Differential role of muscarinic transmission within the entorhinal cortex and basolateral amygdala in the processing of irrelevant stimuli

Abstract

Cholinergic projections to the entorhinal cortex (EC) and basolateral amygdala (BLA) mediate distinct cognitive processes through muscarinic acetylcholine receptors (mAChRs). In this study, we sought to further differentiate the role of muscarinic transmission in these regions in cognition, using the latent inhibition (LI) phenomenon. LI is a cross-species phenomenon manifested as poorer conditioning to a stimulus experienced as irrelevant during an earlier stage of repeated non-reinforced pre-exposure to that stimulus, and is considered to index the ability to ignore, or to in-attend to, irrelevant stimuli. Given our recent findings that systemic administration of the mAChR antagonist scopolamine can produce two contrasting LI abnormalities in rats, ie, abolish LI under conditions yielding LI in non-treated controls, or produce abnormally persistent LI under conditions preventing its expression in non-treated controls, we tested whether mAChR blockade in the EC and BLA would induce LI abolition and persistence, respectively. We found that intra-EC scopolamine infusion (1, 10 mug per hemisphere) abolished LI when infused in pre-exposure or both pre-exposure and conditioning, but not in conditioning alone, whereas intra-BLA scopolamine infusion led to persistent LI when infused in conditioning or both stages, but not in pre-exposure alone. Although cholinergic innervation of the EC and BLA has long been implicated in attention to novel stimuli and in processing of motivationally significant stimuli, respectively, our results provide evidence that EC mAChRs also have a role in the development of inattention to stimuli, whereas BLA mAChRs have a role in re-attending to previously irrelevant stimuli that became motivationally relevant.

Figure 1

Effects of intra-entorhinal cortex scopolamine infusion (1 or 10 μg per hemisphere) before pre-exposure on LI with weak conditioning. Means and standard errors of the log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and non-pre-exposed (NPE) rats infused with vehicle or scopolamine (1, 10 μg) into the entorhinal cortex. Scopolamine was infused in the pre-exposure stage. Forty pre-exposures and two conditioning trials (weak conditioning) were used. Asterisk indicates a significant difference between the PE and NPE groups, namely, presence of LI.

Figure 2

Effects of intra-entorhinal cortex scopolamine infusion (10 μg per hemisphere) before conditioning or both stages on LI with weak conditioning. Means and standard errors of the log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and non-pre-exposed (NPE) rats infused with vehicle or scopolamine (10 μg) into the entorhinal cortex. Scopolamine was infused in the conditioning stage or in both pre-exposure and conditioning. Forty pre-exposures and two conditioning trials (weak conditioning) were used. Asterisk indicates a significant difference between the PE and NPE groups, namely, presence of LI.

Figure 3

Effects of intra-basolateral amygdala scopolamine infusion (10 μg per hemisphere) on LI with weak or strong conditioning. Means and standard errors of the log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and non-pre-exposed (NPE) rats infused with vehicle or scopolamine (10 μg) into the basolateral amygdala that underwent conditioning with two (weak conditioning) or five (strong conditioning) trials. Forty pre-exposures were used. Asterisk indicates a significant difference between the PE and NPE groups, namely, presence of LI.

Figure 4

Effects of intra-basolateral amygdala scopolamine infusion (10 μg per hemisphere) before pre-exposure or conditioning on LI with strong conditioning. Means and standard errors of the log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and non-pre-exposed (NPE) rats infused with vehicle or scopolamine (10 μg) into the basolateral amygdala. Scopolamine was infused either in the pre-exposure stage or in the conditioning stage. Forty pre-exposures and five conditioning trials (strong conditioning) were used. Asterisk indicates a significant difference between the PE and NPE groups, namely, presence of LI.

Figure 5

Neural circuitry through which cholinergic projections modulate the expression of latent inhibition. ACh, acetylcholine; BF, basal forebrain; BLA, basolateral amygdala; DA, dopamine; EC, entorhinal cortex; GLU glutamate; IC, insular cortex; LI, latent inhibition; NAC, nucleus accumbens; PFC, prefrontal cortex; SCOP, scopolamine; VTA, ventral tegmental area. (a) The PFC, EC, IC, and BLA receive cholinergic afferents from the BF. Inputs from the PFC and the BLA to the NAC core, and from the EC and IC to the NAC shell enhance and reduce, respectively, DA release from the VTA to the NAC core. Increased and decreased DA levels in the NAC core are associated with LI abolition and persistence, respectively. (b) Muscarinic blockade in the EC or IC inhibits the inputs of these regions to the NAC shell, causing disinhibition of the VTA and enhancing DA release in the NAC core, and leading to abolition of LI. (c) Muscarinic blockade in the BLA inhibits its inputs to the NAC core. Concurrently, the NAC shell, which receives excitatory inputs from the IC and EC, sends inhibitory inputs to the VTA, reducing DA release in the NAC core. Both of these effects lead to LI persistence. Intra-PFC scopolamine infusion is expected to affect LI similarly. This model is based on the switching model of LI (Weiner, 1990, 2003; Weiner and Feldon, 1997), models of cholinergic-related circuitries mediating attentional processing (Hasselmo and McGaughy, 2004; Sarter et al, 2005; Yeomans, 1995), and LI studies using muscarinic antagonists (Barak, 2009). Figure 5 is adapted from Barak (2009).