Intergenerational Stress Transmission is Associated with Brain Metabotranscriptome Remodeling and Mitochondrial Dysfunction

Abstract

Intergenerational stress increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational stress transmission is a consequence of in utero neurodevelopmental disruptions vs early-life mother-infant interaction is largely unknown. Here, we demonstrated that exposure to traumatic stress in mice during pregnancy, through predator scent exposure, induces in the offspring social deficits and depressive-like behavior. We found, through cross-fostering experiments, that raising of normal pups by traumatized mothers produced a similar behavioral phenotype to that induced in pups raised by their biological traumatized mothers. Good caregiving (by non-traumatized mothers), however, did not completely protect against the prenatal trauma- induced behavioral deficits. These findings support a two-hit stress mechanism of both in utero and early-life parenting (poor caregiving by the traumatized mothers) environments. Associated with the behavioral deficits, we found profound changes in brain metabolomics and transcriptomic (metabotranscriptome). Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid, in the brains of neonatal and adult pups whose mothers were exposed to stress during pregnancy, indicated mitochondrial metabolism dysfunctions and epigenetic mechanisms. Bioinformatic analyses revealed mechanisms involving stress- and hypoxia-response metabolic pathways in the brains of the neonatal mice, which appear to lead to long-lasting alterations in mitochondrial- energy metabolism, and epigenetic processes pertaining to DNA and chromatin modifications. Most strikingly, we demonstrated that an early pharmacological intervention that can correct mitochondria metabolism - lipid metabolism and epigenetic modifications with acetyl-L-carnitine (ALCAR) supplementation - produces long-lasting protection against the behavioral deficits associated with intergenerational transmission of traumatic stress.

Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress

“…BAIAP2L1 promotes cell proliferation by stimulating the EGFR-ERK pathway 42 and regulating short actin bundles during cell movement 43 . A recent study that investigated alterations in brain transcriptomics associated with intergenerational stress transmission reported upregulation of BAIAP2L1 in neonatal and adult mice 44 . In addition, methylation levels of cg00277769 in BAIAP2L1 correlated in blood and brain tissues of human subjects as reported in IMAGE-CpG 31 .…”

Age-Related Neurometabolomic Signature of Mouse Brain

“…For metabolomic studies, brain tissues were homogenized and extracted following the protocols first published in ref 147. We used the data set generated in our previous paper, 148 in which brain metabolic profiling using chromatography coupled to mass spectrometry was carried out on whole homogenate brain tissues collected from 24 h or 12 weeks old mice (West Coast Metabolomics Center, University of CaliforniaDavis). The data set contains three metabolic platforms:…”

“…For metabolomic studies, brain tissues were homogenized and extracted following the protocols first published in ref . We used the data set generated in our previous paper, in which brain metabolic profiling using chromatography coupled to mass spectrometry was carried out on whole homogenate brain tissues collected from 24 h or 12 weeks old mice (West Coast Metabolomics Center, University of CaliforniaDavis). The data set contains three metabolic platforms: (1) primary metabolites, which include carbohydrates and their phosphate derivatives, amino acids, hydroxyl acids, free fatty acids, purines, pyrimidines, aromatics; (2) complex lipids, which include ceramides, sphingomyelins, cholesteryl esters, oxysterols, lyso- and phospholipids, monoacylglycerols, diacylglycerols and triacylglycerols, galactosyl- and glucuronyl lipids; (3) biogenic amines, which include cholines, acylcarnitines, betaines, SAM, SAH, nucleotides and nucleosides, methylated and acetylated amines, di- and oligopeptides. , Automated liner exchange gas chromatography/mass spectrometry (ALEX GC/MS) was used to determine primary metabolites.…”