In the frontal cortex the present study found a relationship
In the frontal cortex, the present study found a relationship between working memory performance and activated Erk2 expression for the E2-only group, where animals that tended to perform better on the WMC measure tended to have higher activated Erk2 expression. This suggests that there is a unique relationship between working memory performance and activated Erk2 expression in the presence of E2 in the frontal cortex, a region that is heavily involved in normal working memory function (Funahashi and Kubota, 1994). It is noteworthy that the beneficial cognitive effects of E2 in this study were specific to working memory, and here the activation of a signaling pathway implicated in cognitive function was linked particularly to E2-only treatment and its effects in a region of the caudatin that plays a significant role in processing working memory information. In contrast to the relationship seen with E2-only treatment, there was no relationship between cognitive performance as measured by WMC errors made and activated Erk2 expression within the E2 + Levo hormone combination treatment group, indicating that the addition of Levo obviated the E2-induced association between cognitive performance and activated Erk2 levels in the brain. In addition, there was a relationship trend within the vehicle group between activated Erk2 expression in the frontal cortex and WMC errors, whereby higher activated Erk2 levels correlated with higher WMC errors, indicating that E2-only treatment may have reversed the relationship between activated Erk2 expression and working memory performance in the control group; this correlation was statistically significant before the correction, but it was not statistically significant after correcting for multiple correlations. Although the relationship between cognitive performance and activated Erk2 levels in the frontal cortex was specific to the WMC measure and the beneficial cognitive effects of E2-only treatment were specific to the WMI measure, it is important to note that these measures of working memory performance are orthogonal and may be governed by different neurological pathways and brain regions. For example, a hippocampal lesion study found that a complete hippocampal lesion in male rats resulted in increased WMC errors compared to WMI errors when tested on an 8-arm radial-arm maze, but no differences were seen between WMC errors and WMI errors in control rats and in rats with partial hippocampal lesions (Jarrard et al., 2012). Thus, the type of memory affected, and the directionality of the cognitive effect following hormone treatment, may be governed by the brain regions and neural pathways that are specific to the hormones examined. There were no treatment-induced differences in activated Erk1 and Erk2 expression in the dorsal hippocampus, CA1/CA2 ventral hippocampus, frontal cortex, entorhinal cortex, or perirhinal cortex. It is important to highlight that the treatment regimen in this study was a chronic and cyclic low-dose injection, whereas studies that have shown E2-induced increases of activated Erk2 expression in the dorsal hippocampus were typically acute or injected at a higher or tonic dose (Fernandez et al., 2008, Harburger et al., 2009, Witty et al., 2013). The growing preclinical and clinical evidence indicates great complexity in the cognitive effects of ovarian hormone loss and hormone therapy. This drives us toward opening new avenues of study to help us understand which factors play into this complexity to truly decipher hormone-related impacts. Many publications indicate that ovarian hormone loss in women, and in rodents, is associated with changes in memory performance across multiple domains of memory, that subsequent E2 treatment can result in beneficial effects on cognitive function, and that the addition of a progestogen can attenuate these E2-induced cognitive benefits (for reviews: Frick, 2015, Koebele and Bimonte-Nelson, 2015, Korol and Pisani, 2015, Maki, 2012, Mennenga and Bimonte-Nelson, 2013, Sherwin, 2006). There are notable exceptions to these outcomes, as the extent and direction of hormone therapy effects are sensitive to a myriad of variables. The details and parameters of how such factors impact outcomes are just beginning to be understood (Koebele and Bimonte-Nelson, 2015, Koebele and Bimonte-Nelson, 2017, Korol and Pisani, 2015). For example, age is a critical factor affecting the efficacy of estrogens on cognitive and brain function, with diminished or lost efficacy as aging ensues (Bean et al., 2014, Foster et al., 2003, Gibbs, 2010, Koebele and Bimonte-Nelson, 2017, Maki, 2013, Mennenga and Bimonte-Nelson, 2013, Talboom et al., 2008). Thus, the hormone treatment effects observed in the present study in middle-aged rats may be more pronounced if tested in young rats and may be attenuated in aged rats.