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Trans-generational effects of early life stress: the role of maternal behavior.

Schmauss C, Lee-McDermott Z, Medina LR - Sci Rep (2014)

Bottom Line: These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex.Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits.Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychiatry and Molecular Therapeutics, Columbia University [2] New York State Psychiatric Institute, New York, NY 10032.

ABSTRACT
Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations. These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex. These behavioral and epigenetic phenotypes are transmitted to the first progeny of IMS Balb/c mothers, but not fathers, and cross-fostering experiments revealed that this transmission is triggered by maternal behavior and modulated by the genetic background of the pups. In the continued absence of the original stressor, this transmission fades in later progenies. An adolescent treatment that lowers the levels of acH4K12 in IMS Balb/c mice augments their emotional abnormality but abolishes their cognitive deficits. Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits. Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented.

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Maternal transmission of increased Gαq expression.(a) Data are mean ± sem (N = 6–8/group; equal numbers of males and females) of real-time RT-PCR measures. A comparison between SFR, IMS, and theophylline-treated IMS (IMS-tph) Balb/c mice (ANOVA (F(2,18) = 8.338; p = 0.0033; post hoc Tukey-Kramer multiple comparisons)) revealed significantly increased Gαq mRNA expression in IMS Balb/c mice that was reversed by adolescent theophylline treatment. Further comparison between SFR, F2 progenies of IMS fathers and mothers, F2 progenies of IMS mothers treated with theophylline (F2-tph), and F3 and F4 progenies of IMS mothers mice revealed significant differences (ANOVA (F(5,45) = 3.234; p = 0.0152) that were resolved post hoc only for the F2 progeny of IMS mothers that exhibited increased Gαq mRNA expression. (b) Gαq mRNA levels in cross-fostered mice. Significant differences revealed by ANOVA, F(2,17) = 12.22, p = 0.0007)) were resolved post hoc for F2-RevCF mice that exhibited increased Gαq expression.
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f2: Maternal transmission of increased Gαq expression.(a) Data are mean ± sem (N = 6–8/group; equal numbers of males and females) of real-time RT-PCR measures. A comparison between SFR, IMS, and theophylline-treated IMS (IMS-tph) Balb/c mice (ANOVA (F(2,18) = 8.338; p = 0.0033; post hoc Tukey-Kramer multiple comparisons)) revealed significantly increased Gαq mRNA expression in IMS Balb/c mice that was reversed by adolescent theophylline treatment. Further comparison between SFR, F2 progenies of IMS fathers and mothers, F2 progenies of IMS mothers treated with theophylline (F2-tph), and F3 and F4 progenies of IMS mothers mice revealed significant differences (ANOVA (F(5,45) = 3.234; p = 0.0152) that were resolved post hoc only for the F2 progeny of IMS mothers that exhibited increased Gαq mRNA expression. (b) Gαq mRNA levels in cross-fostered mice. Significant differences revealed by ANOVA, F(2,17) = 12.22, p = 0.0007)) were resolved post hoc for F2-RevCF mice that exhibited increased Gαq expression.

Mentions: These data suggest that the F2 progeny of IMS females might also exhibit increased acetylation of H4K12, an epigenetic mark of open chromatin and active gene transcription that is likely responsible for increased expression of distinct genes in IMS mice, including the increased Gαq expression described in previous studies56. To test this, we first used real-time PCR to compare forebrain neocortical Gαq mRNA expression levels between SFR, IMS, and F2 to F4 progenies of IMS mice. As shown in Fig. 2a, IMS Balb/c mice exhibit a ~4-fold increase in Gαq mRNA expression that was completely reversed by adolescent treatment with the HDAC-activating dose of theophylline. The F2 progeny of IMS mothers (but not fathers) also exhibited a theophylline-reversible increase in Gαq mRNA expression, but their F3 and F4 progenies reverted to normal Gαq mRNA expression (Fig. 2a). Moreover, similar to the emotional behavior of cross-fostered F2 mice, F2 mice raised by SFR mothers had normal Gαq mRNA expression levels, but Gαq mRNA levels of SFR pups raised by IMS mothers were significantly increased (Fig. 2b).


