Title

ESTRADIOL MODULATION OF METABOLIC SUBSTRATES IN TWO MEMORY SYSTEMS.

Date of Award

August 2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Advisor(s)

Donna L. Korol

Second Advisor

Paul E. Gold

Keywords

Estrogens, Glucose, Glycogen, Hippocampus, Lactate, Multiple memory systems

Subject Categories

Life Sciences

Abstract

Women experience transitional menopause resulting from age-related depletion of ovarian follicles and a dramatic decline in the ovarian hormones estradiol and progesterone. However, at any age, women may undergo surgical or chemical menopause via oophorectomy or from cancer treatments, such as tamoxifen. A host of menopausal symptoms, e.g., hot flashes, mood changes, increased anxiety, and memory changes, over multiple systems such as reproduction, physiology, metabolism, and cognition, relate to hormone loss during the menopausal period. Although hormone replacement therapy has been commonly used for relieving these symptoms, its efficacy for improving cognition remains debatable. Previous results for estrogenic regulation of cognition were confounded by factors such as age, timing and regimen of treatment, and which neural system is engaged. One consistent finding is that estradiol, the predominant estrogen in reproductively cycling females, enhances learning and memory that relies on the hippocampus-based memory system, but impairs cognition engaging other neural systems, such as the striatum-based system. Precisely how estradiol exerts its bidirectional cognitive effects remains unknown despite multiple hypotheses that have been suggested, such as the timing of treatment, estrogen receptor systems, and downstream cellular pathways.

In our current work, we examined the possibility that estradiol promotes astrocyte-neuron coupled energy metabolism in the hippocampus through which it improves hippocampus-sensitive memory given that 1) energy substrates such as glucose and lactate both facilitate learning and memory, 2) glucose in the brain can be stored in glycogen in astrocytes which can be converted into lactate to support neuronal functions; and 3) estradiol regulates metabolism in the brain and periphery. We found that estradiol treatment in ovariectomized rats enhanced glucose levels in the extracellular fluid (ECF) and astrocytic glycogen content in the hippocampus but decreased ECF lactate and beta-hydroxybutyrate (3BHB) tissue levels in the striatum. In addition, estradiol augmented working memory in the delayed spontaneous alternation (dSA) task but not in alternation testing without delay. During dSA, glycogen depletion and extracellular levels of lactate were both amplified by estradiol, while extracellular glucose was unchanged. Moreover, glucose infused into the hippocampus prior to testing improved spatial working memory in oil vehicle-treated rats but not estradiol-treated rats compared to saline-infused control rats. Together, the findings suggest that estradiol facilitates hippocampus-sensitive spatial working memory through promoting glucose-derived astrocytic glycogen storage prior to testing and glycogen depletion leading to lactate release during testing. Overall, our findings unveiled estradiol modulation of astrocyte-neuron coupled energy metabolism in learning and memory and may have implications to the maintenance of brain health and improvement of cognition in menopausal women.

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