Depletion of dietary phytoestrogens reduces hippocampal plasticity and contextual fear memory stability in adult male mouse

Introduction: Phytoestrogens are non-steroidal estrogen analogues and are found primarily in soy products. They have received increasing attention as dietary supplements for estrogen deficiency and as modulators of endogenous estrogen functions, including cognition and emotion. In addition to modifying the levels of circulating sex hormones, phytoestrogens also exert direct effects on estrogen and androgen receptors in the brain and thus effectively modulate the neural circuit functions. Objective: The aim of this study was to investigate the long-term effects of low phytoestrogen intake (similar to 6 weeks) on the hippocampal plasticity and hippocampus-dependent memory formation in the adult C57BL/6 male mice. Methods and Results: In comparison to mice on a diet with normal phytoestrogen content, mice on low phytoestrogen diet showed a significant reduction in the phosphorylation of NR2B subunit, a molecular correlate of plasticity in the Schaffer collateral-CA1 synapse. We observed a profound decrease in long-term potentiation (LTP) in the ventral hippocampus, whereas no effect on plasticity was evident in its dorsal portion. Furthermore, we demonstrated that acute perfusion of slices with an estrogen analogue equol, an isoflovane metabolized from daidzein produced by the bacterial flora in the gut, was able to rescue the observed LTP deficit. Examining potential behavioral correlates of the plasticity attenuation, we found that mice on phytoestrogen-free diet display decreased contextual fear memory at remote but not at recent time points after training. Conclusions: Our data suggests that nutritional phytoestrogens have profound effects on the plasticity in the ventral hippocampus and ventral hippocampus-dependent memory.

Automated summary

Phytoestrogens have significant effects on plasticity in the ventral hippocampus and ventral hippocampus-dependent memory formation in adult male mice, with low phytoestrogen intake leading to reductions in NR2B subunit phosphorylation and long-term potentiation. Acute perfusion with the estrogen analogue equol was able to rescue the observed LTP deficit. Mice on a phytoestrogen-free diet displayed decreased contextual fear memory at remote time points after training.