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Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress

View Article: PubMed Central - PubMed

ABSTRACT

MicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice to chronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors. In humans, pharmacological activation of the glucocorticoid receptor, as well as exposure to childhood trauma, was associated with increased microRNA-15a levels in peripheral blood. Taken together, our results support an important role for microRNA-15a in stress adaptation and the pathogenesis of stress-related psychopathologies.

No MeSH data available.


Related in: MedlinePlus

Mice with Virally Mediated Reduced Levels of BLA-miR-15a Exhibit Increased Anxiety-like Behavior(A–C) Results from the elevated plus maze (EPM) test of mice injected with miR-15a KD or control viruses (ns = 11 and 12, respectively) showing a tendency for differences, F(3, 19) = 2.971, p = 0.058. No significant differences were observed in the time spent in the open arms (A), the number of visits to the open arms (B), or the distance traveled in the open arms (C), according to Bonferroni correction for multiple testing. Data are represented as mean ± SEM.(D–F) Mice injected with miR-15a KD or control viruses (ns = 10 and 9, respectively) that were also subjected to social defeat showed different behavior in the EPM, F(3, 15) = 4.08, p = 0.026; with a significant decrease in the time (D) (U = 13, p = 0.009) and distance (F) (U = 7, p = 0.002) spent in the open arms of the EPM (corrected according to Bonferroni correction for multiple testing). No changes were observed in the number of visits to the open arms (E). Data are represented as mean ± SEM.(G) Representative tracking in the EPM of control mice (upper panel) relative to miR-15a KD mice (lower panel).(H–M) No changes were observed in the locomotor activity and total distance traveled in the open field test between miR-15a KD and control mice under basal conditions (H–J) or following social defeat (K–M). Data in (I)–(J), (L), and (M) are represented as mean ± SEM.∗p < 0.05; ∗∗p < 0.01.See also Figures S4 and S5.
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fig5: Mice with Virally Mediated Reduced Levels of BLA-miR-15a Exhibit Increased Anxiety-like Behavior(A–C) Results from the elevated plus maze (EPM) test of mice injected with miR-15a KD or control viruses (ns = 11 and 12, respectively) showing a tendency for differences, F(3, 19) = 2.971, p = 0.058. No significant differences were observed in the time spent in the open arms (A), the number of visits to the open arms (B), or the distance traveled in the open arms (C), according to Bonferroni correction for multiple testing. Data are represented as mean ± SEM.(D–F) Mice injected with miR-15a KD or control viruses (ns = 10 and 9, respectively) that were also subjected to social defeat showed different behavior in the EPM, F(3, 15) = 4.08, p = 0.026; with a significant decrease in the time (D) (U = 13, p = 0.009) and distance (F) (U = 7, p = 0.002) spent in the open arms of the EPM (corrected according to Bonferroni correction for multiple testing). No changes were observed in the number of visits to the open arms (E). Data are represented as mean ± SEM.(G) Representative tracking in the EPM of control mice (upper panel) relative to miR-15a KD mice (lower panel).(H–M) No changes were observed in the locomotor activity and total distance traveled in the open field test between miR-15a KD and control mice under basal conditions (H–J) or following social defeat (K–M). Data in (I)–(J), (L), and (M) are represented as mean ± SEM.∗p < 0.05; ∗∗p < 0.01.See also Figures S4 and S5.

Mentions: Next, we assessed the miR-15a KD mice for anxiety-like behavior using the EPM test. Under baseline conditions (in which mice were not exposed to chronic social defeat), a tendency toward main effect was observed (p = 0.058). No significant changes were observed in the time spent in the open arms, number of visits to the open arms, or distance traveled in the open arms between the miR-15a KD and control groups (Figures 5A–5C). Similarly, the locomotor activity and the total distance traveled in the open field test showed no differences between these groups (Figures 5H–5J). Intriguingly, however, following chronic social defeat, a main effect between the behavior of miR-15a KD and control mice was observed (p = 0.026). Mice with miR-15a KD spent significantly less time in the open arms (p = 0.009) (Figures 5D and 5G) and traveled less distance in the open arms relative to controls (p = 0.002; Figures 5F and 5G, (asterisks indicate significance following correction with Bonferroni correction for multiple testing). No differences were observed in the number of visits to the open arms, the locomotor activity between the groups, or the total distance traveled in the open field test (Figures 5E and 5K–5M). These results demonstrate that KD of miR-15a levels in the amygdala specifically impaired the recovery and behavioral response of mice following their exposure to chronic stress. In the open field test, miR-15a KD mice spent less time in the center of the arena (p = 0.032), but no changes were observed in the distance traveled in the center or the number of visits to the center (Figure S5C). Following chronic social defeat, miR-15a KD and control mice spent similarly less time in the center of the arena, suggesting a “floor effect.” However, miR-15a KD mice showed a tendency to travel for less distance in the center of the arena (p = 0.060) and made fewer visits to the center of the arena (p = 0.041) (Figure S5D). These results are in accordance with Hartmann et al. (2015), who observed induced anxiety-related behavior following overexpression of FKBP51 in the BLA. Moreover, Attwood et al. (2011) showed that silencing of FKBP51 levels in the BLA by injection of lentiviral short hairpin RNA led to a reduction in anxiety levels in the EPM. Taken together, the present data suggest that amygdalar miR-15a levels are functionally important in regulating the behavioral response to challenge and suggest that this effect is mediated, at least in part, via a reduction of FKBP51 levels.


Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress
Mice with Virally Mediated Reduced Levels of BLA-miR-15a Exhibit Increased Anxiety-like Behavior(A–C) Results from the elevated plus maze (EPM) test of mice injected with miR-15a KD or control viruses (ns = 11 and 12, respectively) showing a tendency for differences, F(3, 19) = 2.971, p = 0.058. No significant differences were observed in the time spent in the open arms (A), the number of visits to the open arms (B), or the distance traveled in the open arms (C), according to Bonferroni correction for multiple testing. Data are represented as mean ± SEM.(D–F) Mice injected with miR-15a KD or control viruses (ns = 10 and 9, respectively) that were also subjected to social defeat showed different behavior in the EPM, F(3, 15) = 4.08, p = 0.026; with a significant decrease in the time (D) (U = 13, p = 0.009) and distance (F) (U = 7, p = 0.002) spent in the open arms of the EPM (corrected according to Bonferroni correction for multiple testing). No changes were observed in the number of visits to the open arms (E). Data are represented as mean ± SEM.(G) Representative tracking in the EPM of control mice (upper panel) relative to miR-15a KD mice (lower panel).(H–M) No changes were observed in the locomotor activity and total distance traveled in the open field test between miR-15a KD and control mice under basal conditions (H–J) or following social defeat (K–M). Data in (I)–(J), (L), and (M) are represented as mean ± SEM.∗p < 0.05; ∗∗p < 0.01.See also Figures S4 and S5.
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fig5: Mice with Virally Mediated Reduced Levels of BLA-miR-15a Exhibit Increased Anxiety-like Behavior(A–C) Results from the elevated plus maze (EPM) test of mice injected with miR-15a KD or control viruses (ns = 11 and 12, respectively) showing a tendency for differences, F(3, 19) = 2.971, p = 0.058. No significant differences were observed in the time spent in the open arms (A), the number of visits to the open arms (B), or the distance traveled in the open arms (C), according to Bonferroni correction for multiple testing. Data are represented as mean ± SEM.(D–F) Mice injected with miR-15a KD or control viruses (ns = 10 and 9, respectively) that were also subjected to social defeat showed different behavior in the EPM, F(3, 15) = 4.08, p = 0.026; with a significant decrease in the time (D) (U = 13, p = 0.009) and distance (F) (U = 7, p = 0.002) spent in the open arms of the EPM (corrected according to Bonferroni correction for multiple testing). No changes were observed in the number of visits to the open arms (E). Data are represented as mean ± SEM.(G) Representative tracking in the EPM of control mice (upper panel) relative to miR-15a KD mice (lower panel).(H–M) No changes were observed in the locomotor activity and total distance traveled in the open field test between miR-15a KD and control mice under basal conditions (H–J) or following social defeat (K–M). Data in (I)–(J), (L), and (M) are represented as mean ± SEM.∗p < 0.05; ∗∗p < 0.01.See also Figures S4 and S5.
Mentions: Next, we assessed the miR-15a KD mice for anxiety-like behavior using the EPM test. Under baseline conditions (in which mice were not exposed to chronic social defeat), a tendency toward main effect was observed (p = 0.058). No significant changes were observed in the time spent in the open arms, number of visits to the open arms, or distance traveled in the open arms between the miR-15a KD and control groups (Figures 5A–5C). Similarly, the locomotor activity and the total distance traveled in the open field test showed no differences between these groups (Figures 5H–5J). Intriguingly, however, following chronic social defeat, a main effect between the behavior of miR-15a KD and control mice was observed (p = 0.026). Mice with miR-15a KD spent significantly less time in the open arms (p = 0.009) (Figures 5D and 5G) and traveled less distance in the open arms relative to controls (p = 0.002; Figures 5F and 5G, (asterisks indicate significance following correction with Bonferroni correction for multiple testing). No differences were observed in the number of visits to the open arms, the locomotor activity between the groups, or the total distance traveled in the open field test (Figures 5E and 5K–5M). These results demonstrate that KD of miR-15a levels in the amygdala specifically impaired the recovery and behavioral response of mice following their exposure to chronic stress. In the open field test, miR-15a KD mice spent less time in the center of the arena (p = 0.032), but no changes were observed in the distance traveled in the center or the number of visits to the center (Figure S5C). Following chronic social defeat, miR-15a KD and control mice spent similarly less time in the center of the arena, suggesting a “floor effect.” However, miR-15a KD mice showed a tendency to travel for less distance in the center of the arena (p = 0.060) and made fewer visits to the center of the arena (p = 0.041) (Figure S5D). These results are in accordance with Hartmann et al. (2015), who observed induced anxiety-related behavior following overexpression of FKBP51 in the BLA. Moreover, Attwood et al. (2011) showed that silencing of FKBP51 levels in the BLA by injection of lentiviral short hairpin RNA led to a reduction in anxiety levels in the EPM. Taken together, the present data suggest that amygdalar miR-15a levels are functionally important in regulating the behavioral response to challenge and suggest that this effect is mediated, at least in part, via a reduction of FKBP51 levels.

View Article: PubMed Central - PubMed

ABSTRACT

MicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice to&nbsp;chronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors. In humans, pharmacological activation of the glucocorticoid receptor, as well as exposure to childhood trauma, was associated with increased microRNA-15a levels in peripheral blood. Taken together, our results support an important role for microRNA-15a&nbsp;in stress adaptation and the pathogenesis of stress-related psychopathologies.

No MeSH data available.


Related in: MedlinePlus