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Altered miRNA landscape of the anterior cingulate cortex is associated with potential loss of key neuronal functions in depressed brain.

ABSTRACT: MicroRNAs (miRNAs), a family of non-coding RNAs, have recently gained a considerable attention in neuropsychiatric disorders. Being a pleiotropic modulator of target gene(s), miRNA has been recognized as central to downstream gene regulatory networks. In the recent past, reports have suggested their role in changing the epigenetic landscape in brain of subjects with major depressive disorder (MDD). Anterior cingulate cortex (ACC) is a brain area implicated in several complex cognitive functions, such as impulse control, emotion, and decision-making and is associated with psychopathology associated with mood regulation. In this study, we examined whether MDD is associated with altered miRNA transcriptome in ACC and whether altered miRNA landscape is associated with modifications in specific gene network(s) at the functional level. Using next generation sequencing (NGS), it was observed that 117 miRNAs (4.61%) were significantly upregulated and 54 (2.13%) were downregulated in MDD subjects (n = 22) compared with non-psychiatric controls (n = 25). Using 24 most significantly upregulated miRNAs in the MDD group, we determined functional enrichment of target genes and found them to be associated with long-term potentiation, neurotrophin signaling, and axon guidance. Intra- and inter-cluster similarities of enriched terms based on overrepresented gene list showed neurobiological functions associated with neuronal growth and survival. Web centric parameters and ontology enrichment functions identified two major domains related to phosphatidyl signaling, GTPase signaling, neuronal migration, and neurotrophin signaling. Our findings of altered miRNA landscape along with a shift in targetome relate to previously reported morphometric changes and neuronal atrophy in ACC of MDD subjects.

SUBMITTER: Yoshino Y

PROVIDER: S-EPMC7655604 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ContextAnhedonia, a core symptom of major depressive disorder (MDD) and highly variable among adolescents with MDD, may involve alterations in the major inhibitory amino acid neurotransmitter system of γ-aminobutyric acid (GABA).ObjectiveTo test whether anterior cingulate cortex (ACC) GABA levels, measured by proton magnetic resonance spectroscopy, are decreased in adolescents with MDD. The associations of GABA alterations with the presence and severity of anhedonia were explored.DesignCase-control, cross-sectional study using single-voxel proton magnetic resonance spectroscopy at 3 T.SettingTwo clinical research divisions at 2 teaching hospitals.ParticipantsTwenty psychotropic medication-free adolescents with MDD (10 anhedonic, 12 female, aged 12-19 years) with episode duration of 8 weeks or more and 21 control subjects group matched for sex and age.Main outcome measuresAnterior cingulate cortex GABA levels expressed as ratios relative to unsuppressed voxel tissue water (w) and anhedonia scores expressed as a continuous variable.ResultsCompared with control subjects, adolescents with MDD had significantly decreased ACC GABA/w (t = 3.2; P < .003). When subjects with MDD were categorized based on the presence of anhedonia, only anhedonic patients had decreased GABA/w levels compared with control subjects (t = 4.08; P < .001; P(Tukey) < .001). Anterior cingulate cortex GABA/w levels were negatively correlated with anhedonia scores for the whole MDD group (r = -0.50; P = .02), as well as for the entire participant sample including the control subjects (r = -0.54; P < .001). Anterior cingulate cortex white matter was also significantly decreased in adolescents with MDD compared with controls (P = .04).ConclusionsThese findings suggest that GABA, the major inhibitory neurotransmitter in the brain, may be implicated in adolescent MDD and, more specifically, in those with anhedonia. In addition, use of a continuous rather than categorical scale of anhedonia, as in the present study, may permit greater specificity in evaluating this important clinical feature.

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Altered miRNA landscape of the anterior cingulate cortex is associated with potential loss of key neuronal functions in depressed brain.

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