Chemogenetic Suppression of Medial Prefrontal-Dorsal Hippocampal Interactions Prevents Estrogenic Enhancement of Memory Consolidation in Female Mice

The importance of the dorsal hippocampus (DH) in mediating the memory-enhancing effects of the sex-steroid hormone 17β-estradiol (E(2)) is well established. However, estrogen receptors (ERs) are highly expressed in other brain regions that support memory formation, including the medial prefrontal cortex (mPFC). The mPFC and DH interact to mediate the formation of several types of memory, and behavioral tasks that recruit the mPFC are enhanced by systemic E(2) administration, making this region a prime candidate for investigating circuit-level questions regarding the estrogenic regulation of memory. Further, infusion of E(2) directly into the DH increases dendritic spine density in both the DH and mPFC, and this effect depends upon rapid activation of cell-signaling pathways in the DH, demonstrating a previously unexplored interaction between the DH and mPFC that led us to question the role of the mPFC in object memory consolidation and the necessity of DH-mPFC interactions in the memory-enhancing effects of E(2). Here, we found that infusion of E(2) directly into the mPFC of ovariectomized mice increased mPFC apical spine density and facilitated object recognition and spatial memory consolidation, demonstrating that E(2) in the mPFC increases spinogenesis and enhances on memory consolidation. Next, chemogenetic suppression of the mPFC blocked the beneficial effects of DH-infused E(2) on memory consolidation, indicating that systems-level DH-mPFC interactions are necessary for the memory-enhancing effects of E(2). Together, these studies provide evidence that E(2) in the mPFC mediates memory formation, and reveal that the DH and mPFC act in concert to support the memory-enhancing effects of E(2) in female mice.