Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior

Abstract

Background: Major depressive disorder is a leading debilitating disease known to occur at a two-fold higher rate in women than in men. The neurotrophic hypothesis of depression suggests that loss of brain-derived neurotrophic factor (BDNF) may increase susceptibility for depression-like behavior, although direct evidence is lacking.

Methods: Using the chronic unpredictable stress (CUS) paradigm, we investigated whether male and female mice with inducible BDNF deletion in the forebrain were more susceptible to depression-related behavior.

Results: We demonstrate that in certain behavioral measures the loss of BDNF lowers the threshold for female mice studied at random throughout estrus to display anxiogenic and anhedonic behaviors after chronic stress compared with wild-type female mice. However, the loss of BDNF in forebrain does not increase the susceptibility to depression-like behavior in male mice.

Conclusions: These gender differences suggest a role for BDNF in mediating some aspects of depression-related behavior in females.

Figure 1

CUS produces significant effects on locomotor activity. (A) CUS produced a significant stress (F_1,42 =4.83, p<0.05) and genotype effect (F_1,42 =4.22, p<0.05) on locomotor activity in females. The female stressed BDNF KOs were significant hypoactivity compared to stressed CTLs and nonstressed BDNF KOs (*p<0.05). (B) CUS produced a significant stress effect (F_1,30 =7.75, p<0.01) on locomotor activity in males. Male BDNF KO mice were hyperactive compared to CTL mice at baseline (*p<0.05). After CUS, male mice (*p<0.05) were significantly less active than their nonstressed cohorts while no significant effect was observed in nonstressed KOs compared to stressed KOs (p>0.05).

Figure 2

Females displayed heightened anxiety following CUS as assessed in the open field test. (A, C) In females, CUS produced a significant stress effect in the duration of time in the open field (F_1,45 =4.06, p<0.05) as well as in the frequency to enter the center area (F_1,45 =6.33, p<0.05). CUS in the BDNF KOs resulted in a significant decrease in duration of time in the center (p<0.05) and in the number of entries in the center (p<0.05) compared to nonstressed BDNF KOs. (B, D) Male mice did not differ in their anxiety behavior before or after stress regardless of genotype.

Figure 3

CUS increases certain depression-like behaviors in females. (A–B) Females, but not males, show a poorer fur state after CUS and there is an additional effect of genotype. (C–D) CUS results in significant alterations in sucrose consumption in female and male mice. Female stressed KOs consumed significantly less sucrose than both nonstressed KOs and stressed CTLs (* p<0.05). (E–F) In the novelty suppressed feeding task, stress significantly increased latency to feed in female mice (F_1,43 =8.79, p<0.005) but no effect in male behavior, and both stressed CTL and KO females took significantly longer to feed than their unstressed cohorts (p<0.05). However, there was a significant difference in male feeding behavior after stress in CTL mice compared to both nonstressed CTLs and stressed KOs(p<0.05).

Figure 4

Corticosterone and BDNF levels following chronic stress. (A–B) Stress did not have a main effect on CORT levels in male or female mice. However, in females, stress and genotype have significant interaction on CORT measures (F_1,42 =11.92, p<0.05). In both sexes, CORT levels are significantly lower in BDNF KOs under non stress conditions (p<0.05). In females, BDNF KO mice show heightened CORT levels after stress compared both to nonstressed KOs and stressed CTLs (p<0.05). However, in males, BDNF KOs displayed significantly lower CORT levels after stress compared to stressed CTLs (p<0.05). (C–D) BDNF levels following chronic stress. For female BDNF levels, there is a significant knockout effect (p=0.0040,F_1,34=9.51) and stress effect(p=0.0185,F_1,34=6.12) while there is no significant interaction effect (p=0.4947,F_1,34=0.48). Multiple comparisons using a Bonferroni t-test indicated that the nonstressed CTLs are significantly different from other three groups (*p<0.05). For male BDNF levels, there is a significant knockout × genotype interaction effect (p=0.0040,F_1,25=10.04). Multiple comparisons using a Bonferroni t-test indicated that, similarly to the females, the nonstressed CTLs are significantly different from the other three groups (* p<0.05).