Estradiol selectively regulates metabolic substrates across memory systems in models of menopause

Estrogen loss at menopause is thought to contribute to specific memory problems commonly encountered by women who are transitioning through or who have experienced menopause. Work in preclinical models suggests that estrogens bidirectionally regulate cognition through direct actions on different neural systems called memory systems, enhancing some types of learning and memory while impairing others. The energy load in the brain during cognitive activity is notoriously high, requiring sufficient provisions of metabolic substrates such as glucose, lactate, or ketones for optimal cognition. Thus, it is possible that estrogens bidirectionally regulate energy substrate availability within each system to produce the improvements and impairments in learning and memory. Indeed, estradiol increases extracellular levels of glucose in the hippocampus, a shift that corresponds to the hormone's beneficial effects on hippocampus-sensitive cognition. In contrast, estradiol decreases levels of lactate and ketones in the striatum, a shift that corresponds to the impairing effects of estradiol on striatum-sensitive cognition. Menopause may thus be associated with both cognitive improvements and impairments depending on estradiol status and on the problem to be solved. We propose that regulation of neural metabolism is one likely mechanism for these bidirectional effects of estradiol on cognition.