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Gene Expression in Frontal Cortex in Major Depression and HIV

ABSTRACT: Major depressive disorder (MDD) is a clinically defined entity with little understanding as to the underlying pathological substrate. Biologically, MDD is characterized by disruption of neurotransmitters, especially serotonin and noradrenaline, which are the main targets of antidepressants. We previously demonstrated significant reduction of glial cell number in the cingulate and dorsolateral prefrontal cortical regions. Unfortunately, individuals living with HIV still have very high rates of MDD, despite the fact that mortality rates have fallen sharply with effective antiretroviral treatment. It is possible that in this treatment era, living with chronic HIV infection may result in long-term neuropathological changes that predispose to MDD. For example, it is known that HIV is associated with a range of inflammatory pathologies, neuronal loss, and dendrite-synaptic damage. In HIV, these neurodegenerative changes have been linked to neurocognitive impairments, however it is also possible that these changes potentiate MDD. In the current study, we sought to determine whether there are changes in gene expression in the MDD brain in the frontal cortex in HIV-context. We identify a large number of genes dysregulated at p<0.05 significance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE17440 | GEO | 2010/02/01

SECONDARY ACCESSION(S): PRJNA123617

REPOSITORIES: GEO

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Project description:Micro-RNAs (miRNAs) are small, non-coding RNAs that regulate gene networks, helping to control cell function and phenotype. MiRNAs in the central nervous system (CNS) are considered to be involved in development, function, and homeostasis. Past genomic studies focused on messenger-RNA (mRNA) expression using large-scale hybridization-based arrays for elucidating gene expression in the brain during HIV-infection. Because miRNAs affect the downstream functions of mRNAs, it is desirable to understand both mRNA and miRNA perturbations, together in the same clinical specimens. HIV infection affects the CNS through inflammation and glial cell activation leading to long-term changes in cellular function of neurons and glia. One mechanism by which this may occur is through changes in the miRNA repertoire. The goals of this study were to: 1. Identify changes in miRNA expression that occurred in HIV; 2. Determine whether detectable miRNA expression of the frontal cortex (FC) could differentiate HIV from HIV/Major Depressive Disorder (MDD, neurobehavioral diagnostic category); 3. Adapt a method to meaningfully integrate gene expression data and miRNA expression data in clinical samples. The present study was performed by pooling RNA isolated from the FC of 3 patients from each of three groups: Control, HIV+, and HIV/MDD, and assessing miRNA expression profile using Applied Biosystems Taqman MicroRNA Array v2.0. A larger sample size of 4 HIV+ patients and 4 HIV/MDD patients were used and non-pooled for gene expression analysis on Affymetrix U133 Plus 2.0 array. We present a method for integrating the two datasets in a Target Bias Analysis. Micro-RNAs were clustered into three types: A) Those with many dysregulated mRNA targets of less stringent significance; B) Fewer dysregulated target-genes of highly stringent significance; C) Spectrum from non-bias to combinations of A and B. In HIV/MDD, more miRNAs were down-regulated than in HIV alone. The dysregulated miRNAs clustered on Chromosomes 14, 17, 19, and X. A small subset of dysregulated genes had many 3’UTR target-sites for dysregulated miRNAs. Specific miRNA families at targeted chromosomal loci are dysregulated. Certain miRNAs serve as key circuits in gene regulatory networks in the adult human brain, and this is affected by HIV, and may be implicated in neurobehavioral disorder. Some genes may serve as hubs of miRNA activity.

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Gene Expression in Frontal Cortex in Major Depression and HIV

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