The critical window hypothesis predicts that estrogen replacement therapy (ERT) must be administered early on the menopause or ovariectomy (OVX) to positively affect cognition. However, the neural substrates, underling the time dependent efficacy of ERT, are still not completely known. In order to address this issue, we submitted female mice to 12 weeks of OVX followed by 5 weeks of chronic ERT (OVX(E2)). Within the first 12 weeks, the OVX animals showed a progressive compromised performance in the object recognition memory (ORM) task. After ERT, OVXE2 mice, but not the control group (OVXoil), were able to recognize the new object in the test session. Further, we evaluated the c-Fos expression in hippocampus, perirhinal cortex (PC) and central amygdala (CeA) of OVXoil and OVX(E2) mice, after context exposure (CTX) or object exploration (OBJ). We observed that ERT increased c-Fos expression unspecifically for CTX and OBJ. In addition, only the OVX(E2) group showed significantly higher c-Fos expression in the PC and CeA after object exploration. Thus, our results showed that delayed chronic ERT improves ORM (compromised by OVX) and increases constitutive c-Fos expression in temporal lobe regions. Furthermore, we showed for the first time that PC and CeA, but not the hippocampus, present a distinct pattern of activation in response to object exploration in ovariectomized females that underwent delayed-ERT.
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