Hamden Jordan E, Salehzadeh Melody, Bajaj Hitasha, Li Michael X, Soma Kiran K
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
J Neuroendocrinol. 2025 Feb;37(2):e13481. doi: 10.1111/jne.13481. Epub 2024 Dec 18.
Glucocorticoids (GCs) are secreted by the adrenal glands and increase in response to stressors (e.g., infection). The brain regulates local GC levels via GC synthesis, regeneration and/or metabolism. Little is known about local GC regulation within discrete brain regions at baseline or in response to stress. We treated male and female C57BL/6J mice at postnatal day 5 (PND5) or PND90 with lipopolysaccharide (LPS; 50 μg/kg bw i.p.) or vehicle and collected blood and brain after 4 h. We microdissected the prefrontal cortex, hippocampus, hypothalamus and amygdala. We measured seven steroids, including corticosterone, via liquid chromatography-tandem mass spectrometry and measured transcripts for key steroidogenic enzymes (Cyp11b1, Hsd11b1, Hsd11b2) via qPCR. At both ages, LPS increased GC levels in blood and all brain regions; however, the increases were much greater at PND90 than at PND5. Interestingly, PND5 corticosterone levels were lower in prefrontal cortex than in blood, but higher in amygdala than in blood. These changes in corticosterone levels align with local changes in steroidogenic enzyme expression, demonstrating robust regional heterogeneity and a possible mechanism for the region-specific effects of early-life stress. In contrast, PND90 corticosterone levels were lower in all brain regions than in blood and similar among regions, and steroidogenic enzyme mRNA levels were generally not affected by LPS. Together, these data indicate that local GC levels within discrete brain regions are more heterogeneous at baseline and in response to LPS at PND5 than at PND90, as a result of increased local GC production and metabolism in the neonatal brain.
糖皮质激素（GCs）由肾上腺分泌，并在应激源（如感染）作用下增加。大脑通过GC合成、再生和/或代谢来调节局部GC水平。关于基线时或应激反应下离散脑区内局部GC调节的情况知之甚少。我们在出生后第5天（PND5）或第90天（PND90）给雄性和雌性C57BL/6J小鼠腹腔注射脂多糖（LPS；50μg/kg体重）或赋形剂，4小时后采集血液和大脑样本。我们对前额叶皮质、海马体、下丘脑和杏仁核进行了显微切割。我们通过液相色谱-串联质谱法测量了七种类固醇，包括皮质酮，并通过qPCR测量了关键类固醇生成酶（Cyp11b1、Hsd11b1、Hsd11b2）的转录本。在两个年龄段，LPS均增加了血液和所有脑区的GC水平；然而，PND90时的增加幅度远大于PND5时。有趣的是，PND5时前额叶皮质中的皮质酮水平低于血液中的水平，但杏仁核中的皮质酮水平高于血液中的水平。皮质酮水平的这些变化与类固醇生成酶表达的局部变化一致，表明存在强大的区域异质性以及早期生活应激区域特异性效应的一种可能机制。相比之下，PND90时所有脑区的皮质酮水平均低于血液中的水平，且各区域之间相似，类固醇生成酶mRNA水平一般不受LPS影响。总之，这些数据表明，由于新生大脑中局部GC产生和代谢增加，离散脑区内局部GC水平在基线时以及对PND5时的LPS反应中比PND90时更加异质。
