Viral-mediated overexpression of the Myelin Transcription Factor 1 (MyT1) in the dentate gyrus attenuates anxiety- and ethanol-related behaviors in rats
Abstract:Rationale Myelin Transcription Factor 1 (MyT1), a member of the Zinc Finger gene family, plays a fundamental role in the nervous system. Recent research has suggested that this transcription factor is associated with the pathophysiology of psychiatric disorders including addiction, schizophrenia, and depression. However, the role of MyT1 in anxiety-and ethanolrelated behaviors is still unknown. Objectives We evaluated the effects of lentiviral-mediated overexpression of MyT1 in the dentate gyrus (DG) on anxiet… Show more
“…After recovery, MyT1 rats and sham controls were tested on a variety of behavioral tasks to assess anxiety‐like behavior and EtOH consumption. MyT1 overexpression was associated with a decrease in anxious behavior on the elevated plus maze, and decreased voluntary EtOH consumption . This result suggests that increasing myelination in the dentate gyrus may have an anxiolytic effect on behavior, while reducing EtOH consumption.…”
Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin-behavior relationship and to develop new treatment strategies for AUDs.
“…After recovery, MyT1 rats and sham controls were tested on a variety of behavioral tasks to assess anxiety‐like behavior and EtOH consumption. MyT1 overexpression was associated with a decrease in anxious behavior on the elevated plus maze, and decreased voluntary EtOH consumption . This result suggests that increasing myelination in the dentate gyrus may have an anxiolytic effect on behavior, while reducing EtOH consumption.…”
Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin-behavior relationship and to develop new treatment strategies for AUDs.
“…To deliver the viruses into the hippocampus, we used stereotaxic injections as previously described for mice and rats ( Bahi et al, 2014b;Bahi and Dreyer, 2017 ). The complete dorsal and ventral hippocampus was targeted (including the CA fields, dentate gyrus, and subiculum) at four stereotaxic coordinates: 1st injection (AP -1.7, ML + / −1.2, DV -1.5); 2nd injection (AP -2.3, ML + / −1.75, DV -1.75); 3rd injection (AP -2.8, ML + / −3, DV -3); 4th injection (AP −3.4, ML + /-3, DV -3.75) ( Devito et al, 2010;Franklin and Paxinos, 1996 ).…”
Section: Construction Production Of the Lentiviral Vectors And Sterementioning
confidence: 99%
“…Spontaneous and exploratory locomotor activity and anxiety were assessed in an OF test, 10 days after the stereotaxic injections, as reported in our previous studies ( Bahi, 2017a;Bahi et al, 2016;Bahi et al, 2014a;Bahi et al, 2014c ). The anxiogenic-like phenotype was supported by decreased time spent in the center and by increased number of fecal boli left in the arena ( Bahi and Dreyer, 2017 ). After each session the arena was cleaned with a 70% pure ethanol solution to remove odor trails.…”
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
Adolescent binge drinking represents a major public health challenge and can lead to persistent neurological and mental conditions, but the underlying pathogenic mechanisms remain poorly understood. Using a mouse model of adolescent binge ethanol treatment (ABET), we found that this treatment induced behavioral changes associated with demyelination in different brain regions. After ABET, adolescent mice exhibited anxiogenic behaviors with no change in locomotion on the elevated plus maze, and impaired spatial memory indicated by a significant reduction in spontaneous alternation in the Y maze test. Both effects persisted into adulthood. Anatomical studies further showed that ABET induced a significant reduction of parvalbumin-positive (PV+) GABAergic interneurons and myelin density in the hippocampus and medial prefrontal cortex (mPFC). While these deficits in PV+ interneurons and myelin persisted into early adulthood in the hippocampus, the myelin density recovered in the mPFC. Moreover, whereas ABET mainly damaged myelin of PV+ axons in the hippocampus, it primarily damaged myelin of PV-negative axons in the mPFC. Thus, our findings reveal that an adolescent binge alcohol treatment regimen disrupts spatial working memory, increases anxiety-like behaviors, and exerts unique temporal and spatial patterns of gray matter demyelination in the hippocampus and mPFC.
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