Dissociation of affective and neuroimmune recovery under plantscapes and behavioral load in a mouse depression model

Background Rapid urbanization and reduced contact with natural settings are paralleled by rising rates of major depressive disorder (MDD). Naturalistic “plantscapes” have emerged as a promising, non-pharmacological intervention, yet their independent and combined effects with behavior remain unclear. Methods 64 female mice were used in this study, which employed a 2×2×2 factorial design for an 8-week intervention. The variables included environment (plant landscape vs. white wall control), housing condition (group housing vs. Solitary housing), and activity condition (activity participation vs. non-participation). Weekly assessments included Open Field Test (OFT) and Sucrose Preference Test (SPT). Terminal endpoints included serum interleukin-1β (IL-1β) levels, ileal 16S rRNA profiling for α/β-diversity, and immunofluorescence staining to assess levels of brain-derived neurotrophic factor (BDNF) and ionized calcium-binding adapter molecule 1 (Iba1). Linear Mixed Models (LMMs) were used to analyze longitudinal behavioral data. Multivariable Linear Regression Models (MLRM) were employed to analyze terminal physiological outcomes and identify significant predictors. Results The intervention period had the largest impact on behavioral recovery in mice, explaining 49.6% and 43.3% of the variance in total distance traveled and sucrose preference, respectively (partial η² = 0.496, 0.433). Behavioral recovery exhibited a clear time dependent effect, with significant improvement mainly observed after Week 4 (p < 0.05). Both plantscape exposure and non-participation in activity were associated with higher locomotor distance and sucrose preference than the white-wall and activity-participation conditions, respectively (all p ≤ 0.003). Environment and housing jointly explained 45.7% of the variance in IL-1β (model: F = 7.861, p = 0.001); group housing halved IL-1β relative to isolation (p < 0.05), and plantscape reduced levels by an additional 30–40% under solitary conditions. Plantscape increased Shannon and Chao-1 indices (p < 0.05) and segregated β-diversity from the control group, while the solitary enriched plantscape combination tripled the abundance of beneficial Bacteroides (p = 0.002).Activity is the only significant factor affecting BDNF levels (t = 2.259, p = 0.035), with the activity participation group showing significantly higher BDNF levels (p = 0.049). Conclusions The intervention period had the greatest impact on behavioral recovery, with improvements becoming most pronounced after Week 4. Both plantscape and non-activity also made significant contributions. Activity was a key factor in neurofunctional recovery, promoting neuroplasticity by increasing BDNF levels. Plantscape intervention supported neurobiological recovery by improving gut microbiota and reducing inflammation. Group housing and social interaction further enhanced immune regulation and emotional recovery. These findings suggest that eco-social interventions combining nature exposure and social interaction are effective strategies for treating depression.