All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Candace Floyd

David Sweatt

Linda Wadiche

Michael Wyss

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In rodents, the ovarian estrogen 17b-estradiol (E2) is a potent modulator of hippocampal function and the hippocampus is critical for many types of learning and memory. Specifically, E2 increase the magnitude of long-term potentiation (LTP) at CA3-CA1 synapses, the density of dendritic spines in CA1 pyramidal cells and current mediated by NR2B-containing NMDA receptors. The E2-induced increase in LTP further requires NR2B-containing NMDARs. While considered a cellular correlate of learning and memory, enhanced LTP does not always predict enhanced learning. The first goal of this dissertation was to investigate the relationship between E2-enhanced LTP and learning and memory in young adult female rats and to determine whether E2-enhanced learning and memory requires NR2B-containing NMDARs. The results in the first part of this dissertation mechanistically link E2-enhanced learning and memory with E2-enhanced magnitude of LTP. The Women's Health Initiative Memory Study reported that estrogen replacement therapy does not protect against dementia and cognitive decline in post-menopausal women. The critical period hypothesis could explain this lack of benefit, stating that a window of time post-menopause may exist during which E2 must be replaced to remain beneficial to cognition. The second goal of this dissertation was to directly test whether such a critical period exists during which time E2 is able to enhance hippocampal physiology, morphology and learning and memory in female rats. It was also determined whether chronic replacement with E2 at physiological levels is sufficient to protect against the loss of E2-enhanced hippocampal function directly caused by long-term ovarian hormone loss. Results from this work are in strong support of the critical period hypothesis as E2 enhances hippocampal function using precisely the same mechanisms in young and aged female rats until 15 months of ovarian hormones loss, being absent after 19 months of ovarian hormone loss. Chronic E2 replacement is not sufficient to completely protect against the loss of E2-effectiveness and thus a more cycling replacement schedule of E2, or E2 along with progesterone to mimic ovarian hormones in ovary intact female rats may be required for maximal protection of hippocampal function.

Share

COinS