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Transcriptome Analysis on Maternal Separation Rats with Depression-related Manifestations Ameliorated by Electroacupuncture

ABSTRACT: Objective: To investigate the mechanisms depression-related manifestations ameliorated by electroacupuncture on genome-wide transcriptomes of the frontal cortex at the molecular level, we evaluated unbiased genome-wide RNA sequencing of depression-related rats suffer from maternal separation (MS). Methods: Rats were randomly divided into control, MS, electro-acupuncture treatment(EA) group . We demonstrated depression-like behavior deficiencies in a sucrose preference test and a forced swimming test in a rat model with neonatal maternal separation. Repeated EA treatment at the acupoints Baihui (GV20) and Yintang (GV29) during the adult period was shown to be remarkably attenuated above behavioral deficits. Sequencing was performed using Hiseq Xten (Illumina, USA). Results: Based on the data from RNA-seq analysis, for mRNA, 48 genes were significantly and differentially expressed in MS rats relative to control rats, with 39 up-regulated genes and 9 down-regulated genes. 40 genes in the EA rats relative to the MS rats show differential expression, with 21 genes up-regulated and 18 genes down-regulated. For lncRNA, 11 genes increased significantly in the MS rats relative and 4 genes decreased relative to controls. 31 genes increased in the EA rats relative to the MS rats while 1 gene decreased. For circRNA, 20 genes increased significantly in the MS rats relative to control rats and 17 genes decreased. 18 genes increased in the EA rats relative to the MS rats while 28 genes decreased. Using ceRNA, we narrowed the targets of mRNA from 31 to 17 genes with a circRNA_miRNA_mRNA network, and narrowed the targets of mRNA from 31 to 8 genes with an lncRNA_miRNA_mRNA network, pointing the way for further studies to verify the genes and describe their function. Conclusions: Our investigation demonstrates the first analysis of the frontal cortex genome-wide transcriptomes in depression rats under maternal separation by RNA-seq technology. These results suggest that EA at GV20 and GV29 ameliorates depression-related manifestations by regulating the expression of multiple genes.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE124387 | GEO | 2019/04/17

REPOSITORIES: GEO

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Project description:Depression is a heterogeneous disorder characterized by a wide range of symptoms, including but not restricted to increased anxiety-like behavior, altered stress responsivity, increased depressive like behavior, decreased pleasure seeking, and altered susceptibility to drugs of abuse. Adding another level of complexity to the disease is the fact that individuals differ in their susceptibility to depression. Research done over the past decade has highlighted the contribution of early life adverse experience to this individual differences in vulnerability to depression. Such studies have been done at the clinical as well as the preclinical level, where rodent and primate models of adverse postnatal environment such as Maternal Separation (MS) are used. MS involves separation of the pup from the dam for 3h every day for the first two weeks of postnatal life. The MS model has been characterized to produce long lasting anxiety-like behavior, depressive behavior and altered stress responsivity in adulthood. While several molecular mechanisms have been hypothesized to mediate the long lasting effects of MS, the serotonin 2a receptor is an attractive candidate, given its role in regulating anxiety-like behavior. So we set out to ask if Maternal Separation alters the 5HT2a responses. In order to assay if MS alters the transcriptional targets of the 5Ht2a receptor, we use a drug that stimulates the 5Ht2a receptor, DOI. The experiment involves injecting both control and MS animals with DOI and looking at the transcriptome induced by DOI under control and MS conditions. This would help understand how the adverse early life experience MS, alters the transcriptional response of an adult rat to stimulation at the 5HT2a receptor, which is physiologically seen in conditions of stress. Maternal Separation (MS) was carried out according to standard protocol. Briefly, upon birth the litters were assigned to either the control or the maternal separation group. Pups from the maternal separation litters were separated from their mother every day for a period of 3 hours from postnatal day 2 (p2) to postnatal day 14 (p14) while the control litters were left undisturbed. After p14, the maternally separated pups were left undisturbed and all litters were weaned at postnatal day 30. Experiments on adult control and MS rats were performed at postnatal day 60. We wanted to ask if a history of adverse experience in early life like MS would alter the transcriptional response of the adult rat to the 5Ht2a agonist DOI. In order to measure the transcriptional changes induced by DOI in control and maternally separated animals, 15 rats (7 - Control and 8 - Maternally Separated) were injected i.p. with either saline or 8 mg/kg DOI. The groups included Control (Control rats injected with saline; n=3), DOI (control rats injected with 8 mg/kg DOI; n=4), MS (MS rats injected with saline, n=4) and MS+ DOI (MS rats injected with 8 mg/kg DOI, n=4). Rats were sacrificed 2 hours after the injection by decapitation. The prefrontal cortex was quickly dissected out and stored at -70 till further use. Total RNA from each rat was extracted, labeled with Cy3 and hybridized onto Agilent Custom Rat Array 8X15K (AMADID: G2509F_16352). Each biological replicate was hybridized onto one array making the total number of arrays 15.

Project description:Intestinal paracellular permeability (IPP) is high at birth and is involved in gut barrier maturation and liver development. Chronic maternal separation (MS) in early life alters intestinal barrier function in adulthood. However, only transient MS commonly occurs in human newborns, but whether a single episode of MS in early postnatal days (PND) affects the maturation of the gut-liver axis has not been explored. The aim of the current study was to evaluate the effect of a single MS of short duration in neonate rats on epithelial barrier integrity in the gut and on gene expression in the liver. Male and female pups were separated from their dams for 4h or not (controls) at PND10 or PND20. Total intestinal paracellular permeability (IPP) was measured through mucosal-to-plasma passage of oral FITC-Dextran 4 KD with or without ML7, a blocker of myosin light chain kinase (MLCK), or Mifepristone (RU486), an antagonist of the glucocorticoid receptor. Dose response to dexamethasone (DEX) on IPP was studied at PND10 and PND20. Bacterial translocation (BT) was assessed in mesenteric lymph nodes (MLN), liver and spleen in the presence or absence of ML7. The hepatic transcriptome was studied using Agilent microarrays and qPCR on PND10 rats pretreated or not with ML7. At PND10, control pups showed basal BT to MLN while liver and spleen were sterile. A short-term MS procedure increased IPP and plasma corticosterone levels, resulted in BT to the liver and spleen and had a clear impact on the hepatic transcriptome. Most notably, several genes involved in cell division were downregulated by MS. In PND10 rats, MS-induced increase of IPP and BT were blocked by ML7 or RU486, thus demonstrating a role of the MLCK pathway and of increased plasma levels of corticosterone in these effects of MS. All these effects of MS were absent in PND20 rats. Consistently, PND20 rats were found less sensitive to DEX exposure than PND10 rats. These results show that the early life period is a critical window for a short-term mother-infant separation, which can alter the development of the gut-liver axis and facilitate bacterial passage to systemic organs.

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Transcriptome Analysis on Maternal Separation Rats with Depression-related Manifestations Ameliorated by Electroacupuncture

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