Aging of hippocampal neurogenesis and soy isoflavone

Throughout life, production of new neurons (granule cells) continues in the hippocampus of mammals including humans. Adult-generated granule cells play an important role in regulation of hippocampus-dependent cognitive functions and emotional behavior [1]. Each process of adult hippocampal neurogenesis is controlled by a variety of extrinsic and intrinsic factors. For instance, physical restraint, immobilization, foot shock and aging, have been shown to decrease production of granule cells. Especially, aged animals with preserved spatial memory exhibit a higher levels of adult hippocampal neurogenesis, while those with spatial memory deficits show a reduction in production of new granule cells. Experimental enhancement of adult hippocampal neurogenesis counteracts cognitive decline in aged animals. Furthermore, defects in adult hippocampal neurogenesis are suggested to be involved in cognitive dysfunction clinically observed in aged people. It is thus expected that the manipulation of adult hippocampal neurogenesis may help to rescue cognitive impairment in elderly people. Estrogens influence not only ovulation and reproductive behavior but also affect cognitive functions via estrogen receptors (ERs) [2]. In non-demented female populations, reductions of endogenous estrogens following menopause are often linked to cognitive deficits, with such decrements being reliably reversed by estrogen replacement. However, many women hesitate to take estrogens because they are afraid it might cause breast and endometrial cancer. Thus, there is now a need for safe and acceptable estrogen substitutes. Phytoestrogens are plant derived compounds that exhibit biological functions comparable to estrogens. Although phytoestrogens consist of a variety of compounds, they can largely be divided into three classes: isoflavones, lignans, and coumestans. Recent studies suggest that dietary and supplemental soy isoflavones can offer some relief for menopausal symptoms including hot flashes and vaginal dryness [3]. However, the mechanisms underlying phytoestrogen action on the brain remain to be elucidated. To get insight into the potential benefits of soy isoflavones on cognitive dysfunction following menopause, we have focused on the effects of daidzein on the adult hippocampal neurogenesis in middle-aged (12-month-old) female mice [4]. Animals received daily intraperitoneal injections of daidzein for four weeks, and the cells at specific stages of neurogenesis were presumptively defined using molecular markers. Administration of daidzein increased the spatial densities of late transient amplifying progenitors (TAPs), neural progenitors, and immature granule cells. However, the densities of primary progenitors and early TAPs were not affected by daidzein. These findings may shed new light on the " critical period " hypothesis of hormone therapy [5]: the use of …