Spatial navigation, sex hormones, and the aging brain - PROJECT SUMMARY The menopausal transition is marked by a rise in gonadotropin secretion and a decline in sex steroid hormones – up to 90% in the case of 17 -estradiol. For many women these pronounced endocrine changes are accompanied by changes in memory and attention (“menopause fog”), yet the influence of endocrine aging on the brain remains severely understudied. Further, navigation has emerged as a promising behavioral marker for detecting individuals at risk for dementia. Animal studies provide powerful evidence that sex hormones impact navigation ability and regulate the synaptic organization of the brain’s navigation circuitry, which overlaps significantly with brain regions impacted earliest in the progression to AD. However, corresponding studies interrogating sex hormones’ role in navigation circuitry have yet to be carried out in humans. This is surprising, given that sex differences in navigation are evident across mammalian species and women constitute two-thirds of the AD population. Few studies have established whether deficits in navigation emerge in midlife or whether age-related changes vary by sex or endocrine status. These represent critical gaps in our understanding of the aging brain and limit efforts to use navigation as a tool for determining AD risk. This Multi- PI proposal brings together an interdisciplinary team of experts in neuroscience, endocrinology, biostatistics, and spatial cognition with strong collaborative ties. Combining immersive, ambulatory virtual environments (VEs) and state-of-the-art brain imaging, we will elucidate the effects of endocrine aging on spatial navigation ability and its neuronal systems. To do so, we will enroll cognitively normal midlife men and women (N=240, ages 45-55), with a balanced distribution of pre-, peri-, and postmenopausal women per STRAW-10 guidelines; this also establishes an initial cohort for future longitudinal studies. Next, we will enroll older adults (N=160, ages 56-80) and younger adults (N=160, ages 18-44), balanced by sex, to assess navigation ability across the adult lifespan. In Aim 1, we will employ state-of-the-art walking VR methods to establish the impact of endocrine aging on navigation behavior during the critical midlife period. Immersive, ambulatory VR paradigms allow us to systematically probe diverse domains of navigation with greater ecological validity than data generated from stationary computers or handheld devices. In Aim 2, we will combine sub-millimeter resolution anatomical imaging of the hippocampus and surrounding tissue, diffusion MRI assessments of white matter microstructure, and innovative fMRI-based recordings of grid cell-like representations in entorhinal cortex to determine the impact of endocrine aging on navigation circuitry at mesoscopic and macroscopic scales. In Aim 3, we will situate navigation abilities in midlife within the context of aging across the adult lifespan. By testing our behavioral paradigms across adulthood (ages 18-80), we will chart sex-based trajectories of navigation behavior, pinpointing aspects of navigation that decline with age – and identifying those that are spared – as a benchmark for future AD studies.
