Liu Rui, Yang Xiao-Dun, Liao Xue-Mei, Xie Xiao-Meng, Su Yun-Ai, Li Ji-Tao, Wang Xiao-Dong, Si Tian-Mei
Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100191, China.
National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100191, China.
Brain Struct Funct. 2016 Dec;221(9):4525-4536. doi: 10.1007/s00429-016-1182-4. Epub 2016 Jan 20.
Adverse experiences early in life hamper the development and maturation of the hippocampus, but how early-life stress perturbs the developmental trajectory of the hippocampus across various life stages and the underlying molecular mechanisms remain to be investigated. In this study, we stressed male mice from postnatal day 2 (P2) to P9, and examined the potential role of CRHR1 in postnatal stress-induced structural remodeling of hippocampal CA3 pyramidal neurons directly after stress (P9), in mid-adolescence (P35) and in adulthood (P90). We found that early-life stress exposure significantly reduced apical dendritic arborization and spine density in CA3 neurons on P9 and P90. Moreover, postnatally stressed neurons underwent increased pruning of spines, especially thin spines, between P35 and P90. These stress-induced immediate and long-term structural abnormalities could be abolished by daily systemic administration of the CRHR1 antagonist antalarmin (20 µg/g of body weight) during stress exposure. However, such treatment strategy failed to attenuate the deleterious stress effects in mid-adolescence on P35. We then extended antalarmin treatment until the end of the second postnatal week, and found that prolonged blockade of CRHR1 could prevent the mid-term impact of early postnatal stress on structural remodeling of CA3 neurons. Our study characterized the influences of early-life stress on the developmental trajectory of hippocampal pyramidal neurons, and highlighted the critical role of CRHR1 in modulating these negative outcomes evoked by early-life stress.
生命早期的不良经历会阻碍海马体的发育和成熟，但生命早期应激如何在不同生命阶段扰乱海马体的发育轨迹以及潜在的分子机制仍有待研究。在本研究中，我们对出生后第2天（P2）至第9天的雄性小鼠施加应激，并研究促肾上腺皮质激素释放激素受体1（CRHR1）在应激后即刻（P9）、青春期中期（P35）和成年期（P90）对出生后应激诱导的海马体CA3锥体神经元结构重塑中的潜在作用。我们发现，生命早期应激暴露显著降低了P9和P90时CA3神经元的顶树突分支和棘密度。此外，出生后受到应激的神经元在P35至P90期间经历了棘的修剪增加，尤其是细棘。这些应激诱导的即刻和长期结构异常可通过在应激暴露期间每日全身给予CRHR1拮抗剂安他敏（20μg/g体重）而消除。然而，这种治疗策略未能减轻青春期中期P35时的有害应激效应。然后，我们将安他敏治疗延长至出生后第二周结束，发现长期阻断CRHR1可预防出生后早期应激对CA3神经元结构重塑的中期影响。我们的研究描述了生命早期应激对海马体锥体神经元发育轨迹的影响，并强调了CRHR1在调节生命早期应激诱发的这些负面结果中的关键作用。
