Brain metabolic alterations in mice subjected to postnatal traumatic stress and in their offspring

Gapp, Katharina; Corcoba, Alberto; Steenwyk, Gretchen van; Mansuy, Isabelle M; Duarte, João M. N.

doi:10.1177/0271678x16667525

Cited by 38 publications

(31 citation statements)

References 55 publications

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“…Mice allocated to be reared in isolation and group originated from 20 and 17 litters respectively. Sample size estimation was based on previous experiments (Duarte et al 2012a;Corcoba et al 2016;Gapp et al 2017).…”

Section: Methodsmentioning

confidence: 99%

Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine‐to‐glutamate ratio and myo‐inositol concentration in the mouse frontal cortex

Corcoba

Gruetter

et al. 2017

Journal of Neurochemistry

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Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate-cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine-to-glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, p < 0.05) and larger Gln/Glu (+7.6%, p < 0.05), relative to those in group housing. Furthermore, glutathione deficiency caused a reduction in whole brain volume and enlargement of ventricles, but social isolation had no effect on these parameters. We conclude that social isolation caused neurochemical alterations that may add to those associated to impaired glutathione synthesis.

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Section: Methodsmentioning

confidence: 99%

Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine‐to‐glutamate ratio and myo‐inositol concentration in the mouse frontal cortex

Corcoba

Gruetter

et al. 2017

Journal of Neurochemistry

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“…To examine the biological factors involved, we recapitulated heritable behavioural and metabolic effects of postnatal trauma across several generations using a previously established model of unpredictable maternal separation combined with unpredictable maternal stress (MSUS) in the mouse, that shows symptoms through up to three generations ( Fig. 1) [2,[4][5][6][7][8][9][10]. We have shown that such postnatal trauma alters small RNA in sperm and that injection of total sperm RNA from exposed male mice into naïve fertilized oocytes elicits symptoms reminiscent of those observed in natural offspring of exposed fathers [2].…”

Section: Introductionmentioning

confidence: 99%

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

et al. 2018

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Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells. Initial evidence suggested that sperm RNA is causally linked to the transmission of symptoms induced by traumatic experiences. Here, we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioural despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.

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“…To examine the biological factors involved, we recapitulated heritable behavioural and metabolic effects of postnatal trauma across several generations using a previously established model of unpredictable maternal separation combined with unpredictable maternal stress (MSUS) in the mouse, that shows symptoms through up to three generations (Fig. 1) 2,7–13 . We have shown that such postnatal trauma alters small RNA in sperm and that injection of total sperm RNA from exposed male mice into naïve fertilized oocytes elicits symptoms reminiscent of those observed in natural offspring of exposed fathers 2 .…”

Section: Introductionmentioning

confidence: 99%

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Gapp

Steenwyk

Germain

et al. 2018

Preprint

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30Psychiatric diseases have a strong heritable component known to not be restricted to 31 DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in 32 germ cells 1,2 . Initial evidence suggested that sperm RNA is causally linked 2,3 to the 33 transmission of symptoms induced by traumatic experiences. Here we show that 34 alterations in long RNA in sperm contribute to the inheritance of specific trauma 35 symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal 36 trauma recapitulates the effects on food intake, glucose response to insulin and risk-37 taking in adulthood whereas the small RNA fraction alters body weight and behavioral 38 despair. Alterations in long RNA are maintained after fertilization, suggesting a direct 39 link between sperm and embryo RNA. 40 41 42 43 Adverse experiences can have long-lasting transgenerational effects on mental and 46 physical health, and often increase disease risk 4,5 . Traumatic stress in early life in 47 particular, can induce pathologies like psychosis, depression and metabolic 48 dysfunctions in adulthood across generations 6 . To examine the biological factors 49 involved, we recapitulated heritable behavioural and metabolic effects of postnatal 50 trauma across several generations using a previously established model of 51 unpredictable maternal separation combined with unpredictable maternal stress 52(MSUS) in the mouse, that shows symptoms through up to three generations ( Fig.1) 2,7-53 13 . We have shown that such postnatal trauma alters small RNA in sperm and that 54 injection of total sperm RNA from exposed male mice into naïve fertilized oocytes elicits 55 symptoms reminiscent of those observed in natural offspring of exposed fathers 2 . Other 56 studies have demonstrated that adult stress 14,15 and environmental insults like altered 57 diet or vinclozolin exposure, or positive factors such as exercise or environmental 58 enrichment can affect small RNA in sperm 16-21 and somatic tissues 22 in the offspring.59Recently, tRNA fragments and their modifications were also found to be affected by 60 nutritional insult, and unmodified or modified sperm small RNA injected into fertilized 61 oocytes could mimic metabolic changes resulting from altered parental diet in the 62 progeny 18,23,24 . These studies therefore suggest that small RNA in sperm can be 63 carrier of heritable information. Here we sought to determine whether long RNA in 64 sperm also contributes to the transmission of the effects of previous exposure. 66 Materials and Methods 68Mice. C57BL/6J mice were housed in a temperature and humidity-controlled facility 69 under a reverse light-dark cycle, and food and water were provided ad libitum. 70 Experimental procedures were performed during the animals' active cycle. All71 experiments were approved by the cantonal veterinary office, Zurich (license 55/12 then 72 57/15).73 74 MSUS paradigm. C57BL/6J primiparous females and males were mated at 2.5-3 75 months of age. Randomly selected dams and litt...

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Brain metabolic alterations in mice subjected to postnatal traumatic stress and in their offspring

Cited by 38 publications

References 55 publications

Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine‐to‐glutamate ratio and myo‐inositol concentration in the mouse frontal cortex

Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine‐to‐glutamate ratio and myo‐inositol concentration in the mouse frontal cortex

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

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