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Effect of Maternal Separation on DOI-induced transcriptome

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE23728 | GEO | 2013/04/01

SECONDARY ACCESSION(S): PRJNA130675

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:Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e. fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ~50–63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-days chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n=18), or Flx non-responder mice (Flx-NR, n=7). Then, Flx-NR mice received 7 sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down- and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology. remark for sample name : ECTR=Flx-NR-ES, C=cort/Veh, CFNR= Flx-NR

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Effect of Maternal Separation on DOI-induced transcriptome

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