Spatial learning and memory impairment at the post-follicular depletion state is associated with reduced hippocampal glucose uptake

The menopausal transition is a complex neuroendocrine aging process affecting brain structure and metabolic function. Such changes are consistent with neurological sequelae noted following the menopausal transition, including cognitive deficits. Although studies in rodent models of the menopause revealed changes in learning and memory, little is known about the structural and metabolic changes in the brain regions serving the cognitive function in these models. The administration 4-vinylcyclohexene diepoxide (VCD) in laboratory animals results in follicular depletion, and thus, is a powerful translational tool that models the human menopause. In the studies presented here, we evaluated behavior, brain structure, and metabolism in young female rats administered with either VCD or vehicle for 15 days across the early, mid, and post-follicular depletion states at 1-, 2-, and 3-months post-final injection, respectively. Additionally, we evaluated the serum hormonal profile and ovarian follicles based on the estrous cycle pattern. Positron emission tomography (PET) was utilized to determine regional brain glucose metabolism in the hippocampus, medial prefrontal cortex, and striatum. Subsequently, the rats were euthanized for ex-vivo magnetic resonance imaging (MRI) to assess regional brain volumes. VCD-induced rats at the post-follicular depleted time points had diminished spatial learning and memory as well as reduced hippocampal glucose uptake. Additionally, VCD-induced rats at post-follicular depletion time points had marked reductions in estradiol, progesterone, and anti-mullerian hormone with an increase in follicle-stimulating hormone. These rats also exhibited fewer ovarian follicles, indicating that substantial ovarian function loss during post-follicular time points impairs the female rats' spatial learning/memory abilities and triggers the metabolic changes in the hippocampus.