Impulsivity and comorbid traits: a multi-step approach for finding putative responsible microRNAs in the amygdala

Abstract

Malfunction of synaptic plasticity in different brain regions, including the amygdala plays a role in impulse control deficits that are characteristics of several psychiatric disorders, such as ADHD, schizophrenia, depression and addiction. Previously, we discovered a locus for impulsivity (Impu1) containing the neuregulin 3 (Nrg3) gene, of which the level of expression determines levels of inhibitory control. MicroRNAs (miRNAs) are potent regulators of gene expression, and have recently emerged as important factors contributing to the development of psychiatric disorders. However, their role in impulsivity, as well as control of Nrg3 expression or malfunction of the amygdala, is not well established. Here, we used the GeneNetwork database of BXD mice to search for correlated traits with impulsivity using an overrepresentation analysis to filter for biologically meaningful traits. We determined that inhibitory control was significantly correlated with expression of miR-190b, -28a, -340, -219a, and -491 in the amygdala, and that the overrepresented correlated traits showed a specific pattern of coregulation with these miRNAs. A bioinformatics analysis identified that miR-190b, by targeting an Nrg3-related network, could affect synaptic plasticity in the amygdala, targeting bot impulsive and compulsive traits. Moreover, miR-28a, -340, -219a, and possibly -491 could act on synaptic function by determining the balance between neuronal outgrowth and differentiation. We propose that these miRNAs are attractive candidates of regulation of amygdala synaptic plasticity, possibly during development but also in maintaining the impulsive phenotype. These results can help us to better understand mechanisms of synaptic dysregulation in psychiatric disorders.

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

“…Interestingly, miR-190b targets several neurotrophins, including NRG3, which is related to impulsivity. In mice, miR-190b expression is positively associated with impulsivity behaviors, a behavioral trait that has also been associated with Pb exposure [64]. Taken together, this suggests that Pb-associated miRNA changes in the placenta may relate to the neurological effects seen in developing children by targeting neurodevelopmentally-and behavior-related signaling pathways.…”

“…For instance, prenatal iAs exposure was associated with 12 dysregulated miRNAs that were enriched for disease pathways related to iAs-associated disease (e.g., immune function) and predicted functional changes in downstream gene expression [38]. With respect to prenatal Pb exposure, dysregulated miRNAs in infants was significantly associated with neurobehavior-related signaling, providing further evidence for the role of epigenetics in Pb-induced neurodevelopmental outcomes [37,64]. Taken together, miRNA dysregulation has explanatory value when considered in the context of in utero exposures and research should be expanded upon.…”

MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior

“…Teens who experienced earlier life stress report higher rates of impulsive behavior [110], and suicide rates among teens are higher than the general population [111]. Using an in-silico approach, Pietrzykowski and Spijker [112] identified several putative candidate miR-NAs in the amygdala important for impulsive behaviors in mice, such as miR-190b, −28a, −340, −219a, and −49. A SNP in the binding regions of miR-641 on the SNAP gene has also been found associated with trait impulsivity [113].…”

A Common Genetic Etiology for Impulsivity and Overeating

“…Recent preclinical data has shown that expression for neuregulin 3 (Nrg3) genes in the amygdala -a key region for fear and emotion processing, and in the prefrontal cortex may be involved in the development of the impulsivity trait (Pietrzykowski & Spijker, 2014). The amygdala and its efferent projections to mesolimbic pathway have been implicated in incentive learning and reward value processing (Blaiss & Janak, 2009).…”