microRNAs miR-124, let-7d and miR-181a regulate Cocaine-induced Plasticity

MicroRNAs play key regulatory roles in cellular processes including neurogenesis, synapse development and plasticity in the brain. Psychostimulants induces strong neuroadaptive changes through a surfeit of gene regulatory mechanisms leading to addiction. MicroRNA profiling for identifying miRNAs regulating cocaine-induced, plasticity-related genes revealed significant regulation of a set of miRNAs upon cocaine administration, especially let-7d, miR-181a and the brain-specific miR-124. These miRNAs target many genes involved in cocaine addiction. Precursor and mature miRNA quantification by qRT-PCR showed that miR-124 and let-7d are significantly downregulated, whereas miR-181a is induced in the mesolimbic dopaminergic system under chronic cocaine administration. Results were confirmed by in situ hybridization, Northern blots, FISH analysis and RNase protection assay. Using lentiviral-mediated miRNA expression, we show a significant downregulation of BDNF and D3R both at mRNA and protein levels by miR-124 and let-7d, respectively. Our data suggest that miR-124, let-7d and miR-181a may be involved in a complex feedback loop with cocaine-responsive plasticity genes, highlighting the possibility that some miRNAs are key regulators of the reward circuit and may be implicated in addiction.     

Chronic methamphetamine regulates the expression of MicroRNAs and putative target genes in the nucleus accumbens of mice

MicroRNAs (miRNAs) are modulators of gene expression that play key regulatory roles in distinct cellular processes. Methamphetamine (METH) induces various aberrant changes in the limbic system by affecting a complex gene regulatory mechanism, yet the involvement of miRNAs in the effects of METH exposure remains unclear. This study identifies METH‐responsive miRNAs and their potential effects in the nucleus accumbens (NAc) of mice. Using miRNA sequencing, we examined the expression of miRNAs in the NAc of saline‐ and METH‐treated mice and identified 45 known miRNAs to be METH responsive. Additionally, we identified two novel miRNA candidates that were METH responsive (novel‐m002C and novel‐m009C). Our target prediction analysis suggested that the known METH‐regulated miRNAs might target genes that are involved in cellular autophagy, cellular metabolism, and immune responses and that the novel METH‐regulated miRNA candidates might target genes that are related to drug addiction. We also matched the predicted targets of METH‐regulated miRNAs with the NAc messenger RNA expression profile, revealing eight putative METH‐regulated target genes (Arc, Capn9, Gbp5, Lefty1, Patl2, Pde4c, Strc, and Vmn1r58). Thus, METH triggers an alteration in NAc miRNA expression, which could contribute to METH‐induced changes in neuron autophagy, metabolism, and immune responses. The differential expression of putative target genes suggests their involvement following exposure to METH. © 2015 Wiley Periodicals, Inc.     

Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: relevance to depression pathophysiology

Stress plays a major role in inducing depression, which may arise from interplay between complex cascades of molecular and cellular events that influence gene expression leading to altered connectivity and neural plasticity. In recent years, microRNAs (miRNAs) have carved their own niche owing to their innate ability to induce disease phenotype by regulating expression of a large number of genes in a cohesive and coordinated manner. In this study, we examined whether miRNAs and associated gene networks have a role in chronic corticosterone (CORT; 50 mg  kg⁻¹ × 21 days)-mediated depression in rats. Rats given chronic CORT showed key behavioral features that resembled depression phenotype. Expression analysis revealed differential regulation of 26 miRNAs (19 upregulated, 7 downregulated) in prefrontal cortex of CORT-treated rats. Interaction between altered miRNAs and target genes showed dense interconnected molecular network, in which multiple genes were predicated to be targeted by the same miRNA. A majority of altered miRNAs showed binding sites for glucocorticoid receptor element, suggesting that there may be a common regulatory mechanism of miRNA regulation by CORT. Functional clustering of predicated target genes yielded disorders such as developmental, inflammatory and psychological that could be relevant to depression. Prediction analysis of the two most prominently affected miRNAs miR-124 and miR-218 resulted into target genes that have been shown to be associated with depression and stress-related disorders. Altogether, our study suggests miRNA-mediated novel mechanism by which chronic CORT may be involved in depression pathophysiology.     

CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury

Cytosine-phosphate-guanine (CpG) preconditioning reprograms the genomic response to stroke to protect the brain against ischemic injury. The mechanisms underlying genomic reprogramming are incompletely understood. MicroRNAs (miRNAs) regulate gene expression; however, their role in modulating gene responses produced by CpG preconditioning is unknown. We evaluated brain miRNA expression in response to CpG preconditioning before and after stroke using microarray. Importantly, we have data from previous gene microarrays under the same conditions, which allowed integration of miRNA and gene expression data to specifically identify regulated miRNA gene targets. CpG preconditioning did not significantly alter miRNA expression before stroke, indicating that miRNA regulation is not critical for the initiation of preconditioning-induced neuroprotection. However, after stroke, differentially regulated miRNAs between CpG- and saline-treated animals associated with the upregulation of several neuroprotective genes, implicating these miRNAs in genomic reprogramming that increases neuroprotection. Statistical analysis revealed that the miRNA targets were enriched in the gene population regulated in the setting of stroke, implying that miRNAs likely orchestrate this gene expression. These data suggest that miRNAs regulate endogenous responses to stroke and that manipulation of these miRNAs may have the potential to acutely activate novel neuroprotective processes that reduce damage.     

