There have been a number of discoveries that have revealed a much greater degree of structural plasticity in the adult brain than previously imagined. After the discovery that estrogens regulate synapse density in the adult rat hypothalamic ventromedial nucleus (VMN) in a sexually-dimorphic fashion, we showed that the ovarian cycle regulates cyclic synaptogenesis on excitatory spine synapses in hippocampal CA1 pyramidal neurons (45). Male rats show much less estrogen-induced synapse formation unless they are treated at birth with an aromatase (P450aro) inhibitor, and this suggests that the developmentally regulated estrogen receptors and aromatase activity in hippocampus are involved in programming the response of the adult hippocampus (36,37). One of the surprises of the synaptogenesis story is that estrogen-induction of synapses is blocked by N-methyl-D-aspartate (NMDA) receptor antagonist treatment, indicating that excitatory amino acids and NMDA receptors are involved in synapse formation. Progesterone (PROG) secreted at the time of ovulation appears to be responsible for down-regulation of estrogen-induced synapses in the CA1 region, and the cellular location of the progestin receptors as well as of the estrogen receptors is a prime question.
The hippocampus also undergoes two other forms of plasticity, in which circulating hormones and excitatory amino acids acting via NMDA receptors are involved. One of these is the ongoing neurogenesis in the adult rat dentate gyrus, which continues for at least 1 yr after birth and can be increased either by adrenalectomy or by treatment with an NMDA receptor antagonist (46). Although the male dentate gyrus is larger than that of the female (33), there is no information at present concerning the role of gonadal hormones in adult life in ongoing neurogenesis, although preliminary data has noted sex differences in neurogenesis in the adult prairie vole (42). Dentate gyrus granule neurons innervate the CA3 region of Ammon's horn, and stress causes apical dendrites of CA3 pyramidal neurons to undergo atrophy by a process that is dependent in part on circulating adrenal steroids and in part on excitatory amino acids acting via NMDA receptors (47). Hibernation also causes dendrites of CA3 pyramidal neurons to undergo an atrophy that is reversed within as little as 1 h of wakening (48,49), but the pharmacology of this process is unknown at present. Stress-induced dendritic atrophy is also reversible (Magarinos and McEwen, unpublished), albeit more slowly than after hibernation, but severe and prolonged social stress (in vervet monkeys) and cold-swim stress (in rats) causes CA3 pyramidal neuron loss in males that is not evident in females (50,51). Thus, there is the possibility that intrinsic sex differences in hippocampal morphology or in response to hormones or excitatory amino acids may have a protective role in the female. Besides the larger dentate gyrus of the male (33), male CA3 neurons have more excrescences for mossy fiber contacts, whereas female CA3 apical dendrites are more extensively branched (35).
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