Learning and Memory Outcomes with Variations in Rodent Models of Menopause: Interactions Between Age, Gynecological Surgery, and Ovarian Hormone Shifts Alter the Course of Healthy Female Aging

The experience of menopause, typically occurring in midlife, can be markedly diverse, with surgical or transitional onset that results in alterations in circulating ovarian hormones and reproductive cyclicity. Such diverse experiences can coincide with the onset of symptoms and indications that impact long-term health outcomes. Indeed, prior work has shown that various facets of the menopausal experience can modulate later cardiovascular, immune, cognitive, and affective risks, making menopause a critical timepoint during aging. While clinical research provides great insight into numerous variables of interest, preclinical research can extend insights into these areas more directly by probing putative mechanisms driving long-term health risks as well as systematic assessment of therapeutic interventions. Reproductive senescence in the female rat differs from that of humans, as ovarian hormone decline and follicular depletion are less pronounced at midlife in the rodent. With advances in rodent modeling, preclinical researchers can probe questions pertaining to age and menopause independently, facilitating systematic exploration of factors affecting aging. This dissertation explores the impact of chronological aging, menopause etiology, and reproductive hormone alterations using a multidisciplinary approach, evaluating numerous dimensions of behavioral and physiological changes including immunology, endocrinology, and behavioral neuroscience. Assessments of chronological aging, both in normal aging and neurodegenerative rodent models, showed that patterns of memory decline differ by memory type, with midlife highlighted as a unique timepoint for learning and memory changes. Using several distinct rodent models of menopause in conjunction with a novel preclinical hysterectomy model, differences in cognitive and physiological profiles were observed. Notably, these effects depended upon age at surgery and ovarian status. Finally, evaluations of hormone therapy which were mapped on to variants of clinically-relevant menopause models provided further context into the patterns of nuanced cognitive effects revealed within the clinical literature. Collectively, these dissertation chapters delineate a myriad of factors to consider when evaluating cognitive and physiological outcomes associated with menopause. Maximizing communication and collaboration across preclinical and clinical realms of menopause research will best leverage and facilitate translational outcomes. Such exchanges will ultimately create a framework to propel the understanding of hormone-brain-cognition relationships, optimizing care for women at midlife and beyond.