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Cited by 190Neurogenesis and neuroplasticity mechanismsStress Responses and CortisolMaternal Mental Health During Pregnancy and Postpartum

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

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Oomen, Charlotte A., Girardi, Carlos E. N., Cahyadi, Rudy, Verbeek, Eva C., Krugers, Harm, Joëls, Marian, Lucassen, Paul J.·2009·PLoS ONE
DOI 10.1371/journal.pone.0003675PMC PMC2629844
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Abstract

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.

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Figures

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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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.CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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 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).CC BY · PubMed Central
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).
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).CC BY · PubMed Central

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Metadata

Authors
Oomen, C. A., Girardi, C. E. N., Cahyadi, R., Verbeek, E. C., Krugers, H., Joëls, M., & Lucassen, P. J.
Affiliations
University of Amsterdam (NL)
Corresponding author
Lucassen, Paul J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2009-01-29
Volume
4
Issue
1
Pages
e3675
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0003675
PMC
PMC2629844
OpenAlex
W2105673253
Cited by
190
References
126
Citations by year
2026: 5 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 12 · 2019: 13 · 2018: 14 · 2017: 17 · 2016: 15 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 9
FWCI
5.54
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, cc-by)
  • UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
maternal deprivation, early life stress, hippocampal neurogenesis, sex differences, structural plasticity, perinatal stress, hypothalamic-pituitary-adrenal axis, astrocytes, gliogenesis, maternal care
MeSH terms
Analysis of Variance, Animals, Animals, Newborn, Astrocytes, Behavior, Animal, Cell Differentiation, Cell Survival, Corticosterone, Female, Male, Maternal Deprivation, Neuroglia, Neuronal Plasticity, Sex Factors, Weight Loss, Rats, Wistar, Dentate Gyrus, Cell Proliferation, Rats, Neurogenesis

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