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, 4 (1), e3675

Opposite Effects of Early Maternal Deprivation on Neurogenesis in Male Versus Female Rats


Opposite Effects of Early Maternal Deprivation on Neurogenesis in Male Versus Female Rats

Charlotte A Oomen et al. PLoS One.


Background: Major depression is more prevalent in women than in men. The underlying neurobiological mechanisms are not well understood, but recent data shows that hippocampal volume reductions in depressed women occur only when depression is preceded by an early life stressor. This underlines the potential importance of early life stress, at least in women, for the vulnerability to develop depression. Perinatal stress exposure in rodents affects critical periods of brain development that persistently alter structural, emotional and neuroendocrine parameters in adult offspring. Moreover, stress inhibits adult hippocampal neurogenesis, a form of structural plasticity that has been implicated a.o. in antidepressant action and is highly abundant early postnatally. We here tested the hypothesis that early life stress differentially affects hippocampal structural plasticity in female versus male offspring.

Principal findings: We show that 24 h of maternal deprivation (MD) at PND3 affects hippocampal structural plasticity at PND21 in a sex-dependent manner. Neurogenesis was significantly increased in male but decreased in female offspring after MD. Since no other structural changes were found in granule cell layer volume, newborn cell survival or proliferation rate, astrocyte number or gliogenesis, this indicates that MD elicits specific changes in subsets of differentiating cells and differentially affects immature neurons. The MD induced sex-specific effects on neurogenesis cannot be explained by differences in maternal care.

Conclusions: Our data shows that early environment has a critical influence on establishing sex differences in neural plasticity and supports the concept that the setpoint for neurogenesis may be determined during perinatal life. It is tempting to speculate that a reduced level of neurogenesis, secondary to early stress exposure, may contribute to maladaptation of the HPA axis and possibly to the increased vulnerability of women to stress-related disorders.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. Basal corticosterone levels on PND4.
A significant increase is found in corticosterone levels after maternal deprivation (MDs, sham injected) compared to controls (both undisturbed CONU and sham-injected CONS). Additional glucose treatment (MDG) failed to normalize this (F(3,55) = 10.30; p<0.0001; post-hoc: CONU = CONS<MDS = MDG at least p<0.05).
Figure 2
Figure 2. Dentate gyrus cell proliferation (Ki-67) on PND4 in CONS and MDS animals.
There was no significant effect of sex (F(2,21) = 0.04; p = 0.95) or treatment (F(3,21) = 1.13; p = 0.30) and no interaction between the two (F(3,21) = 2.45; p = 0,14).
Figure 3
Figure 3. Granular cell layer (GCL) volume on PND21.
There was no effect of any of the treatments on granular cell layer volume. However, significantly lower GCL volumes were found in females (F(1.51) = 122.4; p<0.0001).
Figure 4
Figure 4. Dentate gyrus cell proliferation (Ki-67) on PND21.
A. In males, MD affected dentate cell proliferation rate at PND21 (F(3,28) = 3,2, p = 0.043). Post-hoc analysis revealed a decrease in MD-glucose injected animals (p<0.05). B. In females, there was no effect of treatment (F(3,28) = 0.41 p = 0.75), although a significant lower number of Ki-67 positive cells was found in females when compared to males (F(1,56) = 8.56; p = 0.005).
Figure 5
Figure 5. Number of newborn surviving cells (BrdU+) in the dentate gyrus on PND21.
There was a significant effect of sex, but not of treatment on BrdU positive cell numbers. A. Maternal deprivation did not alter BrdU+ cell numbers in males (F(3,28) = 0.40, p = 0.75), or (B) females (F(3,28) = 1.1, p = 0.37). Irrespective of MD, females had an overall lower number of BrdU-positive cells (F(1,51) = 29.8; p<0.0001).
Figure 6
Figure 6. Doublecortin (DCX) -positive neurons.
A. Photo of the dentate gyrus of a 21 day old CONS male showing extensive immunostaining of DCX in the subgranular zone (sgz) and the first third of the granular cell layer (GCL) with dendrites extending through the granular cell layer (GCL) into the molecular layer (ML). B. High power photomicrograph showing details of the DCX+ cell bodies located in the SGZ and GCL, with extending dendrites in the GCL.
Figure 7
Figure 7. Doublecortin (DCX) -positive neuron numbers on PND21.
A significant treatment×sex interaction revealed a differential effect of MD on males versus females (F(3,48) = 8.04; p<0.0001). A. An increase in DCX+ cell number was found in deprived males (F(3,28) = 4.3, p = 0.018; post-hoc: CONU = CONS<MDS = MDG, at least p<0.05) and a decrease in deprived females (F(3,28) = 4.65, p = 0.013; post-hoc: CONU = CONS>MDS = MDG, at least p<0.05) when compared to controls. A significant effect of sex indicates a general lower amount of DCX+ cells in females (F(1,48) = 65.80; p<0.0001).
Figure 8
Figure 8. Astrocyte numbers.
GFAP-positive astrocyte numbers determined stereologically in the entire hippocampal dentate gyrus on PND21. A. Maternal deprivation did not affect GFAP+ cell number in males (F(3,28) = 1.3, p = 0.28), B. nor females (F(3,28) = 0.05, p = 0.99). However, a significant effect of sex on GFAP+ cell number was found (F(3,56) = 25.01; p<0.0001).
Figure 9
Figure 9. GFAP/BrdU double labeling.
Immunohistochemical double labeling for GFAP and BrdU shows single GFAP+ astrocytes in the hilus with their processes occasionally extending into the sgz. GFAP+ cells reveal brown DAB-staining in their processes and cytoplasm whereas the nucleus is devoid of staining. In the GCL, BrdU+ single cells are stained black by DAB-nickel as indicated (BrdU+) in the granular cell layer (GCL). Shown on the left is a BrdU/GFAP double labeled cell (arrow).
Figure 10
Figure 10. Percentage of GFAP/BrdU double-labeled cells in the dentate gyrus.
There was no effect of MD on the percentage of double labeled cells in both males and females (F(3,24) = 0.40; p = 0.54). No effect of sex was found (F(1,24) = 0.56; p = 0.46).
Figure 11
Figure 11. Licking and grooming on PND1–7 in control and MD litters.
A significant increase in LG was found on PND4 both in males and females compared to their same-sex controls. (PND4 LG-scores: males F(3,21) = 7.31; p = 0.002; post-hoc: MD males>CON males = MD females>CON females, p<0.05).
Figure 12
Figure 12. Arch back nursing.
Arch back nursing towards the entire litter in control and MD litters on PND1–7. There is a significant increase after PND3 (F = 7.89, p = 0.02).

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