No abstract

1The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone 2 production that occurs in most mammalian species. In rodents and nonhuman primates, 3 estrogen and progesterone's impact on the brain is evident across a range of 4 spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of 5 the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we 6 examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain 7 networks at rest in a woman who underwent brain imaging and venipuncture for 30 8 consecutive days. Standardized regression analyses illustrate estrogen and progesterone's 9 widespread influence on cortical dynamics. Time-lagged analyses examined the 10 directionality of these relationships and reveal estrogen's ability to drive connectivity 11 across major functional brain networks, including the Default Mode and Dorsal Attention 12 Networks, whose hubs are densely populated with estrogen receptors. These results 13 reveal the rhythmic nature in which brain networks reorganize across the human 14 menstrual cycle. Neuroimaging studies that densely sample the individual connectome 15 have begun to transform our understanding of the brain's functional organization. As 16 these results indicate, taking endocrine factors into account is critical for fully 17 understanding the intrinsic dynamics of the human brain. The brain is an endocrine organ whose day-to-day function is intimately tied to the action 20 of neuromodulatory hormones [1][2][3][4] . Yet, the study of brain-hormone interactions in human 21 neuroscience has often been woefully myopic in scope: the classical approach of 22 interrogating the brain involves collecting data at a single time point from multiple 23 subjects and averaging across individuals to provide evidence for a 24 hormone-brain-behavior relationship. This cross-sectional approach obscures the rich, 25 rhythmic nature of endogenous hormone production. A promising trend in network 26 neuroscience is to flip the cross-sectional model by tracking small samples of individuals 27 over timescales of weeks, months, or years to provide insight into how biological, 28 behavioral, and state-dependent factors influence intra-and inter-individual variability in 29 the brain's intrinsic network organization [5][6][7] . Neuroimaging studies that densely sample 30 the individual connectome are beginning to transform our understanding of the dynamics 31 of human brain organization. However, these studies commonly overlook sex steroid 32 hormones as a source of variability-a surprising omission given that sex hormones are 33 powerful neuromodulators that display stable circadian, infradian, and circannual 34 rhythms in nearly all mammalian species. In the present study, we illustrate robust, 35 time-dependent interactions between the sex steroid hormones 17β-estradiol and 36 progesterone and the functional network organization of the brain over a complete 37 menstrual cycle, offering compell...

A major challenge in neuroscience is to understand what happens to a brain as it ages. Such insights could make it possible to distinguish between individuals who will undergo typical aging and those at risk for neurodegenerative disease. Over the last quarter century, thousands of human brain imaging studies have probed the neural basis of age-related cognitive decline. “Aging” studies generally enroll adults over the age of 65, a historical precedent rooted in the average age of retirement. A consequence of this research tradition is that it overlooks one of the most significant neuroendocrine changes in a woman’s life: the transition to menopause. The menopausal transition is marked by an overall decline in ovarian sex steroid production—up to 90% in the case of estradiol—a dramatic endocrine change that impacts multiple biological systems, including the brain. Despite sex differences in the risk for dementia, the influence that biological sex and sex hormones have on the aging brain is historically understudied, leaving a critical gap in our understanding of the aging process. In this Perspective article, we highlight the influence that endocrine factors have on the aging brain. We devote particular attention to the neural and cognitive changes that unfold in the middle decade of life, as a function of reproductive aging. We then consider emerging evidence from animal and human studies that other endocrine factors occurring earlier in life (e.g., pregnancy, hormonal birth control use) also shape the aging process. Applying a women’s health lens to the study of the aging brain will advance knowledge of the neuroendocrine basis of cognitive aging and ensure that men and women get the full benefit of our research efforts.

Accumulating evidence suggests that distinct aspects of successful navigation—path integration, spatial-knowledge acquisition, and navigation strategies—change with advanced age. Yet few studies have established whether navigation deficits emerge early in the aging process (prior to age 65) or whether early age-related deficits vary by sex. Here, we probed healthy young adults (ages 18–28) and midlife adults (ages 43–61) on three essential aspects of navigation. We found, first, that path-integration ability shows negligible effects of sex or age. Second, robust sex differences in spatial-knowledge acquisition are observed not only in young adulthood but also, although with diminished effect, at midlife. Third, by midlife, men and women show decreased ability to acquire spatial knowledge and increased reliance on taking habitual paths. Together, our findings indicate that age-related changes in navigation ability and strategy are evident as early as midlife and that path-integration ability is spared, to some extent, in the transition from youth to middle age.

Navigating to goal locations in a known environment (wayfinding) can be accomplished by different strategies, notably by taking habitual, well-learned routes (response strategy) or by inferring novel paths, such as shortcuts, from spatial knowledge of the environment's layout (place strategy). Human and animal neuroscience studies reveal that these strategies reflect different brain systems, with response strategies relying more on activation of the striatum and place strategies associated with activation of the hippocampus. In addition to individual differences in strategy, recent behavioral studies show sex differences such that men use place strategies more than women, and age differences such that older adults use more response strategies than younger adults. This paper takes a comprehensive multilevel approach to understanding these differences, characterizing wayfinding as a complex information processing task. This analysis reveals factors that affect navigation strategy, including availability of the relevant type of environmental knowledge, momentary access to this knowledge, trade-offs between physical and mental effort in different navigation contexts, and risk taking. We consider how strategies are influenced by the computational demands of a navigation task and by factors that affect the neural circuits underlying navigation. We also discuss limitations of laboratory studies to date and outline priorities for future research, including relating wayfinding strategies to independent measures of spatial knowledge, and studying wayfinding strategies in naturalistic environments.