When the 2011 peaceful uprising in Syria turned into war, Amal Alachkar and her family were among the 13 million refugees who had to leave their homes.
Through that life-changing experience, Alachkar was concerned about the long-term, persistent impact and intergenerational transmission of trauma that can be caused by wars, genocides and other catastrophes. Alachkar, now a professor in the UC Irvine School of Pharmacy & Pharmaceutical Sciences, is focusing her research on how and when biological mechanisms lead to the trauma transmission from the parents or even grandparents to children.
In a recent study published in Nature Communications Biology, Alachkar worked collaboratively with an interdisciplinary group that included UCI School of Medicine Senior Associate Dean and Professor Geoff Abbott and Distinguished Professor Pierre Baldi in the School of Information and Computer Sciences.
Alachkar and the team found that early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.
“Given the unique features of ALCAR, this natural supplement can represent an innovative and unique prophylactic and therapeutic strategy, should it be administered in the right time of life,” Alachkar said.
In addition, Alachkar identified 2-hydroxyglutarate (2-HG) as a potential early biomarker for social deficits and depression induced by prenatal stress. Identifying biomarkers enhances the therapeutic management, particularly that blood and urine levels of 2-HG may correspond to its brain levels.
The primary goal of this work was to understand how trauma is transmitted from one generation to another. Alachkar and her team examined the distinctive behavioral impacts and neurobiological mechanisms of in-utero exposure alone versus impaired maternal care alone or combined exposure.
“We hypothesized that prenatal stress acts as a priming factor that synergistically interacts with subsequent early-life challenges to exacerbate the tendency for offspring of traumatized mothers to develop psychiatric disorders later in life,” Alachkar said.
Alachkar demonstrated 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 behavioral deficits, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting.
The behavioral deficits were associated with profound and permanent changes in brain chemistry and transcriptomic abnormalities. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults, whose mothers were exposed during pregnancy 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).
“The use of metabolomics, transcriptomic, and bioinformatics analyses enables us to establish an early prediction of risk,” Alachkar said, “and to develop an early preventive strategy.”
Ultimately, the focus of Alachkar’s research is to study the mechanisms of stress and depression so that scientists and healthcare professionals can prevent the psychiatric disorders rather than just intervene. The COVID-19 pandemic is certainly a current example of a traumatic event bringing stressors that impact not just the current generations but also the generations to come.
The study is, thus, particularly relevant at this moment in human history, as so many pregnant women are exposed to stressful environments such as the COVID-19 pandemic.
“Our findings, although fascinating and novel scientifically,” Alachkar said, “they ring the alarm bells about the hidden and life-long lasting impacts of traumas induced by wars and natural disasters not only on millions of children directly but also the ones yet to be born and maybe their offspring. I don’t want to wait until the disorder or the disease happens, and then try to treat it. I want to prevent it. That is why I am trying to understand the mechanisms of stress and depression, and how that causes the disorders in the offspring.
“The potential impact on the prevention of, or therapeutic intervention in depression is exceptionally high because this disorder touches millions of people globally who have been subject to stress and trauma at some times of their lives. As scientists, we might not be able to prevent human-made wars or some natural disasters, but we hope to mitigate their long-term negative effects on mental health.”