Behavioural and Neurophysiological Consequences of Dysfunction in the Lateral Entorhinal Cortex in Rats

Entorhinal dysfunction is implicated in the pathogenesis of several diseases such as Alzheimer’s disease and medial temporal lobe epilepsy. The entorhinal cortex is also critically involved in memory formation, and in particular, the memory for events separated in time (temporal associative memory; TAM). These memory paradigms also depend on the integrity of the dorsal hippocampus (dHPC) and neocortical regions such as the prelimbic medial prefrontal cortex (PrL). The dHPC and PrL have a unique pattern of connectivity with the lateral portions of the entorhinal cortex (LEC). It may therefore be that the LEC acts as a hub for cortico-limbic communication necessary for TAM. To address this point, I compared the effect of three different types of entorhinal manipulations in rats on the acquisition of a TAM learned through trace eyeblink conditioning (TEBC) while I simultaneously monitored learning-related oscillatory activity in the dHPC and PrL. To induce dysfunction in the LEC, I reversibly inactivated it, induced partial cell loss, or over-expressed abnormal tau. I found that transient inactivation of the LEC, but not partial cell loss or tau over-expression, impaired learning of TEBC. Despite normal learning in animals with cell loss and tau over-expression, these animals had altered learning-related oscillatory activity; partial cell loss in the LEC altered stimulus-evoked oscillatory activity whereas entorhinal tau accumulations attenuated learning-related amplitude-amplitude, phase-phase, and phase-amplitude couplings between the dHPC and PrL. Both groups had increased activity in the PrL which may reflect compensatory activity. These results demonstrate that the LEC is used for the formation of a TAM in normal brains but that the brain can compensate for permanent dysfunction in the LEC. They also reveal that different types of entorhinal dysfunction induce distinct learning-related electrophysiological patterns of activity. Thus, task-related electrophysiological activity may be a more sensitive measure of entorhinal dysfunction than behavioural measures.Ph.D