Translational Rodent Models of Korsakoff Syndrome Reveal the Critical Neuroanatomical Substrates of Memory Dysfunction and Recovery

Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved
in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional
deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported
in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and
cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss
of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While
PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are
left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD
model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial
cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these
regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS.