Lentiviral-mediated let-7d microRNA overexpression induced anxiolytic- and anti-depressant-like behaviors and impaired dopamine D3 receptor expression

Abstract

Generalized anxiety and major depression disorders (MDD) are severe debilitating mood disorders whose etiology are not fully understood, but growing evidence indicates that microRNAs (miRNAs) might play a key role in their neuropathophysiological mechanisms. In the current study, we investigate the role of Lethal-7 (let-7d) miRNA, and its direct target dopamine D3 receptor (D3R) gain-of-function, in the hippocampus, in preclinical models of anxiety and depression in mice. For this purpose, we have constructed a lentiviral vector carrying let-7d miRNA and its anxiolytic effect was investigated by employing the open-field (OF) and the elevated plus maze (EPM) tests. The anti-depressant activity was evaluated using the tail suspension and the forced-swim tests (TST & FST). Our results show that let-7d overexpression significantly improved the measures of anxiety in the OF and EPM tests. In addition, let-7d increased the mobility time in the TST and FST. Interestingly, gene expression interaction analysis shows that the D3R mRNA negatively correlates with let-7d expression. In a different set of experiments, we used a tetracycline-inducible (tet-off) lentiviral vector to overexpress D3R to assess its gain-of-function in the hippocampus on anxiety-and depression-like behaviors. In line, we found that in the absence of doxycycline, D3R produced a significant anxiogenic and depressant-like response. Most importantly, these effects were abrogated when mice were fed doxycycline in drinking water. Our results provide the first evidence for an anxiolytic and

Lentiviral-mediated up-regulation of let-7d microRNA decreases alcohol intake through down-regulating the dopamine D3 receptor

“…It is well-established that, via D3R, DA is a central modulator of accumbal activity that plays critical roles in many drugs of abuse including alcohol. We have shown in a previous study that, like the D3R agonist 7-OH-DPAT, D3R overexpression exacerbated alcohol intake ( Bahi and Dreyer, 2018 ). In contrast, like the D3R selective antagonist SB-277011-A, D3R knockdown using lentiviral-mediated siRNA expression, attenuated voluntary alcohol consumption ( Bahi and Dreyer, 2014 ), which agrees with other findings using SB-277011-A in C57BL/J6 mice ( Rice et al, 2015 ).…”

“…In order to determine the potential role of let-7d in voluntary alcohol intake and preference, the effect of let-7d on the expression of accumbal D3R mRNA in rat was determined. Both gain-of-function and loss-of-function approaches have demonstrated that let-7d was a strong regulator for the expression of D3R ( Bahi and Dreyer, 2018 ). Therefore, and as expected, it has been found that D3R mRNA expression was significantly inhibited by overexpression of let-7d These findings are in line with previous studies from our laboratory, using computational examination and experimental approach, which have demonstrated that D3R might be a direct target gene of let-7d ( Chandrasekar and Dreyer, 2009 ;.…”

“…We have also reported that, in adult C57BL/6J mice, hippocampal overexpression of let-7d induced an anxiolytic-like effect in the open field and elevated plus maze tests, as well as an anti-depressantlike effect in the tail suspension and forced swim tests. In addition, a significant negative correlation between D3R mRNA and let-7d has been found ( Bahi and Dreyer, 2018 ).…”

Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice

“…Growing evidence indicates that let-7d may play a role in the neurobiology of psychiatric disorders [ 68 ]. Let-7d is largely expressed in the brain and is involved in modulating learning and memory [ 69 , 70 ]; however, little is known about its role in stress-related disorders. Interestingly, its upregulation was reported in the nucleus accumbens in a cocaine-conditioned place preference rat model and, in its circulating form, in animals that had undergone chronic social defeat [ 52 , 71 ].…”

Early Life Stress and the Onset of Obesity: Proof of MicroRNAs’ Involvement Through Modulation of Serotonin and Dopamine Systems’ Homeostasis

“…Both receptors, DRD1 and DRD2, are associated with control of food intake, either homeostatic or hedonic, in several areas of the brain ( Wise, 1989 ; Ikeda et al, 2018 ) which indicates that its modulation through miRNAs can modulate the food intake. In addition, overexpression of let-7d is negatively correlated with the expression of DRD3 in the hippocampus of mice ( Bahi and Dreyer, 2018 ). The activity of the DRD3 is controversy in the context of food intake, but some evidences associate it with eating disorders and decreased food intake ( Thomsen et al, 2017 ; González et al, 2019 ).…”