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Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

ABSTRACT: In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

SUBMITTER: Liu MY

PROVIDER: S-EPMC10005958 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

Liu Meng-Ying MY Wei Lu-Lu LL Zhu Xian-Hui XH Ding Hua-Chen HC Liu Xiang-Hu XH Li Huan H Li Yuan-Yuan YY Han Zhou Z Li Lian-Di LD Du Zi-Wei ZW Zhou Ya-Ping YP Zhang Jing J Meng Fan F Tang Yu-Lin YL Liu Xiao X Wang Chun C Zhou Qi-Gang QG

Molecular psychiatry 20221208 3

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechani ...[more]

PMID: 36481932

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Project description:BackgroundStudies show that the hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in depression. Some studies suggest that variation in the serotonin transporter genotype (hereafter 5HTT) modulates both risk for depression and psychopathological HPA axis responsiveness. Rhesus monkeys are well suited to model such relationships. Rhesus macaque models of human psychopathology have assessed the effect of the serotonin transporter (rh5HTT) on levels of cortisol in stressed subjects. These studies show that that under conditions of stress, heterozygous females (Ls) reared under adversity exhibit high levels of cortisol. Studies have not to our knowledge, however, assessed the potential additive effect on the cortisol response in a number of macaque subjects homozygous for the serotonin transporter short allele (ss). Moreover, little is known about the level of the central or peripheral nervous system at which the 5HTT genotype acts to modulate the cortisol response.MethodsThis study assesses a relatively large number of subjects homozygous and heterozygous for the rh5HTT short and long alleles (a) during stress; (b) following a dexamethasone suppression test; and (c) following an adrenocorticotropic hormone (ACTH) challenge. Subjects included 190 infant rhesus macaques (Macaca mulatta - 84 males and 106 females; 118 LL, 60 Ls, and 12 ss subjects), obtaining two blood plasma samples during the stress of separation from their mothers. Then on the following day, we obtained a blood sample following a dexamethasone test, and later that day we obtained a blood sample after an ACTH challenge test. Subjects ranged in age between 90 and 128 days, with a mean age of 107 days.ResultsSubjects homozygous for the short allele had significantly higher levels of cortisol across all test conditions, when compared to those homozygous for the long allele, or those heterozygous with Ls alleles. Subsequent analyses showed a high correlation between individual cortisol levels across the three different tests.ConclusionsThese data suggest that subjects homozygous for the short allele are more likely to show dysregulated cortisol levels in response to stress. Given the correlation in individual responses of the HPA axis across the different tests, our data suggest that the effect of the 5HTT genotype shows some commonality in its regulation of stress, feedback, and ACTH-stimulated cortisol output. Our data suggest that under conditions of stress, the serotonin transporter may modulate HPA axis psychopathology.

Project description:Background"Stress" is an emerging problem in our society, health care system as well as patient care, worldwide. Especially by focusing on pre-gestational, gestational but also lactation phases "stress" is to be considered as an own trans-generational risk factor which is associated with adverse metabolic as well cardiovascular outcomes in mothers and their children. Hence, the maternal hypothalamic-pituitary-adrenotrophic (HPA) axis may be stimulated by various "stress" mechanisms as well as risk factors leading to an adverse in utero environment, e.g. by excess exposure of glucocorticoids, contributing to cardio-metabolic disorders in mothers and their offspring.ObjectiveTo review the evidence of in utero programming by focusing on the impact of maternal "stress", on adverse cardio-metabolic outcomes on their offspring later in life, by identifying underlying (patho-) physiological mechanisms (1) as well as adverse short and long-term cardio-metabolic outcomes (2).MethodsWe conducted a systematic scoping review to identify publications systematically including reviews, interventional, observational, experimental studies as well as human and animal model studies. MEDLINE (PubMed) and EMBASE databases and reference lists were searched. Peer-reviewed articles from January 2000 until August 2020 were included.ResultsOverall, n = 2.634 citations were identified, n = 45 eligible studies were included and synthesized according to their key findings. In brief, maternal hypothalamic-pituitary-adrenotrophic (HPA) axis might play a key role modifying in utero milieu leading to cardio-metabolic diseases in the offspring later in life. However, maternal risk factor "stress", is clearly linked to adverse cardio-metabolic offspring outcomes, postnatally, such as obesity, hyperglycemia, insulin resistance, diabetes mellitus (DM), Metabolic Syndrome (MetS), cardiovascular disease (CD), hypertension, restricted fetal growth as well as reduced birth, adrenal, and pancreas weights.ConclusionsWomen who experienced "stress" as risk factor, as well as their offspring, clearly have a higher risk of adverse short- as well as long-term cardio-metabolic outcomes. Future research work is needed to understand complex transgenerational mechanisms.

Project description:The gastrointestinal (GI) epithelium is constantly renewing, depending upon the intestinal stem cells (ISC) regulated by a spectrum of transcription factors (TFs), including Myb. We noted previously in mice with a p300 mutation (plt6) within the Myb-interaction-domain phenocopied Myb hypomorphic mutant mice with regard to thrombopoiesis, and here, changes in GI homeostasis. p300 is a transcriptional coactivator for many TFs, most prominently cyclic-AMP response element-binding protein (CREB), and also Myb. Studies have highlighted the importance of CREB in proliferation and radiosensitivity, but not in the GI. This prompted us to directly investigate the p300-Myb-CREB axis in the GI. Here, the role of CREB has been defined by generating GI-specific inducible creb knockout (KO) mice. KO mice show efficient and specific deletion of CREB, with no evident compensation by CREM and ATF1. Despite complete KO, only modest effects on proliferation, radiosensitivity and differentiation in the GI under homeostatic or stress conditions were evident, even though CREB target gene pcna (proliferating cell nuclear antigen) was downregulated. creb and p300 mutant lines show increased goblet cells, whereas a reduction in enteroendocrine cells was apparent only in the p300 line, further resembling the Myb hypomorphs. When propagated in vitro, crebKO ISC were defective in organoid formation, suggesting that the GI stroma compensates for CREB loss in vivo, unlike in MybKO studies. Thus, it appears that p300 regulates GI differentiation primarily through Myb, rather than CREB. Finally, active pCREB is elevated in colorectal cancer (CRC) cells and adenomas, and is required for the expression of drug transporter, MRP2, associated with resistance to Oxaliplatin as well as several chromatin cohesion protein that are relevant to CRC therapy. These data raise the prospect that CREB may have a role in GI malignancy as it does in other cancer types, but unlike Myb, is not critical for GI homeostasis.

Dataset Information

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

Publications

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

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