The central corticotropin-releasing factor system mediates maternal neglect in lactating rats

脑促肾上腺皮质激素释放因子(CRF)系统由受体CRF-R1和-R2、配体CRF和urocortin 1-3以及CRF结合蛋白(CRF-BP)组成，CRF-BP可以结合游离的CRF/urocortin 1，使其不能与CRF-Rs结合。在中枢神经系统中，CRF系统启动下丘脑-垂体-肾上腺(HPA)轴，产生焦虑和前抑郁，参与调节社会行为，包括损害母亲行为，称为母亲忽视。因此，在健康的母体大脑中，CRF系统的活动减弱，这是产后必要适应的一部分。对哺乳期小鼠和大鼠的研究表明，在重要的母体大脑区域，即终纹外侧隔、前背侧(AdBNST)和内侧-后侧(MpBNST)床核以及内侧视前区(MPOA)，CRF系统的过度激活以CRF-R特有的方式损害母体行为的各个方面。此外，CRF-BP可以缓冲应激后CRF水平的升高；它支持在应激源暴露后恢复产妇护理。CRF-R信号的增加也影响促母体催产素(OT)的释放。在mpBNST，中枢性CRF-R1阻断后，OT释放增强，提示CRF-R1信号的增加损害了OT的释放。相反，在MPOA中，中枢和局部CRF-R1的激活增加了局部OT的释放，最有可能抵消应激导致的产妇护理下降。关于HPA轴，在未受干扰和应激条件下，adBNST中CRF-R1激活后，血浆ACTH和Cort水平升高。这对母亲的行为没有直接影响，因为急性静脉注射ACTH会提高血浆皮质醇水平，但对产妇护理没有影响。在本项目中，我的目标是显著提高我们对产后大脑中激活的CRF系统的有害影响的理解。室旁核(PVN)与母体行为和HPA轴有关；围产期适应失败可能导致母体护理不足。因此，我计划研究急性/慢性CRF-BP抑制如何影响母亲的行为和HPA轴的反应性。由于PVN将OT投射发送到伏隔核壳核(NAccS)，在NAccS，OT信号介导母体行为和CRF-R的表达，我的目标是研究NAccS中的CRF-R信号如何影响母体行为(高度特异的(ANT-)激动剂)。此外，我计划揭示NAccS或PVN中CRF系统的靶向操作对局部OT释放的影响(微/反透析)以及PVN OT投射到NAccS的激活/抑制如何影响产妇护理(化学遗传学)。由于怀孕期间的压力可能导致NAccS内的结构改变和母亲的忽视，我计划研究这种应激源如何改变重要的母亲大脑区域CRF系统的重要围产期适应，以及如何拯救这些区域(GapmeRs)。

The brain corticotropin-releasing factor (CRF) system consists of the receptors CRF-R1 and -R2, the ligands CRF and Urocortin 1-3, and the CRF-binding protein (CRF-BP), which can bind free CRF/Urocortin 1 making them unavailable for the CRF-Rs. In the CNS, the CRF system initiates the hypothalamo-pituitary-adrenal (HPA) axis, acts anxiogenic and pro-depressive, is involved in modulating social behaviors, including impairing maternal behavior termed maternal neglect. Therefore, the activity of the CRF system attenuated in a healthy maternal brain as part of the essential postpartum adaptations. Studies in lactating mice and rats reveal that a hyper-activated CRF system in important maternal brain regions, i.e. lateral septum, anterior-dorsal (adBNST) and medial-posterior (mpBNST) bed nucleus of the stria terminalis, and the medial preoptic area (MPOA), detrimentally impairs aspects of maternal behavior in a CRF-R-specific manner. Furthermore, the CRF-BP buffers against increased CRF levels after stress; it supports the reinstatement of maternal care following stressor exposure. Increased CRF-R signaling also acts on the release of the pro-maternal oxytocin (OT). In the mpBNST, OT release is enhanced after central CRF-R1 blockade, suggesting that increased CRF-R1 signaling impairs OT release. In contrast, in the MPOA central and local CRF-R1 activation increases local OT release most likely to counterbalance the stress-induced drop of maternal care. Regarding the HPA axis, plasma ACTH and CORT levels increase after CRF-R1 activation in the adBNST under undisturbed and stress conditions. This has no direct impact on maternal behavior as acute intravenous ACTH infusion elevates plasma CORT levels but has no effect on maternal care.In the present project, I aim to advance significantly our understanding of the detrimental effects of an activated CRF system in the postpartum brain. The paraventricular nucleus (PVN) is involved in maternal behavior and the HPA axis; failed peripartum adaptations can lead to deficits in maternal care. Therefore, I plan to study how acute/chronic CRF-BP inhibition affects maternal behavior and HPA axis reactivity. As the PVN sends OT projections to the nucleus accumbens shell (NAccS), where OT signaling mediates maternal behavior and CRF-Rs are expressed, I aim to study how CRF-R signaling in the NAccS affects maternal behavior (highly specific (ant-)agonists). In addition, I plan to reveal how targeted manipulations of the CRF system in the NAccS or PVN impact on local OT release (micro/retrodialysis) as well as activation/inhibition of PVN OT projections to the NAccS affect maternal care (chemogenetics). As stress during pregnancy can lead to structural modifications within the NAccS and maternal neglect, I plan to study how this stressor alters the vital peripartum adaptations of the CRF system in important maternal brain regions and how those can be rescued (GapmeRs).