During the current funding period, we examined in detail the effects of ERT on a variety of markers of the cholinergic basal forebrain system as well as dopaminergic mesocortical and nigrostriatal circuits. Effects were few. The effects that were limited to modest alterations in the vertical limb of the diagonal band (VLDB) and cholinergic innervation of cortex. Many of the discrepancies with respect to these systems could be due to the specific parameters employed such as the dose and schedule of estrogen replacement therapy (ERT). The failure to replicate findings in monkeys previously seen in rodents could also be due to species differences in response to ERT and highlights the need to study estrogen-related processes in a species close to humans. However, in the present proposal, we chose to change directions rather than pursue effects of ERT in primate systems for which robust findings cannot be demonstrated in our model. Instead this new direction focuses on ERT's effects of neurogenesis in monkeys, an exciting finding seen in lower species. We know that ERT influences neurogenesis in rats and we know that neurogenesis occurs in monkeys throughout their lifetime, however, there are no data available on the effect of ERT on neurogenesis in nonhuman primates. Thus it is logical to test the potency of ERT in altering neurogenesis in nonhuman primates, in addition, we will have the opportunity to pursue these studies in a parallel group of monkeys that have ERT+progesterone (P), and thus will be able to determine if P counters any positive effects of ERT on neurogenesis. We will also determine whether the pattern of hormone delivery, that being cyclic or chronic E and P delivery influences neurogenesis in nonhuman primates. Finally, multiple markers for neuroanatomic analyses and single cell gene arrays will be used to characterize the newly differentiated neurons in great detail to reveal their functional and circuitry properties. Given this total change of direction, we feel it is appropriate to request only 3 years of support at this time. Should the experiments in this funding period bear fruit, we will ask for an additional 2 years of funding in a supplement.

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Mount Sinai School of Medicine
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