Effects of continuous vs. cycling estrogen replacement on the acquisition, retention and expression of place- and response-learning in the open-field tower maze Olga Lipatova ⇑ , Dennis Byrd, John T. Green, Donna J. Toufexis University of Vermont, Department of Psychology, 2 Colchester Ave., Burlington, VT 05405, United States article info Article history: Received 14 March 2014 Revised 23 April 2014 Accepted 5 May 2014 Available online 14 May 2014 Keywords: Estrogen Cycling Continuous Place-learning Response-learning abstract Estrogen has been shown to either enhance or impair learning and memory in female rats. The use of different experimental paradigms or estrogen treatment regimens may contribute to these disparate findings. In order to assess the effect of different estradiol (E2) treatments on several aspects of cognition, we trained ovariectomized female rats with either continuous, cycling, or vehicle E2 replacement, in an open-field tower maze task (OFTM) designed to test reference memory in a low-stress environment. In addition, in order to compare two distinct learning and memory systems, rats were trained to use either a dorsolateral striatum-based response type learning or a hippocampal-based place type learning to solve the maze. Results showed that cyclic, but not continuous, E2 replacement facilitated the acquisition of spatial memory in place-learners. Neither E2 regimen affected acquisition in response-learners. Addition- ally, when all experimental groups were performing at asymptote, rats were evaluated for performance stability by changing the location of their start position in the OFTM. Both regimens of E2 disrupted the expression of spatial memory in place-learners following the novel start position. However, E2 replace- ment protected ovariectomized female rats from the disruption of memory expression following a start position change in response-learners. Additionally all experimental groups performed equally well when tested following a 21-day period during which rats were absent from the maze. These results suggest that E2 fluctuation is particularly important in the acquisition of hippocampal-mediated spatial learning, and that hippocampal-based memory may be subject to disruption following environmental change, while striatum-based memory is subject to protection. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction Estrogen is known to modulate several brain regions essential for learning and memory (Becker, Breedlove, Crews, & McCarthy, 2002), and estrogen-induced neuroplasticity in these brain regions has been empirically linked to cognitive function (Barha & Galea, 2010; Brinton, 2009; Woolley, 1998). However, due to a wealth of contradictory data, whether or not estrogen actually benefits or hinders cognition remains the subject of considerable debate. Sources of inconsistent data within both human and non-human literature likely include: differences in the estrogenic compounds used, variable routes of administration, timing of treatment rela- tive to training, different estrogen treatment regimens, estrogen with the simultaneous use of a progestin, and the fact that a variety of behavioral paradigms are utilized (Frick, 2009; Gibbs & Gabor, 2003; Lacreuse, 2006; Sherwin, 2006). The duration of treatment (e.g., acute vs. chronic) as well as whether the treatment produces hormone fluctuations similar to the natural cycle may also be responsible for producing some of the differential outcomes in measures of cognitive function (Frick, 2009; Sherwin & Henry, 2008). Moreover, although the same apparatus is often used for different behavioral procedures, these are usually done by different investigators and hence, on different experimental groups. For instance, the T-maze has been used by two different groups to determine estrogen’s effect on basic spatial learning and on delayed matching to position (Gibbs, 2000; Marriott & Korol, 2003). Thus, investigator-specific differences in handling, housing, estrogen regimen, and cohort make comparisons difficult even when investigators are using the same behavioral apparatus. Con- sequently, although the use of cycling vs. continuous estrogen administration is thought to be an important factor in producing some of the disparate data on estrogen and learning, only a limited number of studies incorporate the use of more than one estrogen http://dx.doi.org/10.1016/j.nlm.2014.05.001 1074-7427/Ó 2014 Elsevier Inc. All rights reserved. ⇑ Corresponding author. Fax: +1 (802) 656 8783. E-mail address: olga.lipatova@uvm.edu (O. Lipatova). Neurobiology of Learning and Memory 114 (2014) 81–89 Contents lists available at ScienceDirect Neurobiology of Learning and Memory journal homepage: www.elsevier.com/locate/ynlme