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. 2019 Aug 21;10(1):3768.
doi: 10.1038/s41467-019-11641-8.

Activating newborn neurons suppresses depression and anxiety-like behaviors

Elif Tunc-Ozcan  1 , Chian-Yu Peng  2 , Yiwen Zhu  3 , Sara R Dunlop  2 , Anis Contractor  3 , John A Kessler  2
Affiliations

Activating newborn neurons suppresses depression and anxiety-like behaviors

Elif Tunc-Ozcan et al. Nat Commun. .

Abstract

The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Silencing newborn dentate gyrus neurons prevents the effects of fluoxetine and alters baseline affective behavior. a Timeline representing the experimental design for determining whether silencing of newborn neurons inhibits the effects of fluoxetine treatment in Ascl1-CreERTM;R26LSL−hM4Di mice. b Total time-spent immobile in tail suspension test, a measure of depression-like behavior (Fluoxetine F1,60 = 23.11, ***P < 0.0001; hM4Di F1,60 = 6.92, *P = 0.011; CNO F1,60 = 15.60, ***P < 0.0001; hM4Di*CNO F1,60 = 5.08, *P = 0.028; Tukey posthoc test + hM4Di + CNO Saline treatment versus other saline treatment groups *P < 0.05; + hM4Di + CNO Fluoxetine treatment versus other fluoxetine treatment groups *P < 0.05). c Distance spent in center exploration in open-field test, a measure of anxiety-like behavior (Fluoxetine F1,60 = 42.32, ***P < 0.0001; hM4Di F1,60 = 28.59, ***P < 0.0001; CNO F1,60 = 5.27, *P = 0.025; hM4Di*CNO F1,60 = 44.46, ***P < 0.0001; Tukey posthoc test + hM4Di + CNO Saline treatment versus other saline treatment groups **P < 0.01; + hM4Di + CNO Fluoxetine treatment versus other fluoxetine treatment groups ***P < 0.0001). d Total distance in open-field test, measure of locomotor activity (Fluoxetine F1,60 = 0.002, P = 0.965; hM4Di F1,60 = 1.297, P = 0.259; CNO F1,60 = 0.138, P = 0.711; hM4Di*CNO F1,60 = 0.030, P = 0.862). Data are presented as means ± s.e.m. and analyzed by three-way ANOVA
Fig. 2
Fig. 2
CNO silencing does not alter the increase in neurogenesis after fluoxetine treatment. a Representative images and quantification of HA-Tag + dentate gyrus cells (By two-way ANOVA: Fluoxetine F1,13 = 16.15, **P = 0.0015; CNO F1,13 = 0.2021, P = 0.660; Interaction F1,13 = 0.0009, P = 0.976). b Representative images and quantification of ki67-positive dentate gyrus cells (by three-way ANOVA: Fluoxetine F1,32 = 59.52, ***P < 0.0001; hM4Di F1,32 = 0.130, P = 0.721; CNO F1,32 = 0.143, P = 0.708; hM4Di*CNO F1,32 = 0.001, P = 0.980). Data are presented as means ± s.e.m. Scale bars 50 μm
Fig. 3
Fig. 3
CNO prevents the fluoxetine-induced increase in activity of dentate gyrus neurons in vivo. a Representative images of HA-Tag + Egr1 + double-labeled dentate gyrus cells. b Quantification of HA-Tag + Egr1 + cells in the dentate gyrus (by two-way ANOVA: Fluoxetine F1,16 = 4.288, P = 0.0549; CNO F1,16 = 26.16, ***P = 0.0001; Interaction F1,16 = 1.184, P = 0.293). c Representative images of c-Fos-positive dentate gyrus cells. d Quantification of c-Fos expression in the dentate gyrus. (by three-way ANOVA: Fluoxetine F1,32 = 21.55, ***P < 0.0001; hM4Di F1,32 = 9.01, **P = 0.005; CNO F1,32 = 10.85, **P = 0.002; hM4Di*CNO F1,32 = 6.14, *P = 0.019; Tukey posthoc test + hM4Di + CNO Saline treatment versus other saline treatment groups *P < 0.05; + hM4Di + CNO Fluoxetine treatment versus other fluoxetine treatment groups *P < 0.05). Data are presented as means ± s.e.m. Scale bars 50 μm
