Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
J Psychiatr Res. 2014 Jun;53:1-7. doi: 10.1016/j.jpsychires.2014.02.015. Epub 2014 Feb 28.
Stressful life events during childhood and adolescence are important risk factors for the development of psychopathologies later in life. The corticotropin releasing hormone (CRH) and the CRH receptor 1 (CRHR1) have been implicated in the link between early life adversity and adult anxiety and depression, with rodent studies identifying the very early postnatal period as highly susceptible to this programming. Here, we investigated whether stress exposure during the peripubertal period - comprising juvenility and puberty - is effective in inducing long-lasting changes in the expression of CRHR1 and CRHR2 in the hippocampus and amygdala, and whether treating animals with a CRHR1 antagonist following stress exposure could reverse behavioral alterations induced by peripuberty stress. We show that peripuberty stress leads to enhanced expression of the Crhr1, but not Crhr2, gene in the hippocampal CA1 and the central nucleus of the amygdala, in association with social deficits in the social exploration test and increased stress-coping behaviors in the forced swim test. Treatment with the CRHR1 antagonist NBI30775 (10 mg/kg) daily for 1 week (from P43 to P49), immediately following peripuberty stress exposure, prevented the occurrence of those psychopathological behaviors at adulthood. These findings highlight peripuberty as a period of plasticity for the enduring modulation of the CRHR1 system and support a growing body of data implicating the CRHR1 system in the programming effects of early life stress on eventual psychopathology. They also support recent evidence indicating that temporarily tackling CRHR1 during development might represent a therapeutic opportunity to correct behavioral trajectories linking early stress to adult psychopathology.
儿童期和青春期的压力性生活事件是导致成年后精神病理发生的重要危险因素。促肾上腺皮质激素释放激素（CRH）及其受体 1（CRHR1）与早期生活逆境与成年焦虑和抑郁之间的联系有关，啮齿动物研究表明，新生儿期极易受到这种编程的影响。在这里，我们研究了青春期前时期（包括幼年期和青春期）的应激暴露是否有效诱导海马体和杏仁核中 CRHR1 和 CRHR2 的表达发生持久变化，以及在应激暴露后用 CRHR1 拮抗剂治疗动物是否可以逆转青春期前应激引起的行为改变。我们发现青春期前应激导致海马体 CA1 和杏仁核中央核中 Crhr1 基因的表达增强，但 Crhr2 基因的表达没有增强，与社会探索测试中的社交缺陷和强迫游泳测试中增加的应激应对行为有关。在青春期前应激暴露后立即（从 P43 到 P49）每天用 CRHR1 拮抗剂 NBI30775（10mg/kg）治疗 1 周，可预防成年期出现这些精神病理行为。这些发现强调了青春期前是 CRHR1 系统持久调节的可塑性时期，并支持越来越多的数据表明 CRHR1 系统参与了早期生活应激对最终精神病理学的编程效应。它们还支持最近的证据表明，在发育过程中暂时解决 CRHR1 可能代表着一种治疗机会，可以纠正将早期应激与成年精神病理学联系起来的行为轨迹。
