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Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability.

ABSTRACT: Exposure to early life stress can interfere with neurodevelopmental trajectories to increase the vulnerability for psychiatric disorders later in life. With this respect, epigenetic mechanisms play a key role for the long-lasting changes in brain functions that may elicit and sustain psychopathologic outcomes. Here, we investigated DNA methylation changes as possible epigenetic mechanism mediating the effect of prenatal stress (PNS), an experimental paradigm associated with behavioral and molecular alterations relevant for psychiatric disorders. We identified 138 genes as being differentially methylated in the prefrontal cortex (PFC) and in the hippocampus (HIP) of male and female adult rats exposed to PNS. Among these genes, miR-30a and Neurod1 emerged as potential players for the negative outcomes associated with PNS exposure. Indeed, in addition to showing consistent methylation differences in both brain regions and in both sexes, and interacting with each other, they are both involved in Axon guidance and Neurotrophin signaling, which are important to neurodevelopmental disorders. We also found a significant reduction in the expression of a panel of genes (CAMK2A, c-JUN, LIMK1, MAP2K1, MAP2K2, PIK3CA and PLCG1) that belong to these two biological pathways and are also validated targets of miR-30a, pointing to a down-regulation of these pathways as a consequence of PNS exposure. Interestingly, we also found that miR-30a levels were significantly upregulated in depressed patients exposed to childhood trauma, as compared to control individuals. Importantly, we also found that a sub-chronic treatment with the atypical antipsychotic drug, lurasidone, during adolescence was able to prevent the up-regulation of miR-30a and normalized the expression of its target genes in response to PNS exposure. Our results demonstrate that miR-30a undergoes epigenetic changes following early life stress exposure and suggest that this miRNA could play a key role in producing broad and long-lasting alterations in neuroplasticity-related pathways, contributing to the etiology of psychiatric disorders.

SUBMITTER: Cattaneo A

PROVIDER: S-EPMC7739180 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability.

Cattaneo Annamaria A Suderman Matthew M Cattane Nadia N Mazzelli Monica M Begni Veronica V Maj Carlo C D'Aprile Ilari I Pariante Carmine M CM Luoni Alessia A Berry Alessandra A Wurst Katharina K Hommers Leif L Domschke Katharina K Cirulli Francesca F Szyf Moshe M Menke Andreas A Riva Marco A MA

Neurobiology of stress 20201123

Exposure to early life stress can interfere with neurodevelopmental trajectories to increase the vulnerability for psychiatric disorders later in life. With this respect, epigenetic mechanisms play a key role for the long-lasting changes in brain functions that may elicit and sustain psychopathologic outcomes. Here, we investigated DNA methylation changes as possible epigenetic mechanism mediating the effect of prenatal stress (PNS), an experimental paradigm associated with behavioral and molecu ...[more]

PMID: 33344724

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Project description:Depressive symptoms associated with bipolar disorder negatively impact health-related quality of life (HRQoL). The efficacy of lurasidone in reducing depressive symptoms has been previously demonstrated. The objective of this study was to examine the direct and indirect effect (mediated through improvement in depression symptoms) of lurasidone in improving patient HRQoL.A secondary analysis of data was conducted of two 6-week, double-blind, placebo-controlled trials assessing the effect of lurasidone (lurasidone monotherapy [20-60 mg/day or 80-120 mg/day]; lurasidone adjunctive to lithium or valproate [20-120 mg/day]) in patients with bipolar depression. Patient HRQoL was measured using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q SF). Depression symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). Analysis of covariance (ANCOVA) was used to estimate the effect of lurasidone on improvement in the Q-LES-Q SF percentage maximum score from baseline to 6 weeks. Path analysis was used to evaluate the total effect (?1), as well as the indirect (?2*?3) and direct (?4) effect of lurasidone on Q-LES-Q SF change through improvements in MADRS.A total of 340 and 485 patients from the monotherapy and adjunctive therapy, respectively, were included in the analysis. At 6-weeks, ANCOVA analyses demonstrated that lurasidone provided significant improvement in adjusted mean Q-LES-Q SF scores in comparison to placebo for monotherapy (22.9 and 22.7 vs. 15.2, both p?<?0.01) and adjunctive therapy (23.1 vs. 17.9, p?=?0.01). Path analyses indicated that lurasidone treatment predicted MADRS improvement (monotherapy: ?2?=?-0.44, p?<?0.001; adjunctive therapy: ?2?=?-0.34, p?=?0.003), which subsequently predicted improvement in Q-LES-Q SF (monotherapy: ?3?=?-0.73, p?<?0.001; adjunctive therapy: ?3?=?-0.75, p?<?0.001); however, the effect of lurasidone on improvement in Q-LES-Q SF was largely mediated by change in MADRS (monotherapy: ?4?=?0.11, p?=?0.13; adjunctive therapy: ?4?=?0.02, p?=?0.77).Lurasidone as a monotherapy and adjunctive to lithium or valproate is an effective treatment for improving HRQoL in patients with bipolar depression. However, improvement in HRQoL was not independent of improvement in depression, indicating that the effect of lurasidone on improving patient HRQoL may act through a reduction in depressive symptoms associated with bipolar disorder.Clinicaltrials.gov identifiers: NCT00868699 and NCT00868452 (both registered March 23, 2009).

Project description:BackgroundBronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.MethodsWild-type and miR-30a-/- neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a-/- mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a-/- male and female lung transcriptome data.ResultsSignificantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a-/- mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a-/- female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a-/- female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.ConclusionsmiR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.

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Dataset Information

Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability.

Publications

Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability.

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