Litvin Yoav, Turner Cortney A, Rios Mariel B, Maras Pamela M, Chaudhury Sraboni, Baker Miriam R, Blandino Peter, Watson Stanley J, Akil Huda, McEwen Bruce
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, United States.
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, United States.
Horm Behav. 2016 Nov;86:64-70. doi: 10.1016/j.yhbeh.2016.09.009. Epub 2016 Sep 28.
We aimed to determine the short-term effects of early-life stress in the form of maternal separation (MS) on anxiety-like behavior in male rat pups. In order to assess anxiety, we measured 40kHz separation-induced ultrasonic vocalizations (USV) on postnatal day (PND) 11. We further aimed to evaluate the potential involvement of two neurochemical systems known to regulate social and anxiety-like behaviors throughout life: oxytocin (OT) and fibroblast growth factor 2 (FGF2). For these purposes, we tested the effects of neonatal administration (on PND1) of an acute dose of FGF2 on USV and its potential interaction with MS. In addition, we validated the anxiolytic effects of OT and measured oxytocin receptor (OTR) gene expression, binding and epigenetic regulation via histone acetylation. Our results show that MS potentiated USV while acute administration of OT and FGF2 attenuated them. Further, we found that both FGF2 and MS increased OTR gene expression and the association of acH3K14 with the OTR promoter in the bed nucleus of the stria terminalis (BNST). Comparable changes, though not as pronounced, were also found for the central amygdala (CeA). Our findings suggest that FGF2 may exert its anxiolytic effects in male MS rats by a compensatory increase in the acetylation of the OTR promoter to overcome reduced OT levels in the BNST.
我们旨在确定母体分离（MS）这种早期生活应激形式对雄性幼鼠焦虑样行为的短期影响。为了评估焦虑，我们在出生后第11天（PND11）测量了40kHz分离诱导的超声波发声（USV）。我们还旨在评估已知在整个生命过程中调节社交和焦虑样行为的两种神经化学系统的潜在作用：催产素（OT）和成纤维细胞生长因子2（FGF2）。出于这些目的，我们测试了新生期（PND1）急性剂量的FGF2对USV的影响及其与MS的潜在相互作用。此外，我们验证了OT的抗焦虑作用，并通过组蛋白乙酰化测量了催产素受体（OTR）基因表达、结合和表观遗传调控。我们的结果表明，MS增强了USV，而急性给予OT和FGF2则减弱了USV。此外，我们发现FGF2和MS均增加了终纹床核（BNST）中OTR基因表达以及acH3K14与OTR启动子的关联。在中央杏仁核（CeA）中也发现了类似的变化，尽管不那么明显。我们的研究结果表明，FGF2可能通过补偿性增加OTR启动子的乙酰化来克服BNST中OT水平的降低，从而对雄性MS大鼠发挥抗焦虑作用。
