In fact, rodent studies highlight the importance of age, in that the aged female rat is less responsive to 17β-estradiol therapy with respect to CA1 synapse number ( Adams et al., 2001a) and cognitive enhancement ( Savonenko and Markowska, 2003), and there appears to be a “window of opportunity” after which intervention is less effective ( Gibbs, 2000 Adams et al., 2001b). A resolution between clinical and basic research may hinge on several issues regarding the schedule and formulation of therapy, and age at the time treatment is initiated ( Simpkins and Singh, 2004). The frequently contradictory data from clinical studies on the cognitive effects of hormone treatment in women have been attributed to several factors ( Turgeon et al., 2004). Whereas preclinical findings are consistent with the view that estrogen therapy may promote healthy cognitive aging ( Zandi et al., 2002), the Women’s Health Initiative (WHI) studies, which used a standard form of combined hormone treatment, not only failed to slow the rate of cognitive decline in healthy postmenopausal women but significantly increased the risk for dementia and stroke ( S. Studies of young rhesus monkeys have also revealed estrogen effects on dorsolateral prefrontal cortex (PFC), including an increase in spine number ( Tang et al., 2004a) in layer I, as well as enhancement of cholinergic and monoaminergic inputs to PFC ( Kritzer and Kohama, 1999 Tinkler et al., 2004). 17β-Estradiol increases spine number in CA1 of ovariectomized young African green monkeys ( Leranth et al., 2002), and in young and aged female rhesus monkeys ( Hao et al., 2003). ![]() The data from nonhuman primates are largely consistent with rodent findings. Effects of estrogens on GABAergic synapses ( Rudick and Woolley, 2001) and cholinergic mediation of hippocampal function in young female rats have been described as well ( Gibbs, 2002 Rudick et al., 2003). ![]() ![]() 17β-Estradiol increases NMDA receptor levels ( Gazzaley et al., 1996) and facilitates NMDA receptor-mediated responses in CA1 pyramidal neurons ( Woolley et al., 1997). For example, there is evidence that 17β-estradiol increases the density of dendritic spines and axospinous synapses on CA1 pyramidal cells of young female rats ( Gould et al., 1990 Woolley and McEwen, 1992), and these effects are NMDA receptor-dependent ( Woolley and McEwen, 1994). These results document that, although the aged primate PFC is vulnerable in the absence of factors such as circulating estrogens, it remains responsive to long-term cyclic 17β-estradiol treatment, and that increased dendritic spine density and altered spine morphology may contribute to the cognitive benefits of such treatment.Īlthough data on cognition, menopause, and hormone treatments for women remain controversial ( Turgeon et al., 2004), the preclinical evidence is unambiguous in demonstrating neuroprotection ( Nilsen and Brinton, 2002) and synaptic effects of estrogens on circuits that mediate memory and cognition ( McEwen, 2001). In contrast, 17β-estradiol administration increased apical and basal dendritic spine density, and induced a shift toward smaller spines, a response linked to increased spine motility, NMDA receptor-mediated activity, and learning. 17β-Estradiol did not affect several parameters such as total dendritic length and branching. Here, we examined potential neurobiological substrates of this effect using intracellular loading and morphometric analyses to test the possibility that the cognitive benefits of hormone treatment are associated with structural plasticity in layer III pyramidal cells in PFC area 46. Long-term cyclic treatment with 17β-estradiol reverses age-related impairment in ovariectomized rhesus monkeys on a test of cognitive function mediated by the prefrontal cortex (PFC).
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