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).
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.
Buckwalter JG, Buckwalter DK, Bluestein BW, Stanczyk FZ . Pregnancy and post partum: changes in cognition and mood. Prog Brain Res 2001; 133: 303–319.
Crawley RA, Dennison K, Carter C . Cognition in pregnancy and the first year post-partum. Psychol Psychother 2003; 76 (Part 1): 69–84.
Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 2006; 9: 268–275.
Leuner B, Mirescu C, Noiman L, Gould E . Maternal experience inhibits the production of immature neurons in the hippocampus during the postpartum period through elevations in adrenal steroids. Hippocampus 2007; 17: 434–442.
van Praag H, Kempermann G, Gage FH . Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999; 2: 266–270.
Kempermann G, van Praag H, Gage FH . Activity-dependent regulation of neuronal plasticity and self repair. Prog Brain Res 2000; 127: 35–48.
Bick-Sander A, Steiner B, Wolf SA, Babu H, Kempermann G . Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring. Proc Natl Acad Sci USA 2006; 103: 3852–3857.
Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 2003; 299: 117–120.
Luppi P . How immune mechanisms are affected by pregnancy. Vaccine 2003; 21: 3352–3357.
About this article
Cite this article
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
Early and late effects of maternal experience on hippocampal neurogenesis, microglia, and the circulating cytokine milieu
Neurobiology of Aging (2019)
Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility
Proceedings of the National Academy of Sciences (2019)
Social Cognitive and Affective Neuroscience (2019)