Trans-generational effects of early life stress: the role of maternal behavior.

Schmauss C, Lee-McDermott Z, Medina LR - Sci Rep (2014)

Maternal transmission of increased Gαq expression.(a) Data are mean ± sem (N = 6–8/group; equal numbers of males and females) of real-time RT-PCR measures. A comparison between SFR, IMS, and theophylline-treated IMS (IMS-tph) Balb/c mice (ANOVA (F(2,18) = 8.338; p = 0.0033; post hoc Tukey-Kramer multiple comparisons)) revealed significantly increased Gαq mRNA expression in IMS Balb/c mice that was reversed by adolescent theophylline treatment. Further comparison between SFR, F2 progenies of IMS fathers and mothers, F2 progenies of IMS mothers treated with theophylline (F2-tph), and F3 and F4 progenies of IMS mothers mice revealed significant differences (ANOVA (F(5,45) = 3.234; p = 0.0152) that were resolved post hoc only for the F2 progeny of IMS mothers that exhibited increased Gαq mRNA expression. (b) Gαq mRNA levels in cross-fostered mice. Significant differences revealed by ANOVA, F(2,17) = 12.22, p = 0.0007)) were resolved post hoc for F2-RevCF mice that exhibited increased Gαq expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4007084&req=5

f2: Maternal transmission of increased Gαq expression.(a) Data are mean ± sem (N = 6–8/group; equal numbers of males and females) of real-time RT-PCR measures. A comparison between SFR, IMS, and theophylline-treated IMS (IMS-tph) Balb/c mice (ANOVA (F(2,18) = 8.338; p = 0.0033; post hoc Tukey-Kramer multiple comparisons)) revealed significantly increased Gαq mRNA expression in IMS Balb/c mice that was reversed by adolescent theophylline treatment. Further comparison between SFR, F2 progenies of IMS fathers and mothers, F2 progenies of IMS mothers treated with theophylline (F2-tph), and F3 and F4 progenies of IMS mothers mice revealed significant differences (ANOVA (F(5,45) = 3.234; p = 0.0152) that were resolved post hoc only for the F2 progeny of IMS mothers that exhibited increased Gαq mRNA expression. (b) Gαq mRNA levels in cross-fostered mice. Significant differences revealed by ANOVA, F(2,17) = 12.22, p = 0.0007)) were resolved post hoc for F2-RevCF mice that exhibited increased Gαq expression.
Mentions: These data suggest that the F2 progeny of IMS females might also exhibit increased acetylation of H4K12, an epigenetic mark of open chromatin and active gene transcription that is likely responsible for increased expression of distinct genes in IMS mice, including the increased Gαq expression described in previous studies56. To test this, we first used real-time PCR to compare forebrain neocortical Gαq mRNA expression levels between SFR, IMS, and F2 to F4 progenies of IMS mice. As shown in Fig. 2a, IMS Balb/c mice exhibit a ~4-fold increase in Gαq mRNA expression that was completely reversed by adolescent treatment with the HDAC-activating dose of theophylline. The F2 progeny of IMS mothers (but not fathers) also exhibited a theophylline-reversible increase in Gαq mRNA expression, but their F3 and F4 progenies reverted to normal Gαq mRNA expression (Fig. 2a). Moreover, similar to the emotional behavior of cross-fostered F2 mice, F2 mice raised by SFR mothers had normal Gαq mRNA expression levels, but Gαq mRNA levels of SFR pups raised by IMS mothers were significantly increased (Fig. 2b).

Bottom Line: These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex.Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits.Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychiatry and Molecular Therapeutics, Columbia University [2] New York State Psychiatric Institute, New York, NY 10032.

ABSTRACT
Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations. These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex. These behavioral and epigenetic phenotypes are transmitted to the first progeny of IMS Balb/c mothers, but not fathers, and cross-fostering experiments revealed that this transmission is triggered by maternal behavior and modulated by the genetic background of the pups. In the continued absence of the original stressor, this transmission fades in later progenies. An adolescent treatment that lowers the levels of acH4K12 in IMS Balb/c mice augments their emotional abnormality but abolishes their cognitive deficits. Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits. Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented.

Show MeSH
Related in: MedlinePlus