Abstract
Norepinephrine (NE) is produced primarily by neurons in the locus coeruleus (LC). Retrograde and ultrastructural examinations reveal that the core of the LC and its surrounding region receives afferent projections from several brain areas which provide multiple neurochemical inputs to the LC with changes in LC neuronal firing, making it a highly coordinated event. Although NE and mediated signaling systems have been studied in relation to suicide and psychiatric disorders that increase the risk of suicide including depression, less is known about the corresponding changes in molecular network within LC. In this study, we examined miRNA networks in the LC of depressed suicide completers and healthy controls. Expression array revealed differential regulation of 13 miRNAs. Interaction between altered miRNAs and target genes showed dense interconnected molecular network. Functional clustering of predicated target genes yielded stress induced disorders that collectively showed the complex nature of suicidal behavior. In addition, 25 miRNAs were pairwise correlated specifically in the depressed suicide group, but not in the control group. Altogether, our study revealed for the first time the involvement of LC based dysregulated miRNA network in disrupting cellular pathways associated with suicidal behavior.
Highlights
Major depressive disorder (MDD) is one of the most debilitating mental disorders world-wide which can lead to significant morbidity and mortality[1, 2]
A considerable amount of attention has been paid to understand the role of locus coeruleus (LC) with perspective of noradrenergic system in suicide, which suggests that dysfunction in central noradrenergic system and associated signaling may lie at the root of psychiatric disorders, including depression, that contribute to suicide[18, 21]
These evidence demonstrate that LC may have high susceptibility to the pathological changes associated with suicide[30]
Summary
Major depressive disorder (MDD) is one of the most debilitating mental disorders world-wide which can lead to significant morbidity and mortality[1, 2]. Any perturbations in the expression of miRNAs may result in the imbalance of homeostasis, which are often reflected as adaptive changes in the regulatory networks that can distinguish normal vs disease states In this regard, in preclinical model of stress-induced behavioral depression, we have shown that in the prefrontal cortex a set of altered miRNAs could transduce wide-spread changes in underlying gene regulatory network implicated in neural plasticity and neural transmission, but they were involved in causing phenotypic changes associated with depression[13]. In preclinical model of stress-induced behavioral depression, we have shown that in the prefrontal cortex a set of altered miRNAs could transduce wide-spread changes in underlying gene regulatory network implicated in neural plasticity and neural transmission, but they were involved in causing phenotypic changes associated with depression[13] Such coordinated changes in miRNA network were found in the prefrontal cortex of depressed suicide individuals[14]. Formation of specific coordinated regulatory network with a non-overlapping set of miRNAs identified in depressed-suicide subjects as compared to healthy group may be critical in induction of suicidal behavior
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