| Estradiol enhances hippocampus- and impairs striatum-sensitive learning. Typical hippocampus-sensitive tasks involve learning the location of rewards based on position relative to extramaze cues. One such task is place learning in which a rat must go to the same room location to retrieve a food reward. In response learning, a striatum-sensitive version of finding food on a maze, the food reward is obtained by making a specific body turn, e.g. right or left, from the start location. My work attempts to understand whether estradiol's enhancement of place and impairment of response learning are due to actions in distinct brain structures. Because it is now known that steroids act on neuronal function through both fast membrane-related and slower genomic pathways, one goal of the proposed set of studies is to determine whether relatively short durations of estradiol treatment are sufficient to influence response learning.;Despite being particularly sensitive to manipulations of the hippocampus and striatum, respectively, place and response learning are undoubtedly accomplished through participation of multiple brain structures, such as the amygdala (Packard et al., 1994; McIntyre et al., 2003), medial septum (Rawlins & Olton, 1982; as reviewed by Gray & McNaughton, 1983), entorhinal cortex (Olton et al., 1982; Hafting et al., 2005) and the frontal cortex (as reviewed by Hollerman et al., 2000; Poldrack & Rodriguez, 2004). The presence of estradiol in any one or combination of these and other structures might produce the demonstrated opposing enhancement and impairment in learning. Experiments 1 and 2 (Chapter 4) identify the hippocampus and striatum as the requisite sites for estradiol actions on place and response learning respectively, when treatment is given across two days.;Estradiol is known to increase activation of various intracellular signaling cascades (as reviewed by Spencer, 2008), many of which have been implicated as beneficial for learning and memory (as reviewed by Bozon et al., 2003). The transcription factor, cAMP response element binding protein (CREB) is increased by estradiol (Zhou et al., 1996; Carstrom et al., 2001; Lee et al., 2004; Abraham & Herbison, 2005; Boulware et al., 2005; Zhou et al., 2005; Szego et al., 2006; Sharma et al., 2007; Grove-Strawser & Mermelstein, 2007) and considered to be a molecular marker of memory (as reviewed by Silva et al., 1998). Based on data in males, estradiol-induced increase in CREB activation would predict enhancement in the use of response strategies. Thus, findings that estradiol activates CREB but impairs response learning are contradictory. One possibility is that our regimen of prolonged estradiol treatment increases activated levels of CREB, measured as phosphorylated CREB (pCREB), in the hippocampus but not striatum. Experiment 3 (Chapter 4) addressed this issue directly by measuring CREB and pCREB with immunohistochemistry in the hippocampus and striatum of rats treated with two days of estradiol before and after training on a response learning task. Oil-treated rats showed a higher striatal to hippocampal ratio of CREB than did estradiol-treated rats before training began.;Estradiol-induced effects on learning through actions in the striatum are particularly intriguing due to the rapid responsiveness of striatal neurons to the presence of estradiol despite the relative lack of classical, nuclear estradiol receptors in this structure (Pfaff & Keiner, 1973; Shughrue et al., 1997; Shughrue & Merchenthaler, 2001). Striatal responses to estradiol have typically been measured through motoric behaviors or neurochemical assessments of dopamine signaling. Findings suggest that the striatum responds rapidly to estradiol treatment, with changes in some functions emerging as soon as 30 minutes following treatment, while changes in others take several days to emerge (Joyce et al., 1984). Differences in timing of effects reflect several factors including how the behavior was induced (drug-induced, lesion-induced), the presence or absence of dopaminergic lesions, and the specific type of behavior being assessed (Becker 1990b; Becker & Beer, 1989; Joyce et al., 1984). Despite the complexity of the findings, one conclusion drawn from these data is that estradiol has the potential to modulate quite rapidly striatal function and consequent motoric behaviors. Experiment 4 directly addressed the possibility that estradiol can also rapidly modulate learning that depends on striatal function. Findings from Experiment 4 (Chapter 5) revealed an impairment in response learning following intrastriatal infusions given as a single treatment two hours prior to training in addition to a series of three infusions 48, 24, and 2 hours prior to training.;Findings from these studies highlight the distinct actions of estradiol in the hippocampus to enhance place learning and in the striatum to impair response learning. By altering the responsiveness of hippocampal and striatal cells to experience, estradiol biases the type of information obtained, resulting in enhanced or impaired learning depending on the task variables. |
