Fig. 7: Age-related dysregulation of FGFR1 signaling contributes to biochemical hallmarks of progressive depression.

a Representative images showing the expression of BDNF in human patients with MDD and normal control dentate gyrus. Scale bar, 100 μm. b Distribution of BDNF H-score according to age in patients with MDD and normal control individuals. Data are represented as best-fit values ± standard error; samples included n = 6 for normal control and n = 3 for with MDD in each group. A linear regression analysis revealed a significant negative correlation between the x and y values in the MDD group (slope −1.62, 95% confidence interval (CI) −2.27 to −0.97; F(1,4) = 48.55, P = 0.0022; R² = 0.9239), indicating a strong linear relationship. By contrast, no significant correlation was observed in the control group (slope −0.1412, 95% CI −0.9448 to 0.6625; F(1,7) = 0.1725, P = 0.6903; R² = 0.02405). ns, not significant; **P < 0.01. c A quantification of BDNF H-score according to age groups showing decreased expression of BDNF in patients with MDD as their age is over 50 years. The data are represented as means ± s.e.m.; samples included n = 5 for normal control under 50 years old, n = 4 for normal control over 50 years old, n = 3 for MDD under 50 years old and n = 3 for MDD over 50 years old. A two-way ANOVA revealed significant main effects of both group (MDD versus control; (F(1,11) = 15.08, P = 0.0025) and age (<50 versus >50 years; F(1,11) = 11.39, P = 0.0062), as well as a significant interaction between factors (F(1,11) = 6.988, P = 0.0228). Post hoc comparisons using Šídák’s multiple comparisons test showed that in the MDD group, <50 participants had significantly higher BDNF H-scores than >50 participants (mean difference 51.33, 95% CI 19.90 to 82.76, P = 0.0029), while no significant difference was found between age groups in the control group (P = 0.5773). ns, not significant; **P < 0.01. d A dot plot showing expression levels of the Notch signaling genes in each region with filtered gene sets of the hippocampal subregions of patients with MDD compared with normal control. e Representative images showing the expression of Numb in human patients’ with MDD and healthy individuals’ dentate gyri. Scale bar, 100 μm. f Distribution of Numb H-score according to age in patients with MDD and healthy individuals. The data are represented as best-fit values ± standard error; samples included n = 6 for normal control and n = 3 for with MDD in each group. Linear regression analysis revealed a significant positive correlation between age and Numb H-score values in the MDD (slope 1.895, 95% CI 0.9629 to 2.827; F(1,4) = 31.86, P = 0.0049; R² =0.8885), indicating a strong linear relationship. By contrast, no significant correlation was observed in the control (slope −0.001081, 95% CI −0.2954 to 0.2932; F(1,7) = 0.00007546, P = 0.9933; R² = 0.00001). ns, not significant; **P < 0.01. g A quantification of Numb H-score according to age groups showing decreased expression of Numb in patients with MDD as their age is over 50 years. The data are represented as means ± s.e.m.; samples included n = 5 for normal control under 50 years old, n = 4 for normal control over 50 years old, n = 3 for MDD under 50 years old and n = 3 for MDD over 50 years old. Two-way ANOVA revealed significant main effects of both group (MDD versus control; F(1,11) = 17.85, P = 0.0014) and age (<50 versus >50; F(1,11) = 14.53, P = 0.0029), as well as a significant interaction between factors (F(1,11) = 12.52, P = 0.0047). Post hoc comparisons using Šídák’s multiple comparisons test showed that Numb H-score was significantly higher in >50 versus <50 years within the MDD (mean difference −56.33, 95% CI −86.96 to −25.70, P = 0.0012) but not in the control (P = 0.9721). ns, not significant; **P < 0.01. h Distribution of FGFR1 or Numb H-score according to BDNF H-score showing negative correlation of Numb H-score as BDNF H-score increases. The data are represented as best-fit values ± standard error; n = 6 for MDD human samples were included for each group. A linear regression analysis revealed a significant negative correlation between Numb (blue) H-score and BDNF H-score (slope −1.058, 95% CI −1.823 to −0.2941; F(1,4) = 14.78, P = 0.0184; R² = 0.787), indicating a strong linear relationship. By contrast, no significant correlation was observed for FGFR1 (orange) (slope 0.2597, 95% CI −0.3281 to 0.8475; F(1,4) = 1.505, P = 0.2872; R² = 0.2734). ns, not significant; *P < 0.05.