Fig. 1: Female mice show abrupt brain substructure volume loss after midlife compared to males, and ovariectomized females have smaller dorsal hippocampal volumes than sham treated females at midlife.

a Schematic showing timing of gonadectomy (GDX) or sham surgery, cognitive assessment by Morris Water Maze (MWM), in vivo MRI, and pathology (PATH) at young, midlife, and old ages. b In vivo MRI was collected from young, midlife, and old female and male mice. Substructure volumes visualized on the mean template (dorsal hippocampus = red, ventral hippocampus = green, cortex = blue, striatum = purple). Sham-treated female (red) and male (blue) volumes are expressed as a percentage of intercranial volume (ICV) for (c) frontal cortex, (d) striatum, and (e) dorsal hippocampus over the lifespan. Males showed gradual atrophy in frontal cortex and striatum from young to midlife to old age. In contrast, females maintained volumes through midlife, followed by atrophy from midlife to old age. Dorsal hippocampus showed atrophy in females from midlife to old age, while males did not have atrophy. Two-way ANOVA indicated a significant interaction between sex and age in dorsal hippocampus (p = 0.0059). n = 12 for all groups (c–e). p values were calculated by two-sided Welch’s t-test. Female sham-treated (solid) and GDX (diagonal lines) substructure volumes, assessed by MRI, expressed as a percentage of intercranial volume (ICV) are shown for (f) whole hippocampus, (g) dorsal hippocampus, and (h) ventral hippocampus. GDX females showed smaller dorsal hippocampus than sham females at midlife (p = 0.014). Female midlife sham n = 6 and midlife GDX n = 8, old sham n = 5 and old GDX n = 8. p values were calculated by two-sided Welch’s t-test. All box plots with center lines showing the medians, boxes indicating the interquartile range, and whiskers indicating a maximum of 1.5 times the interquartile range beyond the box.