Estradiol replacement extends the window of opportunity for hippocampal function

Abstract

We previously reported that treating aged female rats, ovariectomized (OVX) as young adults, with acute proestrous levels of 17β estradiol (E2) increases CA1 spine density, NMDAR/AMPAR ratio, GluN2B-mediated NMDAR current, and LTP at CA3-CA1 synapses if administered by 15, but not at 19, months post-OVX, defining the critical window of opportunity. Importantly, when rats are aged with ovaries intact until OVX at 20 months, hippocampal E2 responsiveness is maintained, indicating the deficit at 19 months post-OVX is a consequence of the duration of hormone deprivation and not chronological age. Here, we find the beneficial effect of E2 on novel object recognition in OVX rats was constrained by the same critical window. Furthermore, chronic low level E2 replacement, commenced by 11 months post-OVX using subcutaneous capsules removed 2 weeks prior to acute proestrous E2 treatment, prevents the loss of hippocampal responsiveness at 19 months post-OVX. These data define the dynamic nature of the critical window showing that chronic replacement with physiological E2 levels within a certain period post-OVX can lengthen the window.

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…As such, fundamental changes may occur in the brain during chronic treatment (e.g., downregulation of ERs) that do not occur after acute treatment. On the other end of the hormonal spectrum, long-term ovariectomy decreased hippocampal neurogenesis and prevented acute E 2 from increasing cell proliferation (Tanapat et al 2005), which is consistent with the detrimental effects of long-term ovariectomy on LTP and memory discussed above Smith et al 2010;Vedder et al 2014). Collectively, these data suggest that either chronically elevated E 2 levels or long-term hormone deprivation may permanently alter the hippocampus to reduce its responsiveness to E 2 .…”

“…Importantly, this loss was not due to aging, as rats of the same age ovariectomized just 1 mo prior to E 2 treatment exhibited increased LTP in response to E 2 (Smith et al 2010). This research group also found that treatment with both acute and chronic E 2 was unable to enhance object recognition memory in rats ovariectomized for 19 mo prior to treatment (Vedder et al 2014), suggesting important parallels between the synaptic and mnemonic responsiveness to E 2 in females. Other investigators have reported similarly detrimental effects of long-term ovariectomy on the ability of chronic E 2 to enhance spatial working memory , supporting the idea that long-term hormone deprivation impairs E 2 's capacity to facilitate hippocampal synaptic plasticity and memory.…”

“…Nonspatial working memory in the T-maze is also improved by systemic E 2 (Wide et al 2004), as is spatial reference memory in the radial arm and Morris water mazes (Packard and Teather 1997a;Heikkinen et al 2002;Gresack and Frick 2006), recognition memory for the location and identity of objects (Vaucher et al 2002;Luine et al 2003;Walf et al 2006;Frye et al 2007;Fernandez et al 2008;Inagaki et al 2010;Zhao et al 2010;Phan et al 2012;Boulware et al 2013), social recognition memory , inhibitory avoidance (Singh et al 1994;Frye andRhodes 2002, but see Foster et al 2003), and trace eyeblink conditioning (Leuner et al 2004). However, not all studies find that E 2 benefits memory in adult females under all conditions, as improvements often depend on methodological variables such as dose (Packard and Teather 1997a;Holmes et al 2002;Leuner et al 2004;Wide et al 2004;Gresack and Frick 2006;Foster 2012;Phan et al 2012), age at treatment (Savonenko and Markowska 2003;Gresack et al 2007;Markham and Juraska 2007), duration of treatment (Luine et al 1998;Markowska and Savonenko 2002) (Bohacek and Daniel 2007), the cognitive demands of the task (Bimonte and Denenberg 1999), and duration of ovariectomy prior to treatment (Gibbs 2000;Daniel et al 2006;Vedder et al 2014). Understanding the extent to which these variables influence the response to E 2 has potential translati...…”

Regulation of object recognition and object placement by ovarian sex steroid hormones

“…It is also important to note that although several studies have used gonadally intact females, the vast majority of studies to date administered exogenous hormones to ovariectomized females because removal of the ovaries eliminates the ovarian hormone fluctuations generated by the estrous cycle. In most studies, treatment was started at the time of ovariectomy or within a week afterwards, but recent data show that long periods of ovarian hormone deprivation after ovariectomy eliminate the memory-enhancing effects of E 2 on OR [16]. As such, timing of treatment to ovariectomy is an important variable for investigators to consider.…”

Sex differences in MDMA-induced toxicity in Sprague-Dawley rats

“…It has been established that estrogen influences synaptic plasticity in the hippocampus and that gonadectomy results in a loss of post-synaptic dendritic spines of hippocampal neurons of the CA1 region (Vedder et al, 2014). Spine density varies with the estrous cycle, peaking at the proestrous stage, shortly before ovulation, when serum estradiol concentrations are highest (Woolley and McEwen, 1992).…”