Exploratory activity, spontaneous alternation, learning and memory abilities were examined in the pyrithiamine-induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's syndrome and pair-fed controls (CT). PTD and CT animals showed normal retention of a single trial of a passive avoidance task acquired prior to the acute stages of thiamine deficiency. While there were no significant group differences in spontaneous activity, PTD animals with extensive damage to internal medullary lamina (IML-lesioned) of thalamus and mammillary body nuclei demonstrated a significant decrease in spontaneous alternation and were significantly impaired in learning both the initial spatial non-matching-to-position (NMTP) task and the reverse MTP task. PTD animals without IML damage (IML-spared) were only impaired on the acquisition of NMTP. Examination of response patterns suggest that the learning impairment was related to an inability to adopt or shift to the appropriate response rule. Performance of PTD IML-lesioned animals on NMTP mixed-delay sessions (4, 30, 60, 90 s) was similar to controls and PTD IML-spared, but was significantly lower on MTP delay trials. These IML-lesioned rats also had significant reductions in thickness of frontal and parietal cortex, corpus callosum and severe neuronal loss in anterior and reticular thalamic nucleic. Four PTD IML-lesioned animals that were unable to learn the NMTP task had more extensive cortical, white matter and thalamic damage than the PTD IML-lesioned animals that did learn the task. These results demonstrate that thiamine deficiency in the rat produces behavioral changes ranging from mild cognitive deficits to severe learning and memory impairments. Pathologic damage following a bout of thiamine deficiency also varies from neuronal loss in select thalamic nuclei to tissue loss in large regions of thalamus, mammillary bodies and cortex. Learning and memory deficits are closely related to the degree of cortical and diencephalic damage.