Four experiments examined the disruptive effects of selective lesions in limbic thalamic nuclei on retrosplenial cortex function, as characterized by striking changes in immediate-early gene activity. Major goals were to test the specificity of these retrosplenial changes, to define better their time course, and to assess the spread of retrosplenial dysfunction with time post-surgery. Experiment I examined the activity of two immediate-early genes (c-Fos, Zif268) in the retrosplenial cortex after unilateral anterior thalamic nuclei lesions (1, 2, or 8 weeks post-surgery). Marked immediate-early gene hypoactivity in the hemisphere ipsilateral to the thalamic lesion was consistent across these different post-surgical intervals and, hence, across different rat strains. Concurrent processing of brain tissues from rats either 4 weeks or 1 year after anterior thalamic lesions (Experiments 2 and 3) enabled direct comparisons across very different survival times. The results confirmed that over time the immediate-early gene disruption expanded from the superficial laminae to the deep laminae of granular b cortex and to the dysgranular subregion, indicative of more global disruptions to retrosplenial cortex with extended survival. Associated, subtle changes to cell morphometry (size and sphericity) were found in the retrosplenial cortex. In contrast, unilateral lesions in the adjacent laterodorsal thalamic nucleus (Experiment 4) did not significantly alter retrosplenial cortex c-Fos activity, so highlighting the anatomical specificity of the anterior thalamic lesion effects. These findings not only indicate that the impact of anterior thalamic lesions on cognition could be enhanced by retrosplenial cortex dysfunction but they also show that the effects could increase with longer post-insult survival. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.