Sanson Alice, Krieg Paula, Schramm Milena M, Kellner Kerstin, Maloumby Rodrigue, Klampfl Stefanie M, Brunton Paula J, Bosch Oliver J
Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Neurobiol Stress. 2024 Mar 27;30:100631. doi: 10.1016/j.ynstr.2024.100631. eCollection 2024 May.
To ensure the unrestricted expression of maternal behaviour peripartum, activity of the corticotropin-releasing factor (CRF) system needs to be minimised. CRF binding protein (CRF-BP) might be crucial for this adaptation, as its primary function is to sequester freely available CRF and urocortin1, thereby dampening CRF receptor (CRF-R) signalling. So far, the role of CRF-BP in the maternal brain has barely been studied, and a potential role in curtailing activation of the stress axis is unknown. We studied gene expression for CRF-BP and both CRF-R within the paraventricular nucleus (PVN) of the hypothalamus. In lactating rats, expression in the parvocellular PVN was significantly higher and expression in the PVN significantly lower compared to virgin rats. Acute CRF-BP inhibition in the PVN with infusion of CRF(6-33) increased basal plasma corticosterone concentrations under unstressed conditions in dams. Furthermore, while acute intra-PVN infusion of CRF increased corticosterone secretion in virgin rats, it was ineffective in vehicle (VEH)-pre-treated lactating rats, probably due to a buffering effect of CRF-BP. Indeed, pre-treatment with CRF(6-33) reinstated a corticosterone response to CRF in lactating rats, highlighting the critical role of CRF-BP in maintaining attenuated stress reactivity in lactation. To our knowledge, this is the first study linking hypothalamic CRF-BP activity to hypothalamic-pituitary-adrenal axis regulation in lactation. In terms of behaviour, acute CRF-BP inhibition in the PVN under non-stress conditions reduced blanket nursing 60 min and licking/grooming 90 min after infusion compared to VEH-treated rats, while increasing maternal aggression towards an intruder. Lastly, chronic intra-PVN inhibition of CRF-BP strongly reduced maternal aggression, with modest effects on maternal motivation and care. Taken together, intact activity of the CRF-BP in the PVN during the postpartum period is essential for the dampened responsiveness of the stress axis, as well as for the full expression of appropriate maternal behaviour.
为确保围产期母体行为不受限制地表达，促肾上腺皮质激素释放因子（CRF）系统的活性需降至最低。CRF结合蛋白（CRF-BP）可能对这种适应性变化至关重要，因为其主要功能是隔离游离的CRF和尿皮质素1，从而减弱CRF受体（CRF-R）信号传导。到目前为止，CRF-BP在母体大脑中的作用几乎未被研究，其在抑制应激轴激活方面的潜在作用尚不清楚。我们研究了下丘脑室旁核（PVN）内CRF-BP和两种CRF-R的基因表达。与未生育的大鼠相比，哺乳期大鼠小细胞PVN中的表达显著更高，而PVN中的表达显著更低。在母鼠PVN中急性抑制CRF-BP，通过注入CRF(6-33)，在无应激条件下增加了母鼠的基础血浆皮质酮浓度。此外，虽然在未生育的大鼠中，急性PVN内注入CRF会增加皮质酮分泌，但在预先用载体（VEH）处理的哺乳期大鼠中却无效，这可能是由于CRF-BP的缓冲作用。事实上，用CRF(6-33)预处理可恢复哺乳期大鼠对CRF的皮质酮反应，突出了CRF-BP在维持哺乳期应激反应减弱中的关键作用。据我们所知，这是第一项将下丘脑CRF-BP活性与哺乳期下丘脑-垂体-肾上腺轴调节联系起来的研究。在行为方面，与VEH处理的大鼠相比，在非应激条件下急性抑制PVN中的CRF-BP会减少注入后60分钟的毯式护理和90分钟的舔舐/梳理行为，同时增加母鼠对入侵者的攻击性。最后，慢性PVN内抑制CRF-BP会强烈降低母鼠的攻击性，对母性动机和照料有适度影响。综上所述，产后期间PVN中CRF-BP的完整活性对于应激轴反应性的减弱以及适当母体行为的充分表达至关重要。
