Blumberg Matthew A, Shipman Ava, Olyha Lidia, Gironda Stephen C, Weiner Jeffrey L
Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Brain Behav. 2025 Mar;15(3):e70369. doi: 10.1002/brb3.70369.
Despite extensive, cross-disciplinary research revealing a relationship between early life stress (ELS) and an increased risk for neuropsychiatric disorders, the underlying processes mediating this relationship are not fully understood. Further, the majority of preclinical studies investigating this relationship have not taken sex differences into consideration. A growing body of work suggests that microglia, resident immune cells of the brain, are impacted by ELS and contribute to some of the maladaptive behavioral phenotypes in adulthood. Here, we utilized an adolescent social isolation (aSI) model of ELS in female rats to test the role of microglia in mediating the effects of ELS on anxiety-related behaviors.
The present study sought to determine whether microglia ablation during aSI could prevent anxiety-like behaviors in female Long Evans rats. A colony-stimulating factor 1 receptor (CSF1-r) inhibitor, PLX3397, was provided in chow to ablate microglia at the start of the isolation period (postnatal day (P) 21-42). During the aSI period, animals performed a battery of behavioral assays including the open field test, elevated plus maze, and successive alleys test. Following completion of the behavioral assays, brain tissue was collected to confirm the efficacy of PLX3397 and identify changes in microglia population density.
Relative to group-housed (GH) controls, aSI rats showed increased locomotor activity in the open field test and higher closed-arm entries on the elevated plus maze. Although PLX3397 effectively ablated microglia across all animals, this treatment had minimal effects on observed aSI-associated phenotypes.
Together, these data suggest that microglia are not required for behavioral adaptations promoted by aSI. Future studies will be needed to assess the role of microglia in the relationship between ELS and maladaptive behavioral phenotypes.
尽管广泛的跨学科研究揭示了早期生活应激（ELS）与神经精神疾病风险增加之间的关系，但介导这种关系的潜在过程尚未完全明了。此外，大多数研究这种关系的临床前研究并未考虑性别差异。越来越多的研究表明，小胶质细胞作为大脑中的常驻免疫细胞，会受到ELS的影响，并导致成年期一些适应不良的行为表型。在此，我们利用雌性大鼠的青少年社会隔离（aSI）模型来测试小胶质细胞在介导ELS对焦虑相关行为影响中的作用。
本研究旨在确定在aSI期间消融小胶质细胞是否可以预防雌性Long Evans大鼠出现焦虑样行为。在隔离期开始时（出生后第（P）21 - 42天），在食物中添加集落刺激因子1受体（CSF1 - r）抑制剂PLX3397以消融小胶质细胞。在aSI期间，动物进行了一系列行为测定，包括旷场试验、高架十字迷宫试验和连续小巷试验。行为测定完成后，收集脑组织以确认PLX3397的疗效并确定小胶质细胞群体密度的变化。
相对于群居（GH）对照，aSI大鼠在旷场试验中表现出更高的运动活性，在高架十字迷宫试验中进入封闭臂的次数更多。尽管PLX3397有效消融了所有动物的小胶质细胞，但这种处理对观察到的与aSI相关的表型影响极小。
总之，这些数据表明小胶质细胞并非aSI促进的行为适应所必需。未来需要进一步研究来评估小胶质细胞在ELS与适应不良行为表型之间关系中的作用。
