Memory deficits plague patients with numerous mental disorders, yet a fundamental lack of knowledge about the neural mechanisms regulating memory formation has hampered the development of therapies to reduce this memory dysfunction. The sex steroid hormone 17?-estradiol (E2) is a potent modulator of hippocampal synaptic plasticity and memory, and likely contributes to sex differences in the prevalence, progression, and severity of many psychiatric and neurodegenerative diseases. However, the neural mechanisms through which E2 regulates memory are poorly understood. Thus, there is an urgent need to identify molecular mechanisms through which E2 regulates learning and memory processes in both sexes. Our long-term goal is to pinpoint the key neural mechanisms through which estrogens regulate hippocampal memory formation in males and females. The overall objective of this application, which is the next step toward attainment of our goal, is to determine the extent to which canonical Wnt signaling and BDNF contribute to the memory enhancing effects of E2. Our central hypothesis is that E2 enhances memory by promoting Wnt signaling, which then epigenetically regulates the transcription and translation of BDNF. These hypotheses were formulated on the basis of published data indicating that Wnt signaling increases BDNF expression6, and our own published data showing that canonical Wnt signaling is necessary for hippocampal memory consolidation in male mice7, histone acetylation is necessary for E2 to enhance hippocampal memory consolidation in female mice8, and that E2 increases hippocampal BDNF protein and H3 acetylation at Bdnf promoters in female mice7. Guided by our strong preliminary data, our hypothesis will be tested in three specific aims designed to: 1) determine the extent to which estrogenic regulation of canonical Wnt signaling facilitates hippocampal memory consolidation, 2) establish the extent to which canonical Wnt signaling and BDNF interact to regulate hippocampal memory consolidation, and 3) identify the molecular mechanisms through which E2 mediates BDNF expression and memory formation. This research is innovative because it utilizes a hypothesis-driven approach that integrates behavioral and biochemical analyses to identify mechanistic relationships among modulatory pathways that regulate hippocampal memory formation in both males and females. The proposed research is significant because it is the first step in a continuum of research designed to provide foundational knowledge about the molecular mechanisms through which E2 regulates memory formation. This work will provide sorely needed insights about estrogenic regulation of memory formation in both sexes that could lead to the generation of novel therapies specifically tailored to reduce memory dysfunction in patients of each sex. Such therapeutic advances would greatly improve the quality of life for millions of patients and their families.
Memory impairments are characteristic of many neurodevelopmental and neuropsychiatric disorders, yet the development of effective treatments to reduce these impairments is hampered by our relatively rudimentary knowledge about the neural mechanisms through which memories are formed in males and females. The pro- posed research is relevant to public health because it will fundamentally advance our understanding of the neural mechanisms underlying memory formation in males and females, which will provide sorely needed in- sights that could lead to the generation of novel therapies specifically tailored to reduce memory dysfunction in patients of each sex. Thus, the proposed research is particularly relevant to the NIMH?s first Strategic Objective of promoting discovery in the brain and behavioral sciences to fuel research on the causes of, and treatments for, mental disorders, and specifically addresses strategy 1.1 which seeks to develop an integrative under- standing of basic brain-behavior processes that provide the foundation for understanding mental disorders.
| Frick, Karyn M; Kim, Jaekyoon; Koss, Wendy A (2018) Estradiol and hippocampal memory in female and male rodents. Curr Opin Behav Sci 23:65-74 |
| Frick, Karyn M; Tuscher, Jennifer J; Koss, Wendy A et al. (2018) Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females. Physiol Behav 187:57-66 |
| Frick, Karyn M; Kim, Jaekyoon (2018) Mechanisms underlying the rapid effects of estradiol and progesterone on hippocampal memory consolidation in female rodents. Horm Behav : |
| Choleris, Elena; Galea, Liisa A M; Sohrabji, Farida et al. (2018) Sex differences in the brain: Implications for behavioral and biomedical research. Neurosci Biobehav Rev 85:126-145 |
