Effects of multiple daily genistein treatments on delayed alternation and a differential reinforcement of low rates of responding task in middle-aged rats

Abstract

The use of extracts that are highly enriched in phytoestrogens, such as genistein, has become popular to promote various aspects of healthy aging, including maintenance of cognitive function. These compounds are promoted to menopausal women as safe, natural alternatives to traditional estrogen therapies, yet their safety and efficacy are poorly understood. Previous research in our lab found that once daily oral treatment of ovariectomized female Long-Evans (LE) rats with the soy phytoestrogen, genistein resulted in subtle deficits in performance on cognitive tasks assessing working memory and response inhibition/timing ability. The present study further modeled exposure of the menopausal woman to genistein by treating 14-month old ovariectomized female LE rats three times daily at a dose of genistein resulting in serum concentrations similar to those that could be achieved in humans consuming either a commercially available soy isoflavone supplement or a diet high in these phytoestrogens. Genistein (3.4 mg/kg) or sucrose control pellets were orally administered to animals daily, 30 minutes before behavioral testing, and again both 4 and 8 hours after the first treatment. The test battery consisted of a delayed spatial alternation task (DSA) that tested working memory and a differential reinforcement of low rates of responding (DRL) task that tested inhibitory control/timing. Genistein treatment impaired DSA performance relative to sucrose controls. Performance on the DRL task was largely unaffected by genistein treatment. Although the impairment measured on DSA was less pronounced than that we have previously reported following chronic treatment with 17β-estradiol, the pattern of the deficit was very similar to that observed with 17β-estradiol.

Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats

“…To our knowledge, this is the first report of the mnemonic effects of phytoestrogen treatment on a striatum-sensitive task. Our previous results indicate that genistein treatment impairs performance on operant conditioning measures of executive function in a delayed spatial alternation task that relies primarily on the prefrontal cortex but also engages cortico-striatal function (Neese et al, 2010, Neese et al, 2012). Importantly, these findings of impaired learning indicate that isoflavone treatment does not produce global cognitive enhancements.…”

“…Studies examining the effects of isoflavones on cognition are particularly sparse and document mixed results in humans (Lee et al, 2005, Zhao and Brinton, 2007). In experiments using laboratory rodents, isoflavones act like estradiol, enhancing performance for some memory tasks but impairing performance on others (Pan et al, 2000, Lund et al 2001, Luine et al 2006, Monteiro et al 2008, Neese et al, 2010, Neese et al 2012). Most research has focused on chronic isoflavone exposure, with few experiments examining the acute actions of isolated soy compounds commonly found in botanical supplements.…”

“…Most research has focused on chronic isoflavone exposure, with few experiments examining the acute actions of isolated soy compounds commonly found in botanical supplements. Genistein, one of the most estrogenic isoflavones with twenty-fold selectivity for estrogen receptor (ER) β over ERα (Kuiper et al, 1998), is widely researched, yet only a handful of studies have investigated its mnemonic effects (Xu et al, 2007, Alonso et al, 2010, Huang and Zhang, 2010, Neese et al, 2010, Neese et al, 2012). Additionally, there have been no examinations of phytoestrogen actions on striatum-sensitive memory to date, which is surprising given that the striatum responds to agonists that target ERβ (Morissette et al, 2008).…”

Low dietary soy isoflavonoids increase hippocampal spine synapse density in ovariectomized rats

“…Work in laboratory animals supports this hypothesis, demonstrating estrogen-like effects of isoflavonoids in rats (Lephart et al, 2002; Luine et al, 2006; Lund et al, 2001; Pisani et al, 2012). However, not all the reported effects on cognitive function have been positive, in either animals (Neese et al, 2012) or humans (Henderson et al, 2012; Soni et al, 2014; St John et al, 2014; Zhao and Brinton, 2007). This may in part be because isoflavonoids do not have the same receptor specificity as the principal mammalian estrogen, estradiol.…”

Improvement in Cognitive Function with Green Soybean Extract May Be Caused by Increased Neuritogenesis and BDNF Expression

“…Soybean is a rich source of proteins, oligosaccharides, dietary fibers, minerals and phytochemicals, particularly isoflavones [1,2]. Numerous beneficial effects of soybean and its components have been reported on cognitive function and oxidative damage [3][4][5][6][7]. Immature soybean seeds are usually green before it is harvested and becomes yellow during maturation.…”