Vázquez Delia M, Eskandari Ramin, Phelka Andrew, López Juan F
Department of Pediatrics, Endocrine Division, University of Michigan, 1150 West Medical Center Drive, 8346 Medical Science Research Building III, Ann Arbor, MI 48109-0646, USA.
Neuropsychopharmacology. 2003 May;28(5):898-909. doi: 10.1038/sj.npp.1300126. Epub 2003 Mar 26.
Corticotropin-releasing hormone (CRH) acts within the brain and pituitary to coordinate the overall endocrinological and behavioral stress response. From postnatal day (PND) 4 to 14, the infant rat displays minimal adrenal response to mild stress. However, maternal deprivation alters the pituitary-adrenal system such that the infants become responsive to specific stimuli. We hypothesized that maternal deprivation would also affect CRH brain circuits. Since tricyclic antidepressants have been shown to decrease the adrenal response to stress in adult rats, we hypothesized that CRH-related changes induced by maternal deprivation would be prevented by this treatment. Thus, we investigated CRH-related molecules on animals that were maternally deprived on PND 13 compared with nondeprived animals. We found that maternal deprivation caused alterations in the gene expression of both CRH receptors (CRHr) 1 and 2 in specific brain regions, and that some of these effects were augmented by chronic isotonic saline injections. There was a significant increase in CRH, CRHr1, and r2 mRNA in the cortex. In amygdala, CRHr1 and r2 mRNAs were decreased. CRHr2 mRNA was also decreased in the ventromedial nucleus of the hypothalamus, whereas an increase was detected in the hippocampal pyramidal cells. One week of desipramine (DES) administration preceding the maternal deprivation event prevented all the deprivation-induced changes in CRHr2 mRNA, regardless of the direction of the original change. We also found that chronic injection treatments enhanced the adrenocortical response and improved the efficiency of negative feedback in maternal deprivation animals. These results demonstrate that maternal deprivation elicits modifications of CRH brain circuits in a site-specific manner, and that the regulation of CRHr2 gene expression is mediated by mechanisms different from those involved with the modulation of CRHr1 in the infant rat.
促肾上腺皮质激素释放激素（CRH）在大脑和垂体中发挥作用，以协调整体内分泌和行为应激反应。从出生后第4天到第14天，幼鼠对轻度应激的肾上腺反应极小。然而，母婴分离会改变垂体-肾上腺系统，使幼鼠对特定刺激产生反应。我们假设母婴分离也会影响CRH脑回路。由于三环类抗抑郁药已被证明可降低成年大鼠对压力的肾上腺反应，我们推测这种治疗可预防母婴分离诱导的与CRH相关的变化。因此，我们研究了与未分离幼鼠相比，在出生后第13天经历母婴分离的动物体内与CRH相关的分子。我们发现母婴分离导致特定脑区中CRH受体（CRHr）1和2的基因表达发生改变，并且其中一些影响因慢性等渗盐水注射而增强。皮质中CRH、CRHr1和r2 mRNA显著增加。杏仁核中CRHr1和r2 mRNA减少。下丘脑腹内侧核中CRHr2 mRNA也减少，而在海马锥体细胞中检测到增加。在母婴分离事件之前给予一周的地昔帕明（DES）可预防所有由分离诱导的CRHr2 mRNA变化，无论原始变化的方向如何。我们还发现慢性注射治疗增强了母婴分离动物的肾上腺皮质反应并改善了负反馈效率。这些结果表明，母婴分离以位点特异性方式引发CRH脑回路的改变，并且CRHr2基因表达的调节由不同于幼鼠中CRHr1调节所涉及的机制介导。
