Changes in hippocampal function of ovariectomized rats after sequential low doses of estradiol to simulate the preovulatory estrogen surge

Eur J Neurosci. 2007 Nov;26(9):2595-612. doi: 10.1111/j.1460-9568.2007.05848.x. Epub 2007 Oct 26.


In adult female rats, robust hippocampal changes occur when estradiol rises on the morning of proestrus. Whether estradiol mediates these changes, however, remains unknown. To address this issue, we used sequential injections of estradiol to simulate two key components of the preovulatory surge: the rapid rise in estradiol on proestrous morning, and the slower rise during the preceding day, diestrus 2. Animals were examined mid-morning of simulated proestrus, and compared to vehicle-treated or intact rats. In both simulated and intact rats, CA1-evoked responses were potentiated in hippocampal slices, and presynaptic mechanisms appeared to contribute. In CA3, multiple population spikes were evoked in response to mossy fiber stimuli, and expression of brain-derived neurotrophic factor was increased. Simulation of proestrous morning also improved performance on object and place recognition tests, in comparison to vehicle treatment. Surprisingly, effects on CA1-evoked responses showed a dependence on estradiol during simulated diestrus 2, as well as a dependence on proestrous morning. Increasing estradiol above the physiological range on proestrous morning paradoxically decreased evoked responses in CA1. However, CA3 pyramidal cell activity increased further, and became synchronized. Together, the results confirm that physiological estradiol levels are sufficient to profoundly affect hippocampal function. In addition: (i) changes on proestrous morning appear to depend on slow increases in estradiol during the preceding day; (ii) effects are extremely sensitive to the peak serum level on proestrous morning; and (iii) there are striking subfield differences within the hippocampus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Animals
  • Brain-Derived Neurotrophic Factor / drug effects
  • Brain-Derived Neurotrophic Factor / metabolism
  • Diestrus / drug effects
  • Diestrus / metabolism
  • Dose-Response Relationship, Drug
  • Estradiol / pharmacology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Learning / drug effects
  • Learning / physiology
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / metabolism
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Organ Culture Techniques
  • Ovariectomy
  • Ovulation / drug effects
  • Ovulation / physiology*
  • Proestrus / drug effects
  • Proestrus / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Time


  • Brain-Derived Neurotrophic Factor
  • Estradiol