下丘脑室旁核的 CRF 结合蛋白活性对哺乳期大鼠的应激适应和正常母性行为至关重要

IF 4.3 2区 医学 Q1 NEUROSCIENCES Neurobiology of Stress Pub Date : 2024-03-27 DOI:10.1016/j.ynstr.2024.100631
Alice Sanson , Paula Krieg , Milena M. Schramm , Kerstin Kellner , Rodrigue Maloumby , Stefanie M. Klampfl , Paula J. Brunton , Oliver J. Bosch
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引用次数: 0

摘要

为了确保围产期母性行为的不受限制表达,需要尽量减少促肾上腺皮质激素释放因子(CRF)系统的活动。CRF结合蛋白(CRF-BP)可能是这种适应的关键,因为它的主要功能是封闭可自由利用的CRF和尿皮质素1,从而抑制CRF受体(CRF-R)的信号传导。我们研究了下丘脑室旁核(PVN)中 CRF-BP 和 CRF-R 的基因表达。与原始大鼠相比,哺乳大鼠下丘脑室旁核(PVN)中Crh-bp的表达明显较高,而Crh-r1的表达则明显较低。通过输注 CRF(6-33)抑制 PVN 中的急性 CRF-BP,可增加母鼠在非应激条件下的基础血浆皮质酮浓度。此外,虽然在PVN内急性输注CRF可增加处女大鼠的皮质酮分泌,但对经车辆(VEH)预处理的泌乳大鼠却无效,这可能是由于CRF-BP的缓冲作用。事实上,CRF(6-33)的预处理恢复了哺乳期大鼠对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,这是首次将哺乳期下丘脑 CRF-BP 活性与下丘脑-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,非应激条件下 PVN 内的急性 CRF-BP 抑制减少了输注后 60 分钟的空白哺乳和 90 分钟的舔舐/梳理,同时增加了母体对入侵者的攻击性。总之,在产后期间,PVN 中 CRF-BP 的完整活性对于抑制应激轴的反应以及充分表达适当的母性行为至关重要。
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CRF binding protein activity in the hypothalamic paraventricular nucleus is essential for stress adaptations and normal maternal behaviour in lactating rats

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, Crh-bp expression in the parvocellular PVN was significantly higher and Crh-r1 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.

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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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