Fig. 4
Fig. 4
Acute activation of newborn dentate gyrus neurons results in antidepressive effects. a Timeline representing experimental design for determining whether enhancing the activity of newborn neurons induces an antidepressant effect in Ascl1-CreERTM;R26LSL−hM3Dq mice. b Total time spent immobile in tail suspension test, a measure of depression-like behavior (hM3Dq F1,20 = 5.86, *P = 0.025; CNO F1,20 = 7.16, *P = 0.015; Interaction F1,20 = 4.72, *P = 0.042; Tukey posthoc test + hM3Dq + CNO versus other groups *P < 0.05). c Center exploration distance in open-field test, a measure of anxiety-like behavior (hM3Dq F1,20 = 4.42, *P = 0.048; CNO F1,20 = 4.65, *P = 0.044; Interaction F1,20 = 4.98, *P = 0.037; Tukey posthoc test + hM3Dq + CNO versus other groups *P < 0.05). d Total distance in open-field test, measure of locomotor activity (hM3Dq F1,20 = 0.005, P = 0.945; CNO F1,20 = 0.418, P = 0.525; Interaction F1,20 = 0.927, P = 0.347). e Representative images and quantification of HA-Tag + Egr1 + double-positive cells in the dentate gyrus (t6 = 2.459, *P = 0.049). f Representative images and quantification of c-Fos expression in the dentate gyrus (hM3Dq F1,16 = 10.11, **P = 0.006; CNO F1,16 = 5.31, *P = 0.035; Interaction F1,16 = 13.79, **P = 0.002; Tukey posthoc test + hM3Dq + CNO versus other groups **P < 0.01). Data are presented as means ± s.e.m. and analyzed by two-way ANOVA (b, c, d, and f) or two-tailed Student’s t-test (e). Scale bar 50 μm
Fig. 5
Fig. 5
Acute activation of newborn dentate gyrus neurons reverses the behavioral effects of unpredictable chronic mild stress (uCMS). a Timeline representing the experimental design for determining whether acutely enhancing the activity of newborn neurons in adult hippocampus reverses the behavioral effects of unpredictable chronic mild stress (uCMS) in Ascl1-CreERTM;R26LSL−hM3Dq mice. b Total time-spent immobile in tail suspension test, a measure of depression-like behavior (uCMS F1,27 = 11.23, **P = 0.002; CNO F1,27 = 19.93, ***P = 0.0001; Interaction F1,27 = 0.313, P = 0.581; Tukey posthoc test Control + Vehicle versus uCMS + Vehicle *P < 0.05). c Center exploration distance in open-field test, a measure of anxiety-like behavior (uCMS F1,27 = 12.1, **P = 0.002; CNO F1,27 = 17.04, ***P = 0.0003; Interaction F1,27 = 0.564, P = 0.459; Tukey posthoc test Control + Vehicle versus uCMS + Vehicle *P < 0.05). d Total distance in open-field test, measure of locomotor activity (uCMS F1,27 = 0.242, P = 0.627; CNO F1,27 = 0.267, P = 0.609; Interaction F1,27 = 0.008, P = 0.930). e Representative images and quantification of c-Fos expression in the dentate gyrus (uCMS F1,12 = 19.19, ***P = 0.0009; CNO F1,12 = 22.01, ***P = 0.0005; Interaction F1,12 = 0.088, P = 0.771; Tukey posthoc test Control + Vehicle versus uCMS + Vehicle *P < 0.05). Data are presented as means ± s.e.m. and analyzed by two-way ANOVA. Scale bar 50 μm
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