Sanchez Kevin, Wu Sienna L, Kakkar Reha, Darling Jeffrey S, Harper Claire S, Fonken Laura K
Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
Brain Behav Immun Health. 2023 May 18;30:100638. doi: 10.1016/j.bbih.2023.100638. eCollection 2023 Jul.
Estrogens are a group of steroid hormones that promote the development and maintenance of the female reproductive system and secondary sex characteristics. Estrogens also modulate immune responses; estrogen loss at menopause increases the risk of inflammatory disorders. Elevated inflammatory responses in the brain can lead to affective behavioral changes, which are characteristic of menopause. Thus, here we examined whether loss of estrogens sensitizes microglia, the primary innate immune cell of the brain, leading to changes in affective behaviors. To test this question, adult C57BL/6 mice underwent an ovariectomy to remove endogenous estrogens and then received estradiol hormone replacement or vehicle. After a one-month recovery, mice received an immune challenge with lipopolysaccharide (LPS) or vehicle control treatment and underwent behavioral testing. Ovariectomized, saline-treated mice exhibited reduced social investigation compared to sham-operated mice. Furthermore, ovariectomized mice that received LPS exhibited an exacerbated decrease in sucrose preference, which was ameliorated by estradiol replacement. These results indicate that ovariectomy modulates affective behaviors at baseline and in response to an inflammatory challenge. Ovariectomy-related behavioral changes were associated with downregulation of , a microglial receptor that limits activation, suggesting that estrogen loss can disinhibit microglia to immune stimuli. Indeed, estradiol treatment reduced ovariectomy-induced increases in and expression after an immune challenge. Changes in microglial reactivity following ovariectomy are likely subtle, as overt changes in microglial morphology (e.g., soma size and branching) were limited. Collectively, these results suggest that a lack of estrogens may allow microglia to confer exaggerated neuroimmune responses, thereby raising vulnerability to adverse affective- and sickness-related behavioral changes.
雌激素是一类甾体激素，可促进女性生殖系统的发育和维持以及第二性征的发育。雌激素还可调节免疫反应；绝经后雌激素水平下降会增加炎症性疾病的风险。大脑中炎症反应的增强会导致情感行为变化，这是绝经的特征。因此，我们在此研究了雌激素的丧失是否会使小胶质细胞（大脑主要的固有免疫细胞）敏感化，从而导致情感行为的变化。为了验证这个问题，成年C57BL/6小鼠接受卵巢切除术以去除内源性雌激素，然后接受雌二醇激素替代治疗或给予赋形剂。经过一个月的恢复后，小鼠接受脂多糖（LPS）免疫刺激或赋形剂对照治疗，并进行行为测试。与假手术小鼠相比，卵巢切除并用生理盐水处理的小鼠表现出社交探究行为减少。此外，接受LPS刺激的卵巢切除小鼠蔗糖偏好性下降加剧，而雌二醇替代治疗可改善这种情况。这些结果表明，卵巢切除术在基线状态以及对炎症刺激的反应中会调节情感行为。与卵巢切除术相关的行为变化与一种限制激活的小胶质细胞受体的下调有关，这表明雌激素丧失会使小胶质细胞对免疫刺激的抑制作用减弱。事实上，免疫刺激后，雌二醇治疗减少了卵巢切除术诱导的该受体表达的增加。卵巢切除术后小胶质细胞反应性的变化可能很细微，因为小胶质细胞形态的明显变化（如胞体大小和分支）有限。总的来说，这些结果表明，雌激素缺乏可能会使小胶质细胞产生过度的神经免疫反应，从而增加出现不良情感和疾病相关行为变化的易感性。
