Date of Award
Master of Science
Karn M. Frick
Devin Mueller, Fred Helmstetter
Aromatase, Estradiol, Hippocampus, Letrozole
The potent estrogen 17beta-Estradiol (E2) plays a critical role in neuroprotection, serving as an important trophic factor for neurons in the hippocampus, basal forebrain, and prefrontal cortex (Brinton, 2001). In the hippocampus, E2 promotes neurogenesis (Tanapat et al., 1999, Prange-Kiel et al., 2006), protects against cell death after ischemic injury (Garcia-Segura et al., 2001, Zhao and Brinton, 2007), and helps maintain spine morphology crucial for synaptic connectivity and memory (Woolley et al., 1990; Gould et al., 1990, Woolley and McEwen, 1992, Li et al., 2004). However, the mechanisms through which E2 promotes synaptic plasticity and enhances memory function are largely unknown. It has been principally assumed that E2's effects on memory are due to E2 synthesized from the ovaries, which are the primary endogenous source of E2 in pre-menopausal females. However, E2 is also synthesized locally in the adult brain of a variety of species, where it regulates synaptic plasticity and can be synthesized in response to behavioral experiences (Prange-Kiel et al., 2003, Kretz et al., 2004, Remage-Healey et al., 2008, Azcoitia et al., 2011). Although de novo E2 may be a critical regulator of memory, very little is known about the functional role of local E2 synthesis in brain regions important for cognition, or the potential mental health implications of a reduction in local E2 synthesis (e.g., during menopause or in neurodegenerative disease). Therefore, the present study examined the role of locally synthesized estrogens in hippocampal memory consolidation. Three studies were used to determine if 1) hippocampal E2 synthesis is necessary for the consolidation of hippocampus-dependent object recognition and spatial memories, 2) experience-induced changes occur in hippocampal E2 levels after behavioral training, and 3) local E2 synthesis contributes to the memory-enhancing effects of exogenous E2. To block hippocampal E2 synthesis, we bilaterally infused into the DH an inhibitor of aromatase, the enzyme that synthesizes E2 from testosterone. We first found that blocking E2 synthesis in the DH during consolidation impaired both object recognition and spatial memory consolidation. We next found that local E2 levels are acutely increased in the DH after object training. This increase in E2 is blocked by DH infusion of an aromatase inhibitor at a dose that impairs memory consolidation in vivo. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory, suggesting that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory consolidation. Combined, these data demonstrate for the first time in mammals that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation.
Tuscher, Jennifer, "The Role of Brain-synthesized E2 in Hippocampal Learning and Memory Consolidation in Female Mice" (2014). Theses and Dissertations. 770.