Short-Term Estradiol Administration in Aging Ovariectomized Rats Provides Lasting Benefits for Memory and the Hippocampus: A Role for Insulin-Like Growth Factor-I

Abstract

We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-α in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ERα resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERα-mediated transcription through ligand-independent mechanisms. Our current goal was to determine whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERα in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling molecule of both ERα and IGF-I receptors, and increased levels of the ERα-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory.

Evidence for Ligand-Independent Activation of Hippocampal Estrogen Receptor-α by IGF-1 in Hippocampus of Ovariectomized Rats

“…The current findings indicating that IGF-1 can activate ER␣ and increase levels of ER␣-regulated proteins in the hippocampus provide a potential mechanism by which ER␣ can be activated and impact cognition in the absence of circulating estrogens. The functional implications for cognition of activation of IGF-1 receptors in the absence of circulating estrogens are evident from previous data from our lab in which antagonism of brain IGF-1 receptors blocked the lasting enhancing effects on cognition in aging ovariectomized rats that had previous estradiol exposure (18). In addition, this chronic antagonism of hippocampal IGF-1 receptors reversed the lasting elevation in hippocampal levels of ER␣ and ChAT that was evident in aging females that had previous estradiol treatment.…”

“…An incision was made in the scalp and fascia that overlie the skull. A hole was drilled in the skull and a 10l Hamilton syringe was lowered to the appropriate depth [coordinates: -0.3 mm anterior-posterior, ϩ1.2 mm medial-lateral, and -4.5 mm dorsal-ventral relative to bregma (18)]. IGF-1 (GroPep, Adelaide, Australia), 2 g/l (25) in a total volume of 1ul or aCSF vehicle (Tocris Bioscience, Bristol, UK) was delivered over a period of 2 minutes.…”

“…These effects persist for months following the termination of estradiol treatment. Shortterm administration of estradiol in midlife also results in lasting increases in levels of IGF-1 receptors in the hippocampus (18). Additionally, the long-term effects of short-term estradiol treatment on memory and on ER␣-regulated proteins were blocked by chronic antagonism of brain IGF-1 receptors that was initiated after the estradiol treatment was terminated.…”

The neuroprotective actions of oestradiol and oestrogen receptors

“…Like oestradiol, IGF1 is a neuroprotective hormone and a local factor that contributes to maintain body and tissue homeostasis, including the regulation of brain plasticity and function 108 . The neuroprotective actions of oestradiol and IGF1 have many points in common, and both factors interact in the regulation of neuronal survival, neuritogenesis, adult neurogenesis, brain cholesterol homeostasis, glucose metabolism, neuroprotection and cognition 82,[109][110][111][112][113][114][115] .…”

Distribution of growth hormone-responsive cells in the mouse brain

“…Therefore, it is conceivable that secondary effects of GH deficiency are more important for the cognitive deficits than impaired brain GHR signaling per se. Several studies have shown that IGF-1 signaling has neuroprotective and neurodevelopmental effects and also influences cognitive processes (Miltiadous et al 2011;O'Kusky and Ye 2012;Aberg et al 2006;Witty et al 2013;Le Greves et al 2005;Molina et al 2013;Sonntag et al 2013;Ramis et al 2013). However, the wide distribution of GH-responsive cells in areas involved in mechanisms of learning and memory, as well as in emotional/motivational processes, provides neuroanatomical evidence that GH signaling may directly affect cognitive processes and the expression of behaviors, independently of changes in IGF-1 circulating levels.…”