抑制BNST-CRF神经元会减少发情期雌性的开臂时间，但不会减少雄性的开臂时间。在APS中，抑制BNST-CRF神经元会减弱雄性的短期惊吓增强，而在动情间期雌性中则会导致持续性APS。值得注意的是，化学遗传学激活BNST-CRF神经元会减少动情间期雌性的APS。
不可预测恐惧条件作用引发性别和发情期特异性的APS，由BNST-CRF神经元进行差异性调节。雌性的持续性APS与生殖激素水平低的激素阶段一致，这与人类PTSD的研究结果相似。APS在人类研究中广泛使用，可能会架起动物和人类研究之间的桥梁，支持生物标志物的开发和更有效的药物治疗。
