intergenerational transmission of trauma

We used a comprehensive approach combining metabolomic, transcriptomic, and bioinformatic analyses to determine the molecular processes that are associated with stress-induced behavioral deficits. We applied cross-fostering procedures to evaluate the distinct contributions to adult behavioral deficits of prenatal trauma and subsequent postnatal inadequate caregiving. To recapitulate intergenerational trauma experience, we modeled stress by exposing mouse dams in the last four days of their pregnancy to a predator odor. We hypothesized that prenatal stress acts as a priming factor that synergistically interacts with subsequent early-life challenges (inadequate caregiving by traumatized mothers) to exacerbate the tendency for offspring of traumatized mothers to develop psychiatric disorders later in life. Therefore, the goal of this work is to we examine the distinctive behavioral impacts and neurobiological mechanisms of in utero exposure alone (prenatal one-hit stress) versus impaired maternal care alone (postnatal one-hit stress) or combined exposure (prenatal and postnatal two-hits stress). The limitations in our understanding of the neurobiological and pathophysiological mechanisms of stress-induced depression, particularly the lack of measurable biochemical and molecular alterations, hamper effective pharmacological interventions to prevent or ameliorate the behavioral deficits. Yet, it is difficult to test the mechanistic involvement of prenatal stress independent of stress effects on the mother care. On the other hand, maternal stress can affect offspring mental outcomes through prenatal programming, particularly epigenetic mechanisms causing permanent neuronal impairments and poor offspring outcomes that persist throughout life 11, 12, 13. This ambiguity is mainly due to the complexity, superposition, and inseparability of prenatal and postnatal mechanisms that are not mutually exclusive.Ĭonverging evidence from human and animal studies supports that exposure to stress during pregnancy negatively affects maternal behavior towards, and the care of, offspring 8, 9, 10. Whether intergenerational trauma transmission and its negative outcomes are a consequence of in utero fetal neurodevelopment disruptions or from poor maternal care by traumatized mothers is still largely ambiguous. Human natural experiments provide evidence for the devastating health consequences in offspring as a result of exposure during pregnancy to existential and acute trauma such as war and natural disasters 5, 6, 7. Unlike other vulnerable conditions, the deleterious impacts of stress during pregnancy are doubled as they affect the mental health of the mothers and the unborn offspring. While stress deleteriously impacts humans worldwide and attacks all segments of societies at this moment in human history, it is disproportionately devastating to individuals in vulnerable situations such as pregnant women. Major depressive disorder (MDD) affects millions of people globally who have been subject to stress and trauma at some times of their lives. Intergenerational trauma increases lifetime susceptibility to depression and is a major risk factor for developing multiple neuropsychiatric disorders such as post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), and schizophrenia 1, 2, 3, 4. Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression. 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). 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. The behavioral deficits were associated with profound changes in the brain metabotranscriptome.

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. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers.

Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother–infant interaction is unknown. Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders.

Intergenerational transmission of trauma