The Animal Core is essential for the extension of the concepts that have been developed during the previous funding periods. In this application the Animal Core continues to provide the unique nonhuman primate (NHP) animal model, a trained staff in NHP research as well as specific methodologies and services that are required to make appropriate and efficient use of this limited resource. Studies involving monkeys currently in protocol will be completed in early 2011 and additional aged female rhesus monkeys will enter protocols and be studied over the five-year funding period. Our current data demonstrate the importance of estrogen treatment (ET) for the maintenance of higher brain function and structure in the absence of normal ovarian function in aged female primates. However, these previous studies have not conclusively identified which modality of ET or combined hormone treatment (HT) regimens are most effective and specifically which effective modalities would be best for clinical applications. The monkeys currently in protocol are committed to these studies. The monkeys that will enter protocols over this funding period will be used to investigate the structural and functional repercussions of altering the time of onset and duration of treatment following ovariectomy (OVX). These studies will investigate two critically important clinical issues;1) Is there a """"""""window of opportunity"""""""" following cessation of ovarian function after which the brain is less responsive to ET/HT, and 2) Do the cognitive benefits of ET/HT started soon after the loss of circulating sex steroids persist after treatment is halted? Resources provided by the Animal Core include clinical care, trained animal care staff, therapeutic support, surgery/necropsy services and endocrine services. In addition, the California National Primate Center (CNPRC) behavior and endocrine staff scientists have participated in the design of the experiments and will be involved in the execution of the total research plan. Appropriately, the current application addresses specific questions that cannot be ethically approached in clinical studies but are effectively addressed in a NHP model. These studies will provide new and important information and insights for designing critical studies in the future. In addition, the results from all of the experiments will have direct and important implications for improved therapies to insure healthy aging in women. Both the use of the NHP model and a Primate Center setting and staff are required in order to effectively conduct such experiments and guarantee the delivery of interpretable data.
The use of the nonhuman primate animal model is considered essential for investigations relating to the role of ovarian hormones in human aging and only a primate center facility and staff can provide the necessary resources and skills to conduct such studies. One of the most pressing issues in women's health is the efficacy and safety of estrogen replacement therapy for menopausal symptoms and cognitive health. This proposal provides the plan, resources and the expertise to conduct studies that address this issue.
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|Garcia, Alexandra N; Depena, Christina K; Yin, Weiling et al. (2016) Testing the critical window of estradiol replacement on gene expression of vasopressin, oxytocin, and their receptors, in the hypothalamus of aging female rats. Mol Cell Endocrinol 419:102-12|
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|Mazid, Sanoara; Hall, Baila S; Odell, Shannon C et al. (2016) Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress. Neurobiol Stress 5:37-53|
|Marques-Lopes, Jose; Lynch, Mary-Katherine; Van Kempen, Tracey A et al. (2015) Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors. Synapse 69:148-65|
|Yin, Weiling; Sun, Zengrong; Mendenhall, John M et al. (2015) Expression of Vesicular Glutamate Transporter 2 (vGluT2) on Large Dense-Core Vesicles within GnRH Neuroterminals of Aging Female Rats. PLoS One 10:e0129633|
|Waters, Elizabeth M; Thompson, Louisa I; Patel, Parth et al. (2015) G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus. J Neurosci 35:2384-97|
|Yin, Weiling; Maguire, Sean M; Pham, Brian et al. (2015) Testing the Critical Window Hypothesis of Timing and Duration of Estradiol Treatment on Hypothalamic Gene Networks in Reproductively Mature and Aging Female Rats. Endocrinology 156:2918-33|
|Almey, Anne; Milner, Teresa A; Brake, Wayne G (2015) Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav 74:125-38|
|Hara, Yuko; Waters, Elizabeth M; McEwen, Bruce S et al. (2015) Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiol Rev 95:785-807|
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