Signal transduction mechanisms within the entorhinal cortex that support latent inhibition of cued fear conditioning

Latent inhibition is a learning-related phenomenon where pre-exposure to a to-be-conditioned CS prior to training results in decreased conditioned responses. Pre-exposed animals receive 20 CS (80 dB white-noise) presentations prior to two pairings of the CS with an aversive US (0.53 mA, 1 sec. foot-shock), which results in significantly less conditioned responses when compared to control non pre-exposed mice. Previous research has demonstrated a critical role for the entorhinal cortex in latent inhibition of cued fear conditioning. However, all previous work has utilized permanent pre-training lesions of the entorhinal cortex to examine its role in latent inhibition, which has not allowed an analysis of its role in development versus expression of latent inhibition. Experiment one utilized direct infusions of muscimol (GABAa receptor agonist; 1mug/mul; 30 minutes prior to pre-exposure) into the entorhinal cortex during pre-exposure, training, or testing. The results demonstrate that the entorhinal cortex is necessary for development and expression of latent inhibition of cued fear conditioning.; It has been demonstrated that NMDA receptor activation, protein kinase A (PKA) and mitogen activated protein kinase (MAPK) are integral for many long-lasting learning and memory tasks. Previous work, utilizing systemic pharmacology, has suggested a role for NMDA receptors, PKA, and MAPK in latent inhibition of cued fear conditioning. However, the site of action of these drugs has yet to be established. Experiments two through four examined the role of NMDA receptors, PKA, and MAPK within the entorhinal cortex in latent inhibition of cued fear conditioning. Direct infusion of the NMDA receptor antagonist APV (5.0 mug/mul; 15 minutes prior to pre-exposure), the camp inhibitor Rp-cAMP (18.0 mug/mul; 30 minutes prior to pre-exposure), or the MAPK inhibitor U0126 (2.0 g/l; 30 minutes prior to pre-exposure) into the entorhinal cortex disrupted latent inhibition of cued fear conditioning in a dose dependent fashion. These results are discussed in relation to potential mechanisms of plasticity that underlie latent inhibition of cued fear conditioning.