i Changes of metabolites related to lipid synthesis/metabolism in adult s → S pups. h Volcano plot showing differentially expressed metabolites in the brains from adult s → S mice. g Heatmap of metabolites significantly changed in the brains of adult s → S mice ( P < 0.05). f Pathway analysis of metabolites significantly changed in the neonatal MET pups (Supplementary Data 2 shows details of number of compounds, hits and p values). Phosphatidylcholines (PC), lysophosphatidylcholines (LPCs), phatidylethanolamines (PE), lysophosphatidylethanolamines (LPE), phosphatidylserine (PS), fatty acids (FA), arachidonic acid, glucoceramides (GlcCer), phosphtatidylglycerols (PG), and the decrease in sphingomyelins (SMs), diacylglycerols (DAG), and triglycerides (TAGs). Increased metabolites in green, and decreased metabolites in red. e Changes of metabolites related to lipid synthesis/metabolism in the neonatal s → S pups. d Changes of metabolites related to histidine metabolism, decreased metabolites in red. c Effect of prenatal exposure to stress on the tricarboxylic acid (TCA) and GABA shunt metabolism. b Volcano plot of metabolites significantly changed in the brains of neonatal s → S mice ( P < 0.05). Two-way ANOVA revealed a significant stage effect ( F 1,35 = 22.82, P 0.05).Ī Heatmap of metabolites significantly changed in the brains of neonatal s → S mice ( P < 0.05). ![]() p Percentage of freezing behavior in contextual fear conditioning assay ( n = 10 c → C, 10 s → S). o Time mice spent to make a decision in T-maze spontaneous assay ( n = 10 c → C, 10 s → S). n Percentage of the alternation choice mice made in the T-maze spontaneous assay ( n = 10 c → C, 10 s → S). j Discrimination index in the social interaction assay ( n = 9 c → C, 9 s → S). i Time mice spent interacting with empty cup and unfamiliar mouse in the social interaction assay ( n = 9 c → C, 9 s → S). g, h Elevated plus maze measure of percent entry to ( h) Closed (unpaired t-test t = 0.05, P = 0.95), and ( g) open arms (unpaired t-test t = 0.74, P = 0.46). e, f Elevated plus maze measure of time spent in ( f) Closed (unpaired t-test t = 0.788, P = 0.44), and ( e) open arms (unpaired t-test t = 0.788, P = 0.44). Two-way ANOVA revealed a significant zone effect ( F 1,36 = 1453, P 0.05). d Time mice spent in the central and peripheral zones in 10 min in the locomotion assay ( n = 10 c → C, 10 s → S). b Time-course of the locomotor activity, ( c) Distance mice travelled in 60 min of the locomotion assay ( n = 10 c → C, 10 s → S). b, c s → S pups display normal locomotor activity. Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.Ī Schematic of the experiment design. 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.
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