Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
J Endocrinol. 2022 Sep 14;255(2):61-74. doi: 10.1530/JOE-22-0049. Print 2022 Nov 1.
The profound programming effects of early life stress (ELS) on brain and behavior are thought to be primarily mediated by adrenal glucocorticoids (GCs). However, in mice, stressors are often administered between postnatal days 2 and 12 (PND2-12), during the stress hyporesponsive period (SHRP), when adrenal GC production is greatly reduced at baseline and in response to stressors. During the SHRP, specific brain regions produce GCs at baseline, but it is unknown if brain GC production increases in response to stressors. We treated mice at PND1 (pre-SHRP), PND5 (SHRP), PND9 (SHRP), and PND13 (post-SHRP) with an acute stressor (isoflurane anesthesia), vehicle control (oxygen), or neither (baseline). We measured a panel of progesterone and six GCs in the blood, hippocampus, cerebral cortex, and hypothalamus via liquid chromatography tandem mass spectrometry. At PND1, baseline corticosterone levels were high and did not increase in response to stress. At PND5, baseline corticosterone levels were very low, increases in brain corticosterone levels were greater than the increase in blood corticosterone levels, and stress had region-specific effects. At PND9, baseline corticosterone levels were low and increased similarly and moderately in response to stress. At PND13, blood corticosterone levels were higher than those at PND9, and corticosterone levels were higher in blood than in brain regions. These data illustrate the rapid and profound changes in stress physiology during neonatal development and suggest that neurosteroid production is a possible mechanism by which ELS has enduring effects on brain and behavior.
早期生活应激（ELS）对大脑和行为的深远编程效应被认为主要是通过肾上腺糖皮质激素（GCs）介导的。然而，在小鼠中，应激源通常在出生后第 2 天至第 12 天（PND2-12）之间给予，此时基础和应激反应时肾上腺 GC 产生大大减少。在 SHRP 期间，特定的大脑区域会在基础水平产生 GCs，但尚不清楚大脑 GC 产生是否会对应激源产生反应。我们在 PND1（SHRP 前）、PND5（SHRP）、PND9（SHRP）和 PND13（SHRP 后）用急性应激源（异氟烷麻醉）、载体对照（氧气）或不处理（基础）处理小鼠。我们通过液相色谱串联质谱法测量了血液、海马体、大脑皮层和下丘脑中的孕激素和六种 GCs。在 PND1 时，基础皮质酮水平较高，且不响应应激而增加。在 PND5 时，基础皮质酮水平非常低，大脑皮质酮水平的增加大于血液皮质酮水平的增加，并且应激具有区域特异性效应。在 PND9 时，基础皮质酮水平较低，并且响应应激而适度增加。在 PND13 时，血液皮质酮水平高于 PND9，并且皮质酮水平在血液中高于大脑区域。这些数据说明了新生儿发育过程中应激生理学的快速而深远的变化，并表明神经甾体的产生可能是 ELS 对大脑和行为产生持久影响的一种机制。
