Project description:Maternal stress, anxiety, and depression increase the risk of psychiatric disorders in the progeny. These maternal effects can extend beyond the first generation and affect the grandchildren. In contrast to paternal, maternal effects can impact the offspring not only during gametogenesis, but also through fetal and early-postnatal life, increasing phenotypic complexity and the overall impact. To better understand its non-genetic structure, we dissected a complex maternally-transmitted phenotype to elementary behaviors and their corresponding transmission mechanisms. Chronic stress and depression are associated with reduced serotonin1A receptor (5-HT1AR) levels, and we reported that 5-HT1AR+/- dams transmit anxiety/stress-reactivity traits to their wild-type offspring. Here we show that the maternal effect is propagated to multiple generations, and that the behavioral traits are not transmitted in unison, but rather via parallel and segregated mechanisms, each with generation-dependent penetrance and gender specificity. The ârisk-avoidanceâ and âhypoactivityâ traits of anxiety were transmitted, via a neuro-immune pathway, consecutively from mother to the wild-type F1, F2, and occasionally F3 generation by iterative non-gametic-programming, while the âincreased stress-reactivityâ trait was transmitted to the F2 generation by gametic-programming. Iterative non-gametic-programming of anxiety was linked, via gene expression changes and clustered DNA hypo/hypermethylation at intragenic enhancers, to sphingolipid metabolism and GPCRs in the F1/F2 hippocampus, suggesting dysregulated lipid raft functioning/transmembrane signaling. Conversely, gametic-programming of behavior was predominantly associated with hypomethylation at different promoter-enhancing sequences within a set of genes with diverse neuronal functions. Since differential methylation appeared only postnatally in F2 neurons and was absent in F3 neurons, it is secondary to earlier F2 gametic changes that survive reprogramming in the early embryo, but are erased in F3 germ-cells. Our data introduce parallel and segregated non-genetic transmission of traits as a mechanism that may explain the propagation and pleiotropy of complex behavioral and psychiatric disease phenotypes across generations. Compared three generations of male offspring from wild-type and 5HT1A-R-/+ Swiss Webster mothers with two replicates per sample. Included as well is F2 embryo transfer from wild-type and het parents in wild-type surogates

Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

Project description:Maternal stress, anxiety, and depression increase the risk of psychiatric disorders in the progeny. These maternal effects can extend beyond the first generation and affect the grandchildren. In contrast to paternal, maternal effects can impact the offspring not only during gametogenesis, but also through fetal and early-postnatal life, increasing phenotypic complexity and the overall impact. To better understand its non-genetic structure, we dissected a complex maternally-transmitted phenotype to elementary behaviors and their corresponding transmission mechanisms. Chronic stress and depression are associated with reduced serotonin1A receptor (5-HT1AR) levels, and we reported that 5-HT1AR+/- dams transmit anxiety/stress-reactivity traits to their wild-type offspring. Here we show that the maternal effect is propagated to multiple generations, and that the behavioral traits are not transmitted in unison, but rather via parallel and segregated mechanisms, each with generation-dependent penetrance and gender specificity. The “risk-avoidance” and “hypoactivity” traits of anxiety were transmitted, via a neuro-immune pathway, consecutively from mother to the wild-type F1, F2, and occasionally F3 generation by iterative non-gametic-programming, while the “increased stress-reactivity” trait was transmitted to the F2 generation by gametic-programming. Iterative non-gametic-programming of anxiety was linked, via gene expression changes and clustered DNA hypo/hypermethylation at intragenic enhancers, to sphingolipid metabolism and GPCRs in the F1/F2 hippocampus, suggesting dysregulated lipid raft functioning/transmembrane signaling. Conversely, gametic-programming of behavior was predominantly associated with hypomethylation at different promoter-enhancing sequences within a set of genes with diverse neuronal functions. Since differential methylation appeared only postnatally in F2 neurons and was absent in F3 neurons, it is secondary to earlier F2 gametic changes that survive reprogramming in the early embryo, but are erased in F3 germ-cells. Our data introduce parallel and segregated non-genetic transmission of traits as a mechanism that may explain the propagation and pleiotropy of complex behavioral and psychiatric disease phenotypes across generations.

Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes.

Project description:Though obesity is a global epidemic, the physiological mechanisms involved are little understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesized that maternal diet influences fetal 5-HT exposure, which then influences central appetite network development and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant low protein fed rat mothers exhibited elevated serum 5-HT, which was also evident in the placenta and fetal brains at E16.5. This increase was associated with reduced hypothalamic expression of 5-HT2CR - the primary 5-HT receptor influencing appetite. As expected, reduced 5-HT2CR expression was associated with impaired sensitivity to 5-HT-mediated appetite suppression. 5-HT primarily achieves effects on appetite via 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We reveal that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC and that 5-HT2AR mRNA is increased in the hypothalamus of in utero growth restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals are more sensitive to 5-HT2AR agonist-induced appetite suppression. These findings may not only reveal a 5-HT-mediated mechanism underlying programming of obesity susceptibility but also provide a promising means to correct it, via a 5-HT2AR agonist treatment. The study was carried out using male Wistar rats (Rattus norvegicus). On postnatal day 3, two experimental groups of offspring were established: controls (offspring of control dams) and recuperated (offspring of dams fed a low-protein diet (8% protein, w/v), but nursed by control dams. The animals were fed with standard chow until 3 months of age where the brains were collected for transcriptomic profiling

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Gene expression changes in response to ancestral maternal obesity

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