Age- and sex-dependent effects of early life stress on hippocampal neurogenesis

Abstract

Early life stress is a well-documented risk factor for the development of psychopathology in genetically predisposed individuals. As it is hard to study how early life stress impacts human brain structure and function, various animal models have been developed to address this issue. The models discussed here reveal that perinatal stress in rodents exerts lasting effects on the stress system as well as on the structure and function of the brain. One of the structural parameters strongly affected by perinatal stress is adult hippocampal neurogenesis. Based on compiled literature data, we report that postnatal stress slightly enhances neurogenesis until the onset of puberty in male rats; when animals reach adulthood, neurogenesis is reduced as a consequence of perinatal stress. By contrast, female rats show a prominent reduction in neurogenesis prior to the onset of puberty, but this effect subsides when animals reach young adulthood. We further present preliminary data that transient treatment with a glucocorticoid receptor antagonist can normalize cell proliferation in maternally deprived female rats, while the compound had no effect in non-deprived rats. Taken together, the data show that neurogenesis is affected by early life stress in an age- and sex-dependent manner and that normalization may be possible during critical stages of brain development.

Keywords: adult neurogenesis; dentate gyrus; hippocampus; maternal deprivation; maternal separation; proliferation; rat; stress.

Figure 1

General scheme highlighting that life events, especially when experienced during the early developmental stage, may strongly impact the development of the brain, especially in genetically susceptible individuals. These gene–environment interactions during development will strongly contribute to the overall brain structure and function as well as stress responsiveness in adulthood.

Figure 2

Meta-analysis of age- and sex-dependent effects of early life adversity on neurogenesis. The graphs show the percentage change in number of Ki-67 and Doublecortin (DCX)-positive cells after perinatal stress (y-axis; 100% is control), as a function of the age at which the change in neurogenesis was determined (x-axis, in weeks). (A) Both in males (top) and females (bottom), the change in number of Ki-67 positive cells due to prenatal (triangle), maternal separation (diamond) or maternal deprivation (square) was negatively correlated to the age at which the effect was determined. (B) In male rodents (top), the number of DCX-positive cells was found to be enhanced by perinatal stress when examined at a very young age. When studied at time-points >2 months of age, generally a decrease in the number of DCX-positive cells was observed. Overall, this resulted in a negative correlation between the effect of early life stress on neurogenesis and the age at which these effects were apparent. In female rats (bottom), we observed a correlation in the opposite direction. The data points are based on the references summarized in Table 1. The one data-point depicted by the filled symbol in the graphs of the females represents the percentage change found in the pilot study described in Figure 4 (not incorporated in Table 1).The striped horizontal line in the graphs indicates the control condition (i.e., the non-stressed groups mentioned in the same publications) against which the number of cells in the stress groups was expressed. The drawn line indicates the best fit for the linear correlation.

Figure 3

Sex-dependent effects of maternal deprivation on neurogenesis. (A) The number of Doublecortin (DCX)-positive neurons in the entire dentate gyrus from 21-days-old male rats, which underwent MD for 24 h at postnatal day (PND) 3, was significantly (*p < 0.05; n = 7 animals) enhanced compared to the non-deprived controls (CON). Half of the animals received glucose (g) on day 3, to compensate for the loss in nutrients, while the remaining animals received saline (s). There was no effect of sucrose compared to saline treatment. (B) The opposite effect was observed in the female littermates: i.e., the number of DCX-positive neurons on PND 21 was significantly reduced in maternally deprived compared to non-deprived rats, regardless of sucrose/saline treatment (n = 7). From Ref. (70).

Figure 4

Brief treatment with the GR antagonist mifepristone protects female rats against the effects of early life stress. Rats were deprived from their mother for 24 h at PND 3, following the procedure as described in Oomen et al. (70). After weaning at PND 21, they were group-housed with same-sex same-littermates. On PND 26–28 each rat received mifepristone twice daily (5 mg of RU-38486 (Sigma) per 100 g of body weight, dissolved first in 15 μl ethanol and then in 1.5 ml coffee cream (Campina, Woerden, The Netherlands) and administered by oral gavage (77). One day later, at PND 29, female rats were transcardially perfused with saline, followed by 4% paraformaldehyde in phosphate buffer (0.1M; pH 7.4). Tissue handling and staining for DCX and the proliferation marker Ki67 was conducted as described in Oomen et al. (70). (A) Typical example of Ki-67 staining in the DG of a control female rat. (B) Typical example of DCX staining in the DG of a control female rat. (C) Cell proliferation at PND 29, as determined with Ki-67 staining, was significantly increased in the hilus of MD female rats treated with mifepristone (MIF) on PND 26–28, compared to those treated with vehicle. MIF had no effect in non-deprived (NMD) rats. No significant differences between the experimental groups were seen in the dentate as a whole (data not shown). For each animal, we counted the number of Ki67-positive cells in every 10th section and from this the total number of Ki67-positive cells per hemisphere was inferred. All bars represent the mean + SEM per group (n = 7–9 animals per group). (D) In the supra-pyramidal blade, a trend (p = 0.08) toward a significant increase in the number of DCX-positive cells in MD female rats treated with MIF vs. those treated with vehicle was observed. Mifepristone did not alter neurogenesis at all in NMD rats. Though the percentage change in the infrapyramidal blade and the dentate gyrus as a whole showed a comparable pattern, these differences were not significant (p > 0.1, data not shown). For each animal, we counted every 10th section sampled in an unbiased stereological manner, yielding up to a total of nine sections per animal. We then expressed the average number of DCX-positive cells per section per animal. All bars represent the mean + SEM per group (n = 11–12 animals per group).