Effects of Early-Life Stress on the Brain and Behaviors: Implications of Early Maternal Separation in Rodents

Abstract

Early-life stress during the prenatal and postnatal periods affects the formation of neural networks that influence brain function throughout life. Previous studies have indicated that maternal separation (MS), a typical rodent model equivalent to early-life stress and, more specifically, to child abuse and/or neglect in humans, can modulate the hypothalamic-pituitary-adrenal (HPA) axis, affecting subsequent neuronal function and emotional behavior. However, the neural basis of the long-lasting effects of early-life stress on brain function has not been clarified. In the present review, we describe the alterations in the HPA-axis activity-focusing on serum corticosterone (CORT)-and in the end products of the HPA axis as well as on the CORT receptor in rodents. We then introduce the brain regions activated during various patterns of MS, including repeated MS and single exposure to MS at various stages before weaning, via an investigation of c-Fos expression, which is a biological marker of neuronal activity. Furthermore, we discuss the alterations in behavior and gene expression in the brains of adult mice exposed to MS. Finally, we ask whether MS repeats itself and whether intergenerational transmission of child abuse and neglect is possible.

Keywords: HPA axis; c-Fos; epigenetics; group-housing; neglect; reward-seeking behavior; transgeneration.

Figure 1

Schematic representation of behavioral analysis under group-housing conditions. Adult male mice are individually tagged with a mouse ID on their back. An infrared camera takes an image for several days. The software recognizes the ID of each mouse and records the X–Y coordinates.

Figure 2

Methylation patterns across Drd1a CpG islands in female maternal separation (MS) mice. (A) Overall methylation is presented as the percentage of methylated sites (n = 9 for control, n = 8 for MS; p < 0.0001). (B) Individual CpG methylation statuses are presented as the percentage of methylated sites (n = 9 for control, n = 8 for MS; 31 CpG sites). * p < 0.05, versus control; ** p < 0.01, versus control (Fisher’s exact test) [61].