Gammie S C, Seasholtz A F, Stevenson S A
Department of Zoology, University of Wisconsin, 1117 West Johnson Street, Madison, WI 53706, USA.
Neuroscience. 2008 Dec 2;157(3):502-12. doi: 10.1016/j.neuroscience.2008.09.026. Epub 2008 Sep 27.
Corticotropin-releasing factor (CRF) binding protein (CRF-BP) is a secreted protein that acts to bind and limit the activity of the neuropeptides, CRF and urocortin (Ucn) 1. We previously selected for high maternal defense (protection of offspring) in mice and found CRF-BP to be elevated in the CNS of selected mice. We also previously determined that both CRF and Ucn 1 are potent inhibitors of offspring protection when administered centrally. Thus, elevated CRF-BP could promote defense by limiting endogenous actions of CRF or Ucn 1. To test this hypothesis, we crossed the deletion for CRF-BP into the mice selected for high maternal defense and evaluated offspring protection and other maternal behaviors. CRF-BP knockout (KO) mice exhibited significant deficits in maternal aggression relative to wild-type (WT) mice in three different measures. Other maternal features were almost identical between groups, including dam and pup weight, litter size, nursing time, and pup retrieval. Both groups performed similarly in a forced swim stress test and aggression in both groups was reduced following the swim test. Virgin KO female mice exhibited higher levels of anxiety-like behavior in terms of decreased time in the light portion of the light/dark box test. For males, no differences in light/dark box or swim test were found. However, increased anxiety-like behavior in male KO mice was identified in terms of contact and approach to a novel object both with and without previous exposure to the swim test. No differences in isolation induced resident intruder male aggression were found between groups. Together, these results indicate that loss of CRF-BP selectively impairs maternal, but not intermale aggression and that loss of the gene induces anxiety-like behavior in males and females, but there are sex differences in terms of how that anxiety is revealed.
促肾上腺皮质激素释放因子（CRF）结合蛋白（CRF-BP）是一种分泌蛋白，其作用是结合并限制神经肽CRF和尿皮质素（Ucn）1的活性。我们之前在小鼠中选择了具有高母性防御能力（对后代的保护）的品系，并发现所选小鼠的中枢神经系统中CRF-BP水平升高。我们之前还确定，当经中枢给药时，CRF和Ucn 1都是后代保护的有效抑制剂。因此，升高的CRF-BP可能通过限制CRF或Ucn 1的内源性作用来促进防御。为了验证这一假设，我们将CRF-BP基因敲除引入到具有高母性防御能力的小鼠品系中，并评估后代保护和其他母性行为。与野生型（WT）小鼠相比，CRF-BP基因敲除（KO）小鼠在三种不同测量方法下的母性攻击行为均表现出显著缺陷。两组之间的其他母性特征几乎相同，包括母鼠和幼崽体重、窝仔数、哺乳时间和找回幼崽的情况。两组在强迫游泳应激试验中的表现相似，且游泳试验后两组的攻击性均降低。未生育的KO雌性小鼠在明暗箱试验的亮区停留时间减少，表现出更高水平的焦虑样行为。对于雄性小鼠，在明暗箱试验或游泳试验中未发现差异。然而，无论是在有或没有先前游泳试验的情况下，雄性KO小鼠在接触和接近新物体方面表现出增加的焦虑样行为。两组之间在隔离诱导的驻留入侵者雄性攻击行为方面未发现差异。总之，这些结果表明，CRF-BP的缺失选择性地损害母性行为，但不影响雄性间的攻击行为，并且该基因的缺失在雄性和雌性中均诱导焦虑样行为，但在焦虑表现方式上存在性别差异。
