Reversible inactivation of the entorhinal cortex disrupts the establishment and expression of latent inhibition of cued fear conditioning in C57BL/6 mice

Abstract

For latent inhibition, preexposure to a conditioned stimulus (CS) prior to training with an unconditioned stimulus (US) results in decreased conditioned responses (CRs) to the CS at the time of testing. The mechanism by which decreased CRs occurs, however, is unknown; CS preexposure may interfere with subsequent conditioning, or modulate the expression of CRs. Previous research has suggested that the entorhinal cortex (EC) is necessary for latent inhibition of a variety of tasks. However, no studies have specifically compared the role of the EC in acquisition vs. expression of latent inhibition. The present study used reversible inactivation of the EC to address this issue. The GABA agonist muscimol (0.5 microg/side) was directly infused into the EC of mice prior to CS preexposure, training, or testing. Our results indicate that muscimol inactivation of the EC before CS preexposure disrupts latent inhibition of cued fear conditioning. Importantly, this same dose of muscimol did not disrupt cued fear conditioning, nor did it affect latent inhibition when infused into the subiculum. Furthermore, inactivation of the EC at testing disrupted the expression of latent inhibition of cued fear conditioning; that is, CS preexposed mice that received entorhinal cortical muscimol infusion at testing showed CRs compared to saline-infused CS preexposed mice. These findings suggest that repeated preexposure to the CS during latent inhibition may alter entorhinal cortical activity thereby allowing the EC to exert inhibitory control over the expression of CRs during testing of CS preexposed mice.

Differential Role of Muscarinic Transmission within the Entorhinal Cortex and Basolateral Amygdala in the Processing of Irrelevant Stimuli

“…Our present results suggest that the capacity of systemic scopolamine to induce these contrasting effects on LI may result from its preferred activity at these brain regions during the two stages of the LI procedure. Our results are also consistent with lesion results, showing that EC lesions or its temporary inactivation during pre-exposure abolish LI (Coutureau et al, 1999;Jeanblanc et al, 2004;Lewis and Gould, 2007a;Seillier et al, 2007;Shohamy et al, 2000;Yee et al, 1995), whereas BLA lesions lead to abnormally persistent LI Weiner, 2004, 2005;Schiller et al, 2006; but see Coutureau et al, 2001). In terms of psychological processes underlying LI, it is believed that during pre-exposure, the acquisition of an association between the PE stimulus and the absence of a significant consequence results in the development of inattention to the stimulus, which inhibits the acquisition and/or the performance of the conditioned response (Bouton, 1993;Lubow and Kaplan, 2005;Weiner, 1990Weiner, , 2003.…”

“…Lewis and Gould (2007a) recently reported the same outcome using reversible inactivation of EC by the GABA agonist muscimol in a similar CER procedure. Muscimol infusion during pre-exposure disrupted LI, whereas inactivation during conditioning had no effect.…”

“…Moreover, reversible EC inactivation, similar to our systemic scopolamine injections, were effective in pre-exposure but not conditioning (Jeanblanc et al, 2004;Lewis and Gould, 2007a;Seillier et al, 2007). No stage selectivity has been tested for BLA lesions.…”

“…Taken together, these and our results imply that the EC may be the site where the stimulus-no outcome association is formed during pre-exposure, but that this region is not involved in processes occurring in conditioning to both the PE and the novel stimulus. In addition, Lewis and Gould (2007a) found that inactivation of the EC during the test stage also disrupted LI, suggesting that the EC has a role in both the formation and the retrieval of the stimulus-no outcome contingency acquired in pre-exposure. As the present study has not tested the effects of muscarinic blockade during the test stage, we cannot extend this interpretation to the cholinergic innervation of the EC.…”

“…As systemic scopolamine abolishes LI when administered in pre-exposure but not in conditioning (Barak and Weiner, 2007), and there is extensive evidence that inactivation of the EC during pre-exposure abolishes LI (Jeanblanc et al, 2004;Lewis and Gould, 2007a;Seillier et al, 2007), we had a strong prediction that intra-EC scopolamine infusion before pre-exposure would abolish LI. Therefore, here we confined the infusion to the pre-exposure stage.…”