School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia.
Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia.
J Neurosci Res. 2022 Nov;100(11):2004-2027. doi: 10.1002/jnr.25115. Epub 2022 Sep 4.
Psychosocial stress promotes and links mood and cardiovascular disorders in a sex-specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippocampal monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippocampal Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females; and repression of hippocampal Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti-inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress-related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex-specific mechanisms and potential approaches to stress-dependent disease.
心理社会应激以性别特异性的方式促进和关联情绪和心血管疾病。然而，动物模型中的发现存在矛盾，在某些情况下与人类的二态性相反。我们研究了中枢神经系统 (CNS)、行为、内分泌、心脏和肝脏在雄性或雌性 C57Bl/6 小鼠中的结果，这些小鼠经历了慢性社会应激（56 天的社会隔离，在最后 20 天的整个过程中每天两次间歇性地进行社会对抗遭遇）。雌性表现出明显的生理和行为变化，包括相对体重减轻，冠状动脉阻力增加，肝炎症和旷场中的触壁行为增加。雄性表现出冠状动脉阻力和心脏缺血耐受性降低，循环和海马单胺水平增加，以及出现快感缺失。共同的 CNS 基因反应包括海马 Maoa 减少和 Htr1b 表达增加，而独特的反应包括下丘脑 Ntrk1 抑制和皮质 Nrf2 和 Htr1b 上调在雌性中；以及海马 Drd1 和下丘脑 Gabra1 和 Oprm 在雄性中的抑制。雄性心脏应激抵抗力下降与心脏瘦素水平以及代谢、线粒体生物发生和抗炎基因表达的抑制有关。这些综合数据揭示了男性和女性对社会应激的不同生物学反应，并且共同证明女性的生物学破坏或适应负荷更大（与人类应激相关的情绪和心血管疾病的倾向一致）。不同的应激生物学和从分子到器官的反应，强调了性别特异性机制和潜在的应激相关疾病治疗方法的重要性。
