INVESTIGATING DE NOVO ESTRADIOL SYNTHESIS IN THE PREFRONTAL CORTEX AS A MODULATOR OF EPISODIC MEMORY IN MICE

Abstract

Age-related memory decline is an increasingly significant public health issue, and the loss of circulating estrogens during menopause is a potential therapeutic target for delaying or preventing this decline. The most potent estrogen, 17β-estradiol (E2) regulates hippocampal synaptic plasticity and enhances the consolidation of memories dependent on the dorsal hippocampus (DH). De novo E2 synthesis via the enzyme aromatase in DH is essential for object recognition (OR) and object placement (OP) memory consolidation in ovariectomized (OVX) female mice (Tuscher et al., 2016). Other regions, such as medial prefrontal cortex (mPFC), play critical roles in these types of memory, but less is known about the involvement of mPFC E2 synthesis in mPFC function and memory. The overall aim of this dissertation was to investigate the extent to which de novo E2 synthesis in the mPFC is necessary for episodic-like memory in female mice, particularly the learning and early consolidation phases. We tested mice on object recognition and object placement and found that a direct infusion of the aromatase inhibitor letrozole impaired memory for both of these tasks. Second, we identified a training-induced increase for the aromatase-encoded gene cyp19a1. Finally, we found that letrozole increased mPFC calcium activity associated with novel object detection, and interestingly this effect was only found in gonadally-intact, but not ovariectomized, females. Together, these data suggest that mPFC locally-synthesized E2 is important for memory and can influence neuronal activity associated with learning. These data add to a growing literature suggesting that locally-synthesized E2 plays an important neuromodulatory function and could be leveraged to develop more effective treatments for age- and menopause- related cognitive decline.