Circulating sex hormones, particularly estrogens, provide neuroprotective effects in the hippocampus to promote synaptic plasticity and verbal/spatial memory throughout adulthood. For women, these effects are lost with the cessation of ovarian estrogen synthesis at menopause, compounding age-related hippocampal neurodegeneration and cognitive decline(6, 7). Furthermore, these neurological changes increase a woman's susceptibility to develop age-related disorders such as Alzheimer's disease (AD)(8, 9). No hormone therapy exists to maintain cognitive function during menopause. Only short-term use of hormone replacement therapy (HRT) is FDA recommended for the management of menopausal symptoms because estrogens in HRT can increase carcinogenic proliferation of breast and uterine tissue and increase cardiovascular disease risk in older women(21-26). These adverse health risks preclude current formulations of HRT from becoming a long- term treatment for preventing hippocampal decline following ovarian estrogen loss. While both estrogen receptors ? and ? (ER?) have been associated with estrogen-mediated neuroprotection and memory following loss of ovarian estrogen, the ER-expressing cell-type mediating these functions is unknown, and the estrogen-regulated gene network has not been characterized at the cell-specific level. We have recently identified estriol, a clinically safe alternative to estrogens in HRT(23-26, 30, 31), as protective for hippocampal synaptic plasticity and spatial memory following loss of ovarian estrogen in a rodent ovariectomy (OVX) model. We hypothesize that estriol treatment is sufficient to maintain hippocampal plasticity and function following the loss of ovarian estrogen, and that these peripheral estrogen effects are mediated primarily by ER? expressed on neurons through the regulation of synapse-associated, cytoskeletal, and survival genes. We will characterize estriol-mediated neuroprotection in the hippocampus using behavioral, electrophysiological, and neuropathological outcome measures in adult and middle-aged OVX mice. Furthermore, we will determine the cell-type and the ER responsible for mediating this effect using ER- conditional knockout mice generated in our lab. Finally, we will characterize the estrogen-sensitive transcriptome of hippocampal neurons in adult and middle-aged mice. This work is significant because it will evaluate a treatment with high clinical relevance specifically for cognitive decline during menopause, use innovative conditional knockout models to reveal the cellular and molecular targets of the protective effects of estrogen in the hippocampus, and identify gene expression changes in adult and middle-aged mice to help characterize the estrogen-sensitive gene network in hippocampal neurons occurring during both surgical/early menopause and natural menopause. It will also warrant clinical trials of estriol to prevent cognitive decline from menopause. Together, this proposal supports the National Institute on Aging mission to explore research questions that significantly contribute to informed decision-making for relieving menopausal symptoms.
Cognitive decline occurs in women during menopause following the loss of the neuroprotective effects of estrogen and is associated with the etiology of Alzheimer's disease, but there are no therapeutics currently recommended or being evaluated in clinical trials to prevent this cognitive decline. With an aging female population, ths lack of therapeutics comes at a tremendous socioeconomic cost, and treatments that could delay or prevent the onset of cognitive decline during menopause remain an unmet, yet pressing clinical need. We propose a novel strategy to prevent cognitive decline in a preclinical menopause model through estrogen receptor ? (ER?)-mediated neuroprotection, which would be safe and effective for translational dosing in human clinical trials, and we aim to determine the cellular mediator of estrogen's neuroprotective effects in the hippocampus and to characterize the estrogen-sensitive transcriptome in the hippocampal neurons, to ultimately advance our understanding of how estrogens promote hippocampal synaptic plasticity and function to improve the cognitive health of menopausal women worldwide.
| Kammel, Laura G; Wei, Weizheng; Jami, Shekib A et al. (2018) Enhanced GABAergic Tonic Inhibition Reduces Intrinsic Excitability of Hippocampal CA1 Pyramidal Cells in Experimental Autoimmune Encephalomyelitis. Neuroscience 395:89-100 |
| Gandal, Michael J; Haney, Jillian R; Parikshak, Neelroop N et al. (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359:693-697 |
