Medial prefrontal cortical estradiol rapidly alters memory system bias in female rats: ultrastructural analysis reveals membrane-associated estrogen receptors as potential mediators

Endocrinology. 2014 Nov;155(11):4422-32. doi: 10.1210/en.2014-1463. Epub 2014 Sep 11.


High plasma levels of estradiol (E2) are associated with use of a place memory system over a response memory system. We examined whether infusing estradiol into the medial prefrontal cortex (mPFC) or anterior cingulate cortex (AC) could affect memory system bias in female rats. We also examined the ultrastructural distribution of estrogen receptor (ER)-α, ERβ, and G protein-coupled estrogen receptor 1 (GPER1) in the mPFC of female rats as a mechanism for the behavioral effects of E2 in the mPFC. Each rat was infused bilaterally with either E2 (0.13 μg) or vehicle into the mPFC or AC. The majority of E2 mPFC rats used place memory. In contrast, the majority of mPFC vehicle rats and AC E2 or vehicle rats used response memory. These data show that mPFC E2 rapidly biases females to use place memory. Electron microscopic analysis demonstrated that ERα, ERβ, and GPER1 are localized in the mPFC, almost exclusively at extranuclear sites. This is the first time that GPER1 has been localized to the mPFC of rats and the first time that ERα and ERβ have been described at extranuclear sites in the rat mPFC. The majority of receptors were observed on axons and axon terminals, suggesting that estrogens alter presynaptic transmission in the mPFC. This provides a mechanism via which ERs could rapidly alter transmission in the mPFC to alter PFC-dependent behaviors, such as memory system bias. The discrete nature of immunolabeling for these membrane-associated ERs may explain the discrepancy in previous light microscopy studies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Cell Membrane / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / physiology*
  • Estrogen Receptor beta / physiology*
  • Female
  • Maze Learning / drug effects
  • Membrane Proteins / physiology*
  • Memory / drug effects*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / ultrastructure
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / physiology*
  • Time Factors


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Gper1 protein, rat
  • Membrane Proteins
  • Receptors, G-Protein-Coupled
  • Estradiol