MicroRNA and mRNA profiling of cerebral cortex in a transgenic mouse model of Alzheimer’s disease by RNA sequencing

In a previous study, we found that long non-coding genes in Alzheimer’s disease (AD) are a result of endogenous gene disorders caused by the recruitment of microRNA (miRNA) and mRNA, and that miR-200a-3p and other representative miRNAs can mediate cognitive impairment and thus serve as new biomarkers for AD. In this study, we investigated the abnormal expression of miRNA and mRNA and the pathogenesis of AD at the epigenetic level. To this aim, we performed RNA sequencing and an integrative analysis of the cerebral cortex of the widely used amyloid precursor protein and presenilin-1 double transgenic mouse model of AD. Overall, 129 mRNAs and 68 miRNAs were aberrantly expressed. Among these, eight down-regulated miRNAs and seven up-regulated miRNAs appeared as promising noninvasive biomarkers and therapeutic targets. The main enriched signaling pathways involved mitogen-activated kinase protein, phosphatidylinositol 3-kinase-protein kinase B, mechanistic target of rapamycin kinase, forkhead box O, and autophagy. An miRNA-mRNA network between dysregulated miRNAs and corresponding target genes connected with AD progression was also constructed. These miRNAs and mRNAs are potential biomarkers and therapeutic targets for new treatment strategies, early diagnosis, and prevention of AD. The present results provide a novel perspective on the role of miRNAs and mRNAs in AD. This study was approved by the Experimental Animal Care and Use Committee of Institute of Medicinal Biotechnology of Beijing, China (approval No. IMB-201909-D6) on September 6, 2019.

Chinese Library Classification No. R446.1; R741.04; Q344+.13     

Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter

MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon^© LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM as expected. However, most of the miRNA expression variability that correlated with the presence of early AD-related pathology was seen in GM. We confirm that downregulation of a set of miRNAs in GM (including several miR-15/107 genes and miR-29 paralogs) correlated strongly with the density of diffuse amyloid plaques detected in adjacent tissue. A few miRNAs were differentially expressed in WM, including miR-212 that is downregulated in AD and miR-424 which is upregulated in AD. The expression of certain miRNAs correlates with other miRNAs across different cases, and particular subsets of miRNAs are coordinately expressed in relation to AD-related pathology. These data support the hypothesis that patterns of miRNA expression in cortical GM may contribute to AD pathogenetically, because the aggregate change in miRNA expression observed early in the disease would be predicted to cause profound changes in gene expression.     

Evaluation of Six SNPs of MicroRNA Machinery Genes and Risk of Schizophrenia

MicroRNAs (miRNAs) are small regulatory RNAs that modulate the expression of approximately half of all human genes. Small changes in miRNA expression have been associated with several psychiatric and neurological disorders, but whether the polymorphisms in genes involved in the processing of miRNAs into maturity influence the susceptibility of a person to schizophrenia (SZ) has not yet been elucidated. In this study, we investigated the association between SZ risk and single-nucleotide polymorphisms (SNPs) in microRNA machinery genes. We assessed the associations between SZ as a risk and six potentially functional SNPs from five miRNA processing genes (DROSHA, DGCR8, DICER, AGO1, and GEMIN4) in a case-control study of 256 Chinese SZ patients and 252 frequency-matched (age, gender, and ethnicity) controls. All the SNPs (rs10719, rs3757, rs3742330, rs636832, rs7813, and rs3744741) were genotyped by high resolution melting method. We found that two SNPs in the DGCR8 and DICER gene were significantly associated with the altered SZ risk. The genotype or allele frequency of rs3742330 in DICER was significantly different in patients and controls. Moreover, the recessive model of rs3757 in DGCR8 (AA vs. GA/GG) exhibited a significantly increased risk with an odds ratio (OR) of 3.73 [95 % confidence interval (CI), 1.03–13.52, P?=?0.032]; the dominant model of rs3742330 in DICER (AA vs. AG/GG) exhibited a significantly increased risk with OR of 1.49 (95 % CI, 1.04–2.13; P?=?0.028). Other SNPs and the haplotype of GEMIN4 (rs3744741 and rs7813) did not show any association with SZ. Our results suggested that the specific genetic variants in microRNA machinery genes may affect SZ susceptibility.     

MicroRNA networks surrounding APP and amyloid-β metabolism--implications for Alzheimer's disease

MicroRNAs (miRNAs) are small non-coding RNA regulators of protein synthesis that function as "fine-tuning" tools of gene expression in development and tissue homeostasis. Their profiles are significantly altered in neurodegenerative diseases such as Alzheimer's disease (AD) that is characterized by both amyloid-β (Aβ) and tau deposition in brain. A key challenge remains in determining how changes in miRNA profiles translate into biological function in a physiological and pathological context. The key lies in identifying specific target genes for deregulated miRNAs and understanding which pathogenic factors trigger their deregulation. Here we review the literature about the intricate network of miRNAs surrounding the regulation of the amyloid precursor protein (APP) from which Aβ is derived by proteolytic cleavage. Normal brain function is highly sensitive to any changes in APP metabolism and miRNAs function at several steps to ensure that the correct APP end product is produced and in the right form and abundance. Disruptions in this miRNA regulatory network may therefore alter Aβ production, which in turn can affect miRNA expression.