Flaxseed Supplementation Confers Resilience to Stress-Induced Depression-Like Behaviors via GDNF Epigenetic Modulation in the Ventral Tegmental Area of Rats.

OBJECTIVE

To study the improvement of dietary flaxseed supplementation on resilience to chronic stress-induced depression-like behaviors of rats and investigate whether these behavioral effects are associated with alterations in glial cell line-derived neurotrophic factor (GDNF) promoter methylation and expression in the ventral tegmental area (VTA).

METHODS

Forty-eight male rats were randomly grouped to chronic unpredictable stress (CUS) alone, or with flaxseeds oil (CUS/FO), or flaxseed flour (CUS/FF), flaxseed oil alone (FO), flaxseed flour alone (FF), or not any treatments (blank control, BC). FO, FF, CUS/FO, CUS/FF rats treated flaxseeds oil or flour for 5 weeks. During the second week of the 5-week period, CUS, CUS/FO, CUS/FL rats were subjected to chronic unpredictable stress for 4 weeks. Sucrose preference test (SPT) and forced swim test (FST) were used to rats' behavioral performance. The methylation levels, mRNA and protein expression of GDNF gene in the VTA were also measured after behavioral test.

RESULTS

CUS/FO rats exhibited a significantly higher sucrose preference rate (SPR) in the SPT than CUS rats (p<0.05). CUS/FO and CUS/FF rats both exhibited significantly shorter immobility time, longer climbing and swimming time in the FST than CUS rats (ps<0.05). FO rats also showed a significantly increased SPR compared with BC (p<0.05). Both GDNF protein and mRNA level in CUS/FO rats were significantly higher compared with CUS alone (ps<0.05). There was significantly lower GDNF gene promotor methylation in CUS/FO, CUS/FF compared with CUS alone (ps<0.05).

CONCLUSION

Flaxseed supplementation, particularly flaxseed oil, confers resilience to chronic stress and attenuates depression-like behaviors in rat. In addition, enhancing hedonic capacity may be a key mechanism by which flaxseed promotes resilience to stress. These behavioral improvements may be mediated, at least in part, by decreased methylation of the GDNF gene promoter and subsequently up-regulation of GDNF gene expression in the VTA, highlighting an epigenetic mechanism linking dietary interventions to stress-related behavioral outcomes.