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产前应激会改变促肾上腺皮质激素释放激素(CRH)神经元中氯离子稳态的早期建立,导致胎儿下丘脑-垂体-肾上腺(HPA)轴功能失调。

Early establishment of chloride homeostasis in CRH neurons is altered by prenatal stress leading to fetal HPA axis dysregulation.

作者信息

Watanabe Miho, Sinha Adya Saran, Shinmyo Yohei, Fukuda Atsuo

机构信息

Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

出版信息

Front Mol Neurosci. 2024 Mar 21;17:1373337. doi: 10.3389/fnmol.2024.1373337. eCollection 2024.

Abstract

Corticotropin-releasing hormone (CRH) neurons play an important role in the regulation of neuroendocrine responses to stress. The excitability of CRH neurons is regulated by inhibitory GABAergic inputs. However, it is unclear when GABAergic regulation of CRH neurons is established during fetal brain development. Furthermore, the exact progression of the developmental shift of GABA action from depolarization to hyperpolarization remains unelucidated. Considering the importance of CRH neuron function in subsequent hypothalamic-pituitary-adrenal (HPA) axis regulation during this critical phase of development, we investigated the ontogeny of GABAergic inputs to CRH neurons and consequent development of chloride homeostasis. Both CRH neuron soma in the paraventricular nucleus (PVN) and axons projecting to the median eminence could be identified at embryonic day 15 (E15). Using acute slices containing the PVN of CRF-VenusΔNeo mice, gramicidin perforated-patch clamp-recordings of CRH neurons at E15, postnatal day 0 (P0), and P7 were performed to evaluate the developmental shift of GABA action. The equilibrium potential of GABA (E) was similar between E15 and P0 and showed a further hyperpolarizing shift between P0 and P7 that was comparable to E values in adult CRH neurons. GABA primarily acted as an inhibitory signal at E15 and KCC2 expression was detected in CRH neurons at this age. Activation of the HPA axis has been proposed as the primary mechanism through which prenatal maternal stress shapes fetal development and subsequent long-term disease risk. We therefore examined the impact of maternal food restriction stress on the development of chloride homeostasis in CRH neurons. We observed a depolarization shift of E in CRH neurons of pups exposed to maternal food restriction stress. These results suggest that Cl homeostasis in early developmental CRH neurons attains mature intracellular Cl levels, GABA acts primarily as inhibitory, and CRH neurons mature and function early compared with neurons in other brain regions, such as the cortex and hippocampus. Maternal food restriction stress alters chloride homeostasis in CRH neurons of pups, reducing their inhibitory control by GABA. This may contribute to increased CRH neuron activity and cause activation of the HPA axis in pups.

摘要

促肾上腺皮质激素释放激素(CRH)神经元在调节对应激的神经内分泌反应中起重要作用。CRH神经元的兴奋性受抑制性γ-氨基丁酸(GABA)能输入的调节。然而,在胎儿脑发育过程中,GABA对CRH神经元的调节何时建立尚不清楚。此外,GABA作用从去极化到超极化的发育转变的确切进程仍未阐明。鉴于在这个关键发育阶段CRH神经元功能对随后下丘脑-垂体-肾上腺(HPA)轴调节的重要性,我们研究了CRH神经元GABA能输入的个体发生以及氯离子稳态的相应发育。在胚胎第15天(E15)就能识别室旁核(PVN)中的CRH神经元胞体以及投射到正中隆起的轴突。使用含有CRF-VenusΔNeo小鼠PVN的急性脑片,在E15、出生后第0天(P0)和P7对CRH神经元进行短杆菌肽穿孔膜片钳记录,以评估GABA作用的发育转变。E15和P0之间GABA的平衡电位(E)相似,且在P0和P7之间呈现进一步的超极化转变,这与成年CRH神经元的E值相当。在E15时,GABA主要作为抑制性信号起作用,且在这个年龄段的CRH神经元中检测到了钾-氯共转运体2(KCC2)的表达。产前母体应激影响胎儿发育及随后长期疾病风险的主要机制被认为是HPA轴的激活。因此,我们研究了母体食物限制应激对CRH神经元氯离子稳态发育的影响。我们观察到暴露于母体食物限制应激的幼崽的CRH神经元中E出现去极化转变。这些结果表明,早期发育的CRH神经元中的氯离子稳态达到了成熟的细胞内氯离子水平,GABA主要起抑制作用,并且与其他脑区(如皮层和海马体)的神经元相比,CRH神经元成熟和发挥功能较早。母体食物限制应激会改变幼崽CRH神经元中的氯离子稳态,减少GABA对它们的抑制控制。这可能导致CRH神经元活动增加,并引起幼崽HPA轴的激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/801f/10994000/bcf84b04d67f/fnmol-17-1373337-g001.jpg

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