The broad goal of our continued program of research is to decipher the cognitive and brain effects of transitional and surgical variants of menopause, including optimizing cognitive aging by discovering efficacious hormone therapy (HT) options in the context of menopause variations seen in women. This incorporates determining memory and brain changes as transitional menopause ensues when ovaries are undergoing follicular depletion, as well as the optimal parameters for interventions subsequent to transitional and surgical menopause variants. Menopause has been associated with cognitive decline and increased dementia risk. However, factors driving these outcomes, and which HT parameters alter effects, are undetermined. Importance is underscored given that most women are living at least one-third of their lives in a menopausal state encompassed by numerous variations (with or without a uterus, follicular deplete ovaries, or HT). In the current grant period, we had 23 publications; using the rat model, we showed that transitional menopause detrimentally impacted memory, that effects were most pronounced during perimenopause when follicles were undergoing early depletion, that higher androstenedione levels were associated with worse memory outcomes, and that short-term hysterectomy (uterus removal) alone impaired memory. We found that progesterone impaired memory, and that these effects were modulated by the GABAergic system. We also showed that several clinically-used synthetic progestins impaired memory, and identified one that enhanced memory: Levonorgestrel (Levo). When taking oral contraceptives or HT, a woman with a uterus must include a progestin along with estrogens to offset estrogen-induced hyperplasia. Thus, we performed an individual versus combination study, and showed that 17β-estradiol (E2) and Levo each enhanced memory when given alone, but impaired memory when given in combination. We also found that E2- induced cognitive benefits were associated with cholinergic integrity, building on literature showing estrogen- cholinergic interactions. This renewal addresses critical questions stemming from these collective findings. Aim 1 tests whether varied E2 regimens attenuate memory impairments associated with the perimenopausal transition, and assesses novel progestins that are anti-androgenic or have minimal androgenicity, with a goal to find options that do not reverse beneficial E2 effects on cognition and the brain. Aim 2 determines how variations in menopause type, including hysterectomy, impact cognition and the brain, testing effects of a temporal window, age, and follicular depletion state. Aim 3 defines how menopause variants and clinically-used HTs interact with candidate neurotransmitter systems in mechanistic detail, systematically examining GABAergic signaling and cholinergic circuitry. We combine behavioral, physiological, and neurobiological approaches in the framework of a blinded and randomized animal model research progra...