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

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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).