Medial diencephalon, comprising the mammillary bodies and anterior thalamic nuclei, is important for memory in both humans and animals. However, there is still uncertainty regarding how this region supports memory processes. The mammillary bodies and anterior thalamic nuclei form part of the Papez circuit, a network of brain regions important for episodic memory. Lesions within the medial diencephalon cause distal hypofunctionality in the rest of the Papez circuit, and most consistently in the retrosplenial/posterior cingulate cortex. Patients with diencephalic amnesia often exhibit glucose hypometabolism in the posterior cingulate cortex and animals with medial diencephalic lesions dramatically reduce immediate early gene expression in the retrosplenial cortex. It is still unknown whether these distal effects contribute to the memory impairments. This body of work investigated the distal hypofunctionality following lesions of the mammillothalamic tract in rats, a white matter bundle that connects the mammillary bodies to the anterior thalamic nuclei within the medial diencephalon. Mammillothalamic tract lesions were found to reduce expression levels of the immediate early gene zif268 in the retrosplenial cortex. However, no significant changes were found in the fine dendritic microstructure of the small pyramidal neurones located in the superficial layers of the rostral granular retrosplenial cortex, which receive the anterior thalamic nuclei input. To determine whether the reduced immediate early gene expression contributes to the spatial memory impairments associated with mammillothalamic tract lesions, antisense oligodeoxynucleotides were infused into either the retrosplenial cortex or the dorsal hippocampus. These infusions had no effect on spatial memory performance; however, it was not possible to verify that they were effective in knocking-down zif268 or c-fos at the molecular level. This work expands our understanding of the distal effects of mammillothalamic tract lesions but further studies are needed to determine whether they contribute to the memory impairments observed.