Estradiol can act to protect against hippocampal damage resulting from transient global ischemia, but little is known about the functional consequences of such neuroprotection. The present study examines whether acute estradiol administered prior to the induction of transient global ischemia protects against hippocampal cell death and deficits in performance on a spatial learning task. Ovariectomized female rats were primed with estradiol benzoate or oil vehicle 48 and 24 hrs prior to experiencing one of three durations of 4-vessel occlusion (0, 5, or 10 min). Performance on the cued and hidden platform versions of the Morris water maze was assessed one week following ischemia. On the cued platform task, neither hormone treatment nor ischemia significantly influenced acquisition. When tested on the hidden platform task, however, oil-treated rats exhibited impairments in spatial learning after either 5 or 10 min of ischemia while estradiol-treated rats showed no impairments after 5 min of ischemia and only mild impairments after 10 min of ischemia. Immediately following behavioral testing, rats were perfused and survival of CA1 pyramidal cells was assessed. Ischemia was associated with the loss of CA1 pyramidal cells but rats that received estradiol prior to ischemia showed less severe damage. Furthermore, the extent of cell loss was correlated with degree of spatial bias expressed on a probe trial following hidden platform training. These findings indicate that acute exposure to estradiol prior to ischemia is both neuroprotective and functionally protective. Keywords estrogen; ischemia; cardiac arrest; hippocampus; neuroprotection; spatial learning; water maze Acute pretreatment with estradiol protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemiaTransient global ischemia leads to the dramatic loss of neurons in the CA1 region of the hippocampus in humans (Horn and Schlote, 1992;Tanabe et al., 1999;Taraszewska et al., 2002), non-human primates (Zola-Morgan et al., 1992), and rodents (Pulsinelli et al., 1982). This neuronal damage can be accompanied by severe impairments in cognition. For example, human survivors of ischemic strokes typically exhibit disruptions in performance on tasks requiring attention, learning and memory (Elwan et al., 1994;Volpe et al., 1986; Address Correspondence to: Noah J. Sandstrom, Department of Psychology, Williams College, 18 Hoxsey Street, Williamstown, MA 01267, Phone: 413-597-4107, Fax: 413-597-2085, E-mail: Noah.Sandstrom@williams.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain...