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Biomarker Discovery in Attention Deficit Hyperactivity Disorder: RNA sequencing of Whole Blood in Discordant Twin and Case-Controlled Cohorts

ABSTRACT: Biomarker Discovery in Attention Deficit Hyperactivity Disorder: RNA sequencing of Whole Blood in Discordant Twin and Case-Controlled Cohorts

PROVIDER: PRJNA667703 | ENA |

REPOSITORIES: ENA

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Effect of methylphenidate on gene expression profiles of Attention Deficit Hyperactivity Disorder patients and unaffected controls.

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Biomarker Discovery in Attention Deficit Hyperactivity Disorder: RNA sequencing of Whole Blood in Discordant Twin and Case-Controlled Cohorts

Project description:We found RNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control.

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Project description:Background: Stress exacerbates symptoms of schizophrenia and attention deficit hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. Here we investigated whether a 6-day variable stressor (VS) altered sustained attention and the cholinergic attention system in male and female rats. Methods: Sustained attention was tested with the sustained attention task (SAT). Successful performance on SAT relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus basalis of Meynert (NBM). Thus, we evaluated whether VS altered the morphology of these neurons with a novel approach using Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNAseq to identify VS-induced transcriptional changes in the NBM. Results: VS impaired attentional performance in SAT and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of males. Quantification of global transcriptional changes revealed that, although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes.

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