Antidepressive and BDNF effects of enriched environment treatment across ages in mice lacking BDNF expression through promoter IV

Abstract

Reduced promoter IV-driven expression of brain-derived neurotrophic factor (BDNF) is implicated in stress and major depression. We previously reported that defective promoter IV (KIV) caused depression-like behavior in young adult mice, which was reversed more effectively by enriched environment treatment (EET) than antidepressants. The effects of promoter IV-BDNF deficiency and EET over the life stages remain unknown. Since early-life development (ED) involves dynamic epigenetic processes, we hypothesized that EET during ED would provide maximum antidepressive effects that would persist later in life due to enhanced, long-lasting BDNF induction. We tested this hypothesis by determining EET effects across three life stages: ED (0-2 months), young adult (2-4 months), and old adult (12-14 months). KIV mice at all life stages showed depression-like behavior in the open-field and tail-suspension tests compared with wild-type mice. Two months of EET reduced depression-like behavior in ED and young adult, but not old adult mice, with the largest effect in ED KIV mice. This effect lasted for 1 month after discontinuance of EET only in ED mice. BDNF protein induction by EET in the hippocampus and frontal cortex was also the largest in ED mice and persisted only in the hippocampus of ED KIV mice after discontinuance of EET. No gender-specific effects were observed. The results suggest that defective promoter IV causes depression-like behavior, regardless of age and gender, and that EET during ED is particularly beneficial to individuals with promoter IV-BDNF deficiency, while additional treatment may be needed for older adults.

Figure 1

(a) Research design. Male and female wild type (WT) and KIV mice received 2 months of enriched environment treatment (EET: red arrows) or standard condition treatment (SCT: blue arrows) from birth (early-life development: ED), 2 months (young adult: YA) or 12 months of age (old adult: OA), then received 1 month of SCT. Depression-like behavior and brain-derived neurotrophic factor (BDNF) levels were measured after EET (test 1: T₁) and consequent SCT (test 2: T₂). (b–e) Age and gender effects of deficiency of promoter IV-driven BDNF on total activity (b); distance moved (c); and time in center (d) in the open-field test, and immobility time in the tail-suspension test (e). Results from KIV-SCT mice (male: left; female: right) at T₁ are shown as % WT-SCT. Asterisks on the columns show a significant difference between WT and KIV mice. KIV, knock-in BDNF-promoter IV; SCT, standard condition treatment; WT, wild-type. *P<0.05, **P<0.01, ***P<0.005. N=12–16.

Figure 2

EET effects on total activity in the open-field test across ages (male: left; female: right). (a) Total activity in WT and KIV mice after 2 months of EET (SCT/EET, T₁), then after 1 month of SCT (SCT–SCT/EET–SCT, T₂). Asterisks on the columns show a significant difference between genotypes. (b). EET effects shown by % SCT across ages at T₁ (top) and at T₂ (bottom). Asterisks on the columns show a significant effect of EET compared with SCT. ED, early-life development; EET, enriched environment treatment; KIV, knock-in BDNF-promoter IV; OA, old adult; SCT, standard condition treatment; WT, wild-type; YA, young adult. *P<0.05, **P<0.01, ***P<0.005. N=10–16 (shown at the columns).

Figure 3

EET effects on time in the center in the open-field test across ages. (a) Time in center measured at T₁ (SCT/EET) and at T₂ (SCT–SCT/EET–SCT). Asterisks on the columns show a significant difference between genotypes. (b) EET effects shown as % SCT across ages at T₁ (top) and at T₂ (bottom). Asterisks on the columns show a significant effect of EET (vs SCT). ED, early-life development; EET, enriched environment treatment; OA, old adult; SCT, standard condition treatment; YA, young adult. *P<0.05, **P<0.01, ***P<0.005. N=10–16.

Figure 4

EET effects on immobility time in the tail-suspension test across ages. (a). Immobility time in WT and KIV mice at T₁ (SCT/EET) and T₂ (SCT–SCT/EET–SCT). Asterisks on the columns show a significant difference between genotypes. (b). EET effects shown as % SCT across ages at T₁ (top) and at T₂ (bottom). Asterisks on the columns show a significant effect of EET compared with SCT. ED, early-life development; EET, enriched environment treatment; KIV, knock-in BDNF-promoter IV; OA, old adult; SCT, standard condition treatment; WT, wild-type; YA, young adult. *P<0.05, **P<0.01, ***P<0.005. N=11–16.

Figure 5

EET effects on BDNF protein levels in the hippocampus (left) and frontal cortex (right) measured by ELISA. (a) BDNF levels in WT and KIV mice after EET (SCT/EET, T₁), then after 1 month of SCT (SCT–SCT/EET–SCT, T₂). Asterisks on the columns show a significant difference between genotypes. Data are combined (N=8–10) from male (N=4–5) and female (N=4–5) mice because no gender differences were observed. (b) EET effects shown as % SCT across ages at T₁ (top) and at T₂ (bottom). Asterisks on the columns show a significant effect of EET compared to SCT. BDNF, brain-derived neurotrophic factor; ED, early-life development; EET, enriched environment treatment; KIV, knock-in BDNF-promoter IV; OA, old adult; SCT, standard condition treatment; WT, wild-type; YA, young adult. *P<0.05, **P<0.01, ***P<0.005.