Dendritic spines are postsynaptic sites of excitatory input in the mammalian nervous system. Despite much information about their structure, their functional significance remains unknown. It has been reported that females in proestrus, when estrogen levels are elevated, have a greater density of apical dendritic spines on pyramidal neurons in area CA1 of the hippocampus than females in other stages of estrous ). Here we replicate these findings and in addition, show that females in proestrus have a greater density of spines in area CA1 of the hippocampus than males. Moreover, this sex difference in spine density is affected in opposite directions by stressful experience. In response to one acute stressful event of intermittent tailshocks, spine density was enhanced in the male hippocampus but reduced in the female hippocampus. The decrease in the female was observed for those that were stressed during diestrus 2 and perfused 24 hr later during proestrus. The opposing effects of stress were not evident immediately after the stressor but rather occurred within 24 hr and were evident on apical and to a lesser extent on basal dendrites of pyramidal cells in area CA1. Neither sex nor stress affected spine density on pyramidal neurons in somatosensory cortex. Sex differences in hippocampal spine density correlated with sex hormones, estradiol and testosterone, whereas stress effects on spine density were not directly associated with differences in the stress hormones, glucocorticoids. In summary, males and females have different levels of dendritic spine density in the hippocampus under unstressed conditions, and their neuronal anatomy can respond in opposite directions to the same stressful event.

Dendritic spines are sources of synaptic contact that can be altered by experience and, as such, may be involved in memories for that experience. Here we tested whether the acquisition of new memories is associated with changes in the density of dendritic spines. Adult male rats were trained using the trace eyeblink conditioning paradigm, an associative learning task that requires the hippocampus for acquisition. Additional groups were exposed to the same number of stimuli presented in an explicitly unpaired manner or were naive. Twenty-four hours later, the density of dendritic spines was measured using Golgi impregnation. Trace conditioning was associated with an increase in the density of dendritic spines on the pyramidal cells of area CA1 of the hippocampus, an effect that was prevented by blocking acquisition of the learned response with a competitive NMDA receptor antagonist. Training with delay conditioning, a similar task that does not require the hippocampus, also produced an increase in spine density. The learning-induced increase in dendritic spine density was specific to basal dendrites of pyramidal cells in the CA1 region of the hippocampus. Changes did not occur on their apical dendrites or on cells in the dentate gyrus or somatosensory cortex. These results suggest that the formation and expression of associative memories increase the availability of dendritic spines and the potential for synaptic contact.

Dendritic spines in the hippocampus are sources of synaptic contact that may be involved in processes of learning and memory [Moser (1999) Cell. Mol. Life Sci., 55, 593-600]. These structures are sensitive to sex differences as females in proestrus possess a greater density than males and females in other stages of the estrous cycle (NMDA) receptors prevents the increase in spine density as females transition from diestrus 2 to proestrus, when estrogen levels are rising. Antagonism of NMDA receptors during exposure to the stressful event also prevented the changes in spine density in males and females, despite differences in the direction of these effects. Thus, the stress-induced increase in spine density was prevented in the male hippocampus as was the stress-induced decrease in spine density in the female hippocampus. NMDA receptor antagonism during exposure to the stressful event did not alter corticosterone levels or the corticosterone response to stress. These data suggest that both increases and decreases in spine density can be dependent on NMDA receptor activation.