Lifestyle factors including nutrition, may play a role in the development of cognitive impairment. Previous studies based in the United States have shown that nutrient deficiencies in vitamin B-12 and folate can increase the risk of developing mild cognitive impairment in adults, while high levels of potassium increase the risk of cognitive impairment. Among the Tsimane and Moseten subsistence communities in Bolivia, there is a low prevalence of Alzheimer’s dementia and related diseases, but any impacts of micronutrients on cognitive impairment have not been assessed. Using a mixed longitudinal design to estimate nutrient intake via 855 dietary recall questionnaires (24-hour) from 370 Tsimane and Moseten aged 43-85 years (mean age 62 years, 47% male), a culturally specific dementia assessment (3MSE, KIKA, neurological exam) was conducted, and individuals were diagnosed as having normal cognition, mild cognitive impairment, or dementia. Logistic regressions with clustered standard errors (to account for multiple dietary questionnaires per individual) examined the association between dietary intake and cognitive impairment. Controlling for age, sex, body mass index, and education, those with higher daily caloric intake had a lower odds ratio of cognitive impairment, with every 100 additional calories associated with decreased risk (OR = 0.95, p=0.032). Higher B-12 intake was associated with lower cognitive impairment, while higher potassium intake was associated with greater cognitive impairment. The presented data indicate a correlation between diet and nutrition and cognitive impairment within a subsistence population. This observation underscores the potential tradeoffs individuals face in allocating resources towards survival versus the upkeep of cognitive faculties, reflecting broader considerations in life history strategies.

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.

Hysterectomy is the second most common gynecological surgery performed in women. Half of these surgeries involve removal of the uterus alone, and half involve concomitant removal of the ovaries. While the field has retained the notion that the nonpregnant uterus is dormant, more recent findings suggest that hysterectomy is associated with cognitive detriment. Of note, the clinical literature suggests that an earlier age at hysterectomy, with or without concomitant ovarian removal, increases dementia risk, implicating age at surgery as a variable of interest. While preclinical work in a rodent model of hysterectomy has demonstrated spatial working memory impairments, the role of age at surgery has yet to be addressed. The current experiment utilized a rodent model of hysterectomy to investigate the importance of age at surgery in post- surgical cognitive outcomes and to evaluate relative protein expression related to brain activity, FosB and ∆FosB, in regions critical to spatial learning processes. Young adult and middle-aged female rats underwent sham surgery, hysterectomy, or hysterectomy with ovariectomy, and were tested on a behavioral battery that evaluated spatial working and reference memory. Following the behavioral battery, animals were sacrificed and brain tissues from the Dorsal Hippocampus and Entorhinal Cortex were processed via Western Blot for relative FosB and ∆FosB expression. Behavioral analyses demonstrated that animals receiving hysterectomy, regardless of age or ovarian status, were generally impaired in learning a complex spatial working memory task. However, rats that received hysterectomy in middle-age uniquely demonstrated persistent working memory impairment, particularly with a high working memory demand. Subsequent neurobiological analyses revealed young rats that underwent hysterectomy had reduced relative FosB expression in the Entorhinal Cortex compared to sham controls, where no significant effects were observed for rats that received surgery in middle-age. Finally, unique relationships between neurobiological and behavioral outcomes were observed largely for sham rats, suggesting that such surgical manipulations might modulate these relationships. Taken together, these findings suggest that age at surgery plays an important role in learning and memory outcomes following hysterectomy, and demonstrate the need for further research into the role of the uterus in communications between the reproductive tract and brain.