Decrease in hippocampal neurogenesis during pregnancy: a link to immunity

Changes in cognitive performance, such as deficits in learning and memory, have been extensively reported in women during pregnancy. Most previous studies attributed these changes to emotional and hormonal alterations,1, 2 while the cellular mechanisms that underlie changes in cognitive abilities remain largely unknown. Learning and especially memory were recently associated with the formation of new neurons in the dentate gyrus of the hippocampus. Since levels of hippocampal neurogenesis vary in response to a wide range of intrinsic and extrinsic factors, we considered the possibility that neurogenesis is deviated during pregnancy, thus providing potential explanation for the changes in maternal cognitive performance during that period.

We examined neurogenesis levels in pregnant mice by injecting the cell-proliferation marker, bromodeoxyuridine (BrdU), at different stages of pregnancy. We analyzed the hippocampi 14 days after the first injection of BrdU and labeled them, as previously described,3 with antibodies to BrdU and to doublecortin (DCX), a marker for immature neurons. We observed a significant decrease in the number of newly formed neurons (BrdU+/DCX+) in the dentate gyrus of the pregnant mice during the second and the third trimesters of pregnancy compared to the virgin control animals (Figures 1a and b; only the data for the second trimester are shown). These differences were consistent within other inbred and outbred strains (Figure 1b).

Figure 1
figure1

Pregnancy induces a transient reduction in hippocampal neurogenesis. BrdU was injected every 12 h (for a total of four injections) on the days indicated. In the controls, BrdU was injected according to the same regimen in virgin age-matched mice. The mice were killed 14 days after the first BrdU injection, and their brains were excised and examined by immunohistochemical staining.3 (a) BrdU labeling in the dentate gyrus of virgin versus pregnant (BrdU on gestational days (GD) 11–12) mice (scale bar 100 μm). (b) Table summarizing the numbers of BrdU+/DCX+ cells in the dentate gyrus of virgin and pregnant mice of different strains; mice (C57BL/6) after delivery (BrdU given on post-delivery day (PD) 21); and mice (C57BL/6) given unlimited voluntary access to a running wheel during the entire experimental period compared to control mice that were maintained in standard cages (BrdU given on GD 11–12). Data are expressed as mean±s.e.m. Statistical significance was determined using the Student's t-test or ANOVA (F=4.234; P=0.0251) and statistical data are provided in the right column (n=4–5). Lines indicate groups that varied statistically according to Fisher's PLSD test (95%). (c) Quantification of BrdU+ cells and BrdU+/ DCX+ cells in the dentate gyrus of strain-matched wild-type (CD1), nude and splenocyte-replenished nude mice (virgin and pregnant). Statistical analysis was performed using ANOVA (F=67.918; P=0.0001; n=4–5 per group). *Indicates differences significant at the 95% level according to the Fisher's PLSD test. Data are expressed as mean±s.e.m.

In agreement with previous report,4 we found that hippocampal neurogenesis returned to normal levels approximately 21 days postpartum (PD) (Figure 1b).

In an attempt to examine whether this decrease in neurogenesis is amenable to modulation, we examined the effect of physical activity (voluntary wheel running), which is known to induce adult hippocampal neurogenesis.5, 6 We analyzed the neurogenesis levels in mice placed in housing conditions that enabled voluntary wheel running during their pregnancy. We found that as a result of physical activity, hippocampal neurogenesis in pregnant mice was maintained at a level similar to that observed in virgin controls (Figure 1b). Since physical activity is often recommended to pregnant women, and was even reported to induce neurogenesis in the offspring,7 exercise comprises a potential noninvasive means to overcome the pregnancy-induced decrease in neurogenesis.

Mechanistically, it would be reasonable to assume that the observed reduction in neurogenesis is a direct outcome of hormonal changes. Hormones are known to affect adult neurogenesis, even postpartum.4 However, in a recent study performed by Shingo et al.,8 it was shown that pregnancy-related hormones, such as estrogen and progesterone, have no effect on adult hippocampal neurogenesis, with the exception of prolactin, which directly induces neurogenesis only in the olfactory bulb of pregnant mice. These results led us to consider the possibility that the pregnancy-induced reduction in neurogenesis might not be directly caused by hormonal changes, but rather may be an outcome of other physiological adaptations to pregnancy, such as pregnancy-induced changes in the immune response.

Our group recently showed that the immune system and, in particular, the adaptive immune response contribute to adult hippocampal neurogenesis.3 During pregnancy, to enable the survival of a fetus, which may be viewed as a semi-allogeneic graft, the immune system undergoes major changes, among them are alternations in T-cell activity.9 We therefore anticipated that if the pregnancy-induced decrease in neurogenesis is immune-dependent, no reduction in neurogenesis would be observed in immune-deficient mice during pregnancy. We repeated the same experimental paradigm of BrdU injection utilizing nude mice, which lack the entire T-cell population. We observed that in pregnant nude mice, there was only a modest reduction in neurogenesis during pregnancy (Figure 1c). However, when we reconstituted these nude mice with T cells from wild-type mice and mated them 8 days after reconstitution, we were able to restore the pregnancy-induced decrease in neurogenesis (Figure 1c). These results, thus, suggest a dependence of the observed reduction in hippocampal neurogenesis on the presence of T cells; however, the specific contribution of T-cell immunity and the underlying mechanism by which they control neurogenesis require further investigation.

Our study demonstrates a transient decrease in hippocampal neurogenesis during pregnancy, a phenomenon that is subjected to modulation by physical activity. Thus, these findings provide a novel insight into changes in cognitive function during pregnancy, shedding light on the adaptation of the body to this unique phase.

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Correspondence to M Schwartz.

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Rolls, A., Schori, H., London, A. et al. Decrease in hippocampal neurogenesis during pregnancy: a link to immunity. Mol Psychiatry 13, 468–469 (2008). https://doi.org/10.1038/sj.mp.4002126

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