In this renewal, we hypothesize that type of menopause and associated hormone changes relate to cognitive responsiveness to hormone therapy (HT). The initial grant used rats to assess variations in HTs with surgical menopause (Ovx), and transitional menopause using 4-vinylcyclohexene diepoxide (VCD). VCD-treated rats undergo ovarian failure; follicles and estrogens deplete, androgens become unopposed, and gonadotropins increase, a profile resembling transitionally menopausal women. Data from the initial grant lay the foundation for testing new hypotheses regarding transitional versus surgical menopause. In women, both transitional and surgical menopause have been related to memory changes. However, most rodent studies have tested cognitive effects after Ovx. Despite insight rat models yield regarding surgical hormone loss, surgical menopause models <13% of women. Here, we examine how different menopause types impact cognitive and brain aging, and aim to determine optimal parameters for the menopause transition and HT.
Four aims are proposed, using rats:
Aim 1) We found that androstenedione (Andro) relates to impaired memory. Since Andro is directly converted to estrone, and we have shown estrone-induced memory impairments, we hypothesize that Andro's conversion to estrone impairs memory.
Aim 1 tests whether Andro's conversion to estrogens, or androgen receptor stimulation, underlies its cognitive detriments.
Aim 2) Clinical studies support a critical window during which HT benefits cognition. Rat studies support this; however, these studies used Ovx rats, and gave only 17?-estradiol (E2). E2 is naturally-occurring in women and rats, but is present only in trace amounts in conjugated equine estrogens (CEE) HT. In rats, we found that CEE enhanced memory after surgical menopause, but impaired memory after transitional menopause when given after follicle depletion.
Aim 2 tests cognitive change during and after different types of menopause, and whether giving CEE before or during follicular depletion impairs memory, as compared to E2.
Aim 3) We found that the HT progestin medroxyprogesterone acetate (MPA) impaired cognition in Ovx rats, and decreased hippocampal glutamic acid decarboxylase (GAD) protein, possibly compensating for GABAA receptor (GABAAR) stimulation. Another progestin, norethindrone acetate (NETA), enhanced memory in Ovx rats. We hypothesize that NETA antagonizes the GABAAR, reducing GABAAR-mediated inhibition, enhancing memory.
Aim 3 will determine whether the GABAergic system underlies MPA- and NETA-induced memory changes.
Aim 4). This aim tests whether MPA or NETA impacts the effects of CEE or E2. MPA was chosen for this aim to test the HT Prempro (CEE+MPA); NETA was chosen due to its potential to be part of a novel combination HT, as it is used in contraceptives and it enhanced rat cognition. In each study, we will quantify GAD and cholinergic markers, each previously shown to relate to cognition, in brains of cognitively characterized rats. Multiple regression and growth modeling will test relations between the GABAergic system, cholinergic system, hormone levels, and cognition in both menopause models. This work will yield insight into cognitive effects of the menopause transition, variations in menopause type and HTs, and related mechanisms.

Public Health Relevance

The overarching goal of our continued program of research is to use the rat model to understand how menopause and related ovarian hormone changes impact cognitive and brain aging, and to use this information to determine optimal parameters of the menopause transition and hormone therapies. In this renewal, we systematically assess the trajectory of hormonal and cognitive change with transitional versus surgical menopause, and test whether hormone therapy effects are altered by background hormone milieu, menopause type, type of estrogen and progestin, and temporal period since menopause initiation. A key goal is to determine an optimal window of sensitivity for hormone therapy, for both transitional and surgical menopause, as well as gain understanding of underlying mechanisms of the cognitive effects.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Roberts, Luci
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Arizona State University-Tempe Campus
Schools of Arts and Sciences
United States
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Tyor, William R; Bimonte-Nelson, Heather (2018) A mouse model of HIV-associated neurocognitive disorders: a brain-behavior approach to discover disease mechanisms and novel treatments. J Neurovirol 24:180-184
Prakapenka, Alesia V; Hiroi, Ryoko; Quihuis, Alicia M et al. (2018) Contrasting effects of individual versus combined estrogen and progestogen regimens as working memory load increases in middle-aged ovariectomized rats: one plus one does not equal two. Neurobiol Aging 64:1-14
Koebele, Stephanie V; Bimonte-Nelson, Heather A (2017) The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory. Exp Gerontol 94:14-23
Koebele, Stephanie V; Mennenga, Sarah E; Hiroi, Ryoko et al. (2017) Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory. Horm Behav 87:96-114
Prakapenka, Alesia V; Bimonte-Nelson, Heather A; Sirianni, Rachael W (2017) Engineering poly(lactic-co-glycolic acid) (PLGA) micro- and nano-carriers for Controlled Delivery of 17?-Estradiol. Ann Biomed Eng 45:1697-1709
Braden, B Blair; Andrews, Madeline G; Acosta, Jazmin I et al. (2017) A comparison of progestins within three classes: Differential effects on learning and memory in the aging surgically menopausal rat. Behav Brain Res 322:258-268
Hiroi, R; Carbone, D L; Zuloaga, D G et al. (2016) Sex-dependent programming effects of prenatal glucocorticoid treatment on the developing serotonin system and stress-related behaviors in adulthood. Neuroscience 320:43-56
Hiroi, Ryoko; Weyrich, Giulia; Koebele, Stephanie V et al. (2016) Benefits of Hormone Therapy Estrogens Depend on Estrogen Type: 17?-Estradiol and Conjugated Equine Estrogens Have Differential Effects on Cognitive, Anxiety-Like, and Depressive-Like Behaviors and Increase Tryptophan Hydroxylase-2 mRNA Levels in Dorsal Ra Front Neurosci 10:517
Koebele, Stephanie V; Bimonte-Nelson, Heather A (2016) Modeling menopause: The utility of rodents in translational behavioral endocrinology research. Maturitas 87:5-17
Braden, B Blair; Kingston, Melissa L; Koenig, Elizabeth N et al. (2015) The GABAA antagonist bicuculline attenuates progesterone-induced memory impairments in middle-aged ovariectomized rats. Front Aging Neurosci 7:149

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