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

Abstract

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.

BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function

“…The significant increase in PSD-95, and nonsignificant increase in pAkt-ir in Val mice during proestrus, is consistent with our previous demonstration that PSD-95-ir and pAkt-ir increase during proestrus in wild-type mice and rats (13,28). Furthermore, the increase in BDNF mRNA during proestrus is consistent with previous studies in female rats, which showed that BDNF mRNA and protein expression increase during proestrus (7,10,11).…”

“…Increases in circulating estradiol induce hippocampal BDNF mRNA and protein, and increase activation of the BDNF receptor TrkB, in female mice and rats (7)(8)(9)(10)(11)(12)(13). BDNF signaling is important for estradiol to enhance hippocampal synaptic plasticity, because TrkB inhibitors block the estradiol-mediated increase in hippocampal excitability, synaptic protein expression, and dendritic spine formation in rat hippocampal slice cultures (7,14).…”

Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: Evidence that the duration of hormone deprivation after ovariectomy compromises 17β-estradiol effectiveness in altering CA1 spines

“…Increases in CA1 apical spine density are seen after two injections given at this temporal regimen, which corresponded to when our designated behavioral test was given. It should be noted that 10µg injections of 17β-estradiol likely yield greater serum estradiol levels than observed in a cycling female rat (Scharfman et al, 2007;Sims et al, 1996;Woolley and McEwen, 1993), although these levels dramatically decrease within 24 hours of injection (Sims et al, 1996;Woolley and McEwen, 1993). The 5µg dose most likely yields serum estradiol levels within/slightly above the range of that found in a cycling, proestrous rat (Scharfman et al, 2007).…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…Thus, it is not entirely clear what is the actual concentration of estradiol acting at receptors in the brain. In addition, although a range of 17b-estradiol doses has been used in different studies, the majority are reported to fall within physiologic levels of plasma estradiol levels; however, higher doses of 17b-estradiol are thought to produce supraphysiological levels of plasma estradiol (MacLusky et al, 2005;Scharfman et al, 2007;Phan et al, 2012;). On the other hand, it has been argued that such concentrations are representative of local estradiol levels within the brain and that such concentrations are required to initiate rapid molecular and cellular responses (see section IV; Cornil et al, 2006;Hojo et al, 2009 for greater discussion).…”