Liu Jing, Zhang Weizheng, Bai Yuting, Fu Rui, Lin Miao, Li Jialong, Nie Liangteng, Dang Xiaohui, Wang Qiao, Zhu Yunmeng, Li Lu, Guo Xing, Zhang Lizi, Qu Yishan, Huang Kaizhe, Han Xiao, Shang Shufeng, Xiao Jiayu, Li Yin, Huang Caihong, Jia Rui, He Zhixiong, Tai Fadao
Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, China.
School of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, China.
Neuroendocrinology. 2025;115(6-7):493-519. doi: 10.1159/000544839. Epub 2025 Feb 25.
Chronic social isolation (CSI) stress leads to numerous maladaptive changes in physiology and psychology, however, very little is known about the effects of longer time-scale CSI and there are divergent views regarding the underlying mechanisms. This study aimed to elucidate the common neuroendocrine mechanisms underlying the maladaptive changes caused by 14-week (14wk) and 20-week (20wk) CSI.
We investigated the impacts of 14wk and 20wk CSI on anxiety-/depression-like behaviors in male C57BL/6N mice with classical behavioral tests, and the immunofluorescence (IF) method was used for quantification of the arginine vasopressin (AVP)/oxytocin (OT) positive neurons in the PVN and screening out the differential activation brain regions (DABrs) on exposure of tail suspension. The expression of Avpr1a and Oxtr in the lateral septum (LS) was assessed by quantitative RT-PCR (qPCR), and the function of LSD Avpr1a+/+ neurons in emotion regulation was verified with pharmacological approaches. The concentration of AVP/OT in plasma was examined with the enzyme-linked immunosorbent assay (ELISA).
14wk and 20wk CSI increased anxiety-/depression-like behaviors and altered levels of exploratory locomotion in opposite directions, which are likely due to an imbalance of the AVP/OT system within the PVN and peripheral plasma, differential activation of LSD and thalamic brain regions, and abnormal expression of Avpr1a in LS. Pharmacological results demonstrated that Avpr1a+/+ neurons in the LSD were involved in emotion regulation.
This study suggests that the imbalance of the AVP/OT system and the dysfunction of Avpr1a+/+ neurons in the LSD were engaged in common neuroendocrinology mechanisms for anxiety/depression induced by long-term CSI.
慢性社会隔离（CSI）应激会导致生理和心理上出现许多适应不良的变化，然而，对于较长时间尺度的CSI的影响知之甚少，并且关于其潜在机制存在不同观点。本研究旨在阐明14周（14wk）和20周（20wk）CSI所引起的适应不良变化的共同神经内分泌机制。
我们通过经典行为测试研究了14wk和20wk CSI对雄性C57BL/6N小鼠焦虑/抑郁样行为的影响，并采用免疫荧光（IF）方法对室旁核（PVN）中精氨酸加压素（AVP）/催产素（OT）阳性神经元进行定量，并筛选出尾部悬吊暴露时的差异激活脑区（DABrs）。通过定量逆转录聚合酶链反应（qPCR）评估外侧隔（LS）中Avpr1a和Oxtr的表达，并采用药理学方法验证LS中Avpr1a+/+神经元在情绪调节中的功能。采用酶联免疫吸附测定（ELISA）检测血浆中AVP/OT的浓度。
14wk和20wk CSI增加了焦虑/抑郁样行为，并在相反方向改变了探索性运动水平，这可能是由于PVN和外周血浆中AVP/OT系统失衡、LS和丘脑脑区的差异激活以及LS中Avpr1a的异常表达所致。药理学结果表明，LS中的Avpr1a+/+神经元参与情绪调节。
本研究表明，AVP/OT系统失衡以及LS中Avpr1a+/+神经元功能障碍参与了长期CSI诱导的焦虑/抑郁的共同神经内分泌机制。
