Anterior thalamic lesions produce chronic and profuse transcriptional deregulation in retrosplenial cortex: a model of retrosplenial hypoactivity and covert pathology

Anterior thalamic lesions are thought to produce ʹcovertpathologyʹ in retrosplenial cortex, but the causes are unknown. Using microarray analyses we tested the hypothesis that thalamic damage causes a chronic, hypofunction of metabolic and plasticity-related pathways (Experiment 1). Rats with unilateral, anterior thalamic lesions were exposed to a novel environment for 20 min, and granular retrosplenial tissue sampled from both hemispheres 30 min, 2 hours and 8 hours later. Complementary statistical approaches (analyses of variance, predictive patterning and gene set-enrichment analysis) revealed pervasive gene expression differences between retrosplenial cortex ipsilateral to the thalamic lesion and contralateral to the lesion. Selected gene differences were validated by QPCR, immunohistochemistry (Experiment 1) and in situ hybridization (Experiment 2). Following thalamic lesions, the retrosplenial cortex undergoes profuse cellular transcriptome changes including lower relative levels of specific mRNAs that are involved in energy metabolism and neuronal plasticity. These changes in functional gene expression might be driven largely by decreases in the expression of genes encoding transcription factors including brd8, c-fos, fra-2, klf5, nfix, nr4a1, smad3, smarcc2 and zfp9, with far fewer (nfat5, neuroD1 and RXRg) showing increases. These findings have implications for conditions such as diencephalic amnesia and Alzheimerʹs disease in which both anterior thalamic pathology and retrosplenial cortex hypometabolism are prominent.