To reveal the neurobiological underpinnings of estrogen-induced enhancement of memory function mediated by the prefrontal cortex, we investigated the effect of estrogen on dendritic spine numbers in area 46. However, spine and synapse analyses comparable to those existing for the hippocampus are lacking in this region. Ovariectomy (OVX) and ovarian hormone replacement have been shown to affect the density of catecholaminergic and cholinergic fibers in the dorsolateral prefrontal cortex of young adult monkeys ( Kritzer and Kohama, 1998, 1999). Several recent human clinical and animal behavioral studies suggest that estrogen replacement enhances performance on working memory tasks that are reliant on the prefrontal cortex ( Roberts et al., 1997 Duff and Hampson, 2000 Keenan et al., 2001 Solis-Ortiz and Marquez-Rangel, 2001 Rapp et al., 2003). Estrogen replacement has also been shown to be protective against neocortical ischemic damage in a rodent model of stroke ( Wise et al., 2000). Spine density on pyramidal neurons in rat hippocampal CA1 varies with the estrous cycle and is sensitive to experimentally induced estrogen depletion and replacement ( Gould et al., 1990 Woolley et al., 1990 Woolley and McEwen, 1992). The effect of estrogen on brain regions that are not directly associated with reproduction has been the subject of numerous studies over the past decade, with hormonal effects on hippocampus as the primary focus of these studies. The present results suggest that estrogenвЂ™s effects on synaptic organization influence select neocortical layers and regions in a primate model, and provide a morphological basis for enhanced prefrontal cortical functions following estrogen replacement.Д¬ognition, dendritic spines, hormone replacement, macaque monkey, plasticity, steroids, visual cortex Introduction Spine numbers in layer I of area 46 were significantly increased (55%) in the ovariectomy + estrogen group compared to the ovariectomy + vehicle group, yet spine numbers in layer I of area V1o were equivalent across the two groups. Using an antibody against the spine-associated protein, spinophilin, spine numbers were estimated in layer I of area 46 and in layer I of the opercular portion of area V1 (V1o). Young female monkeys were ovariectomized and administered either estradiol cypionate or vehicle by intramuscular injection.

Therefore, we investigated the effects of estrogen on dendritic spines in the prefrontal and primary visual cortices of young rhesus monkeys. Moreover, it is not known if such an estrogen effect would be manifested throughout the neocortex or primarily in the regions involved in cognition.

However, the potential for similar estrogen-induced increases in spines and synapses in the prefrontal cortex has not been investigated in primates. While studies have shown that estrogen affects hippocampal spine density and function, behavioral studies in humans and nonhuman primates have also implicated the prefrontal cortex in the effects of estrogen on cognition.