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Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

ABSTRACT: Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.

SUBMITTER: Alhassen S

PROVIDER: S-EPMC8225861 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

Alhassen Sammy S Chen Siwei S Alhassen Lamees L Phan Alvin A Khoudari Mohammad M De Silva Angele A Barhoosh Huda H Wang Zitong Z Parrocha Chelsea C Shapiro Emily E Henrich Charity C Wang Zicheng Z Mutesa Leon L Baldi Pierre P Abbott Geoffrey W GW Alachkar Amal A

Communications biology 20210624 1

Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in ...[more]

PMID: 34168265

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Project description:ABSTRACTObjective/Background: Despite increasing attention on transgenerational trauma, currently no comprehensive model and measure exists to be applied on various populations. This study represents the first step in the validation of such a model and a related scale. The Historical Intergenerational Trauma Questionnaire (HITT-Q) assesses family and offspring self-reported vulnerability and resilience, as well as offspring historical moral injury and current levels of insidious trauma.Method: We developed the HITT-Q based on the cross-population model (HITT model; [Starrs, C. & Békés, V. (2024). Historical and transgenerational trauma: A conceptual framework. Traumatology. In Press]) which incorporates key findings in existing population specific studies. For initial validation of the model and its measurement, Holocaust survivors' offspring (N = 1104) completed the HITT-Q, measures of current mental health symptoms (PTSD, C-PTSD, anxiety, and depression), and a resilience scale.Results: In line with the HITT model, confirmatory factor analyses supported a 12-factor solution with the following factors under theorized dimensions: I. Family Vulnerability: (1) Dysregulated and Trauma-related Communication; (2)Trauma-influenced Parenting, (3) Fear; (4) Distress; II. (5) Family Resilience, III. Offspring Vulnerability: (6) Escape; (7) Heightened Responsibility; (8) Trauma-related distress; IV. Offspring Resilience: (9) Coping; (10) Belonging; (11) Values; V. (12) Historical Moral injury. The 12-factor model showed acceptable to good internal validity, and comparison with an existing measure of transgenerational Holocaust trauma indicated good concurrent validity. Finally, the HITT-Q demonstrated predictive validity for mental health symptoms and current resilience.Conclusions: The current study represents the first step in validating the HITT-Q as a comprehensive measure of historical intergenerational vulnerability and resilience. Our findings provide strong support for the underlying model, and suggest that the HITT-Q represents a valuable scale for both research and historical trauma-informed care.

Project description:Early life stress in humans (i.e. maltreatment, violence exposure, loss of a loved one) and in rodents (i.e. disrupted attachment or nesting, electric shock, restraint, predator odor) occurs during critical steps of neural circuit formation. ELS in humans is associated with increased risk for developmental psychopathology, including anxious and depressive phenotypes. The biological mechanisms underlying these potentially persistent maladaptive changes involve long-term epigenetic modifications, which have been suggested to be potentially transmissible to subsequent generations. DNA methylation is an epigenetic mechanism that modifies gene expression patterns in response to environmental challenges and influences mutation rates. It remains to be seen whether a functionally relevant fraction of DNA methylation marks can escape genome-wide erasures that occur in primordial germ cells and after fertilization within the zygote. Early life-stress-triggered changes in epigenetic mediated transmission of acquired behavioral traits among humans have been assessed mainly by targeting genes involved in the hypothalamic-pituitary-adrenal (HPA) axis, such as NR3C1 and FKBP5. Recently, researchers examining epigenetic transmission have begun to apply genome-wide approaches. In humans, reduced representation bisulfite sequencing (RRBS) was performed on peripheral samples that were obtained from individuals who were prenatally exposed to the "Dutch Hunger Winter", resulting in two Differentially Methylated Regions (DMRs) in INSR and CPTIA genes that were functionally, biologically and technically validated, and significantly associated with birth weights and LDL cholesterol levels in offspring. In rodents, non-genomic intergenerational transmission of anxiety which was associated with differentially methylated enhancers that were putatively involved in lipid signaling and synaptic/neurotransmission in hippocampal granule cells, was discovered also using RRBS. Finally, transgenerational transmission of altered behaviors was associated with sperm-derived microRNAs produced by ELS male mice. The field of epigenetic transmission is just beginning to enter the epigenomic era by using genome-wide analyses. Such approaches remain of strong interest to human studies, first in order to help to assess the relevance of the previous targeted studies, and second to discover new important epigenetic modifications of potential clinical importance. New discoveries may help to assess how transmittable the negative impact of stress may be to offspring. The latter may open doors for future treatments and resilience-promoting interventions, as well as new approaches to treat the effects of childhood trauma before the onset of psychiatric disorder.

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Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

Publications

Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

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