Genetically Induced Cholinergic Hyper-Innervation Enhances Taste Learning

Abstract

Acute inhibition of acetylcholine (ACh) has been shown to impair many forms of simple learning, and notably conditioned taste aversion (CTA). The most adhered-to theory that has emerged as a result of this work - that ACh increases a taste's perceived novelty, and thereby its associability - would be further strengthened by evidence showing that enhanced cholinergic function improves learning above normal levels. Experimental testing of this corollary hypothesis has been limited, however, by side-effects of pharmacological ACh agonism and by the absence of a model that achieves long-term increases in cholinergic signaling. Here, we present this further test of the ACh hypothesis, making use of mice lacking the p75 pan-neurotrophin receptor gene, which show a resultant over-abundance of cholinergic neurons in sub-regions of the basal forebrain (BF). We first demonstrate that the p75-/- abnormality directly affects portions of the CTA circuit, locating mouse gustatory cortex (GC) using a functional assay and then using immunohistochemisty to demonstrate cholinergic hyper-innervation of GC in the mutant mice - hyper-innervation that is unaccompanied by changes in cell numbers or compensatory changes in muscarinic receptor densities. We then demonstrate that both p75-/- and wild-type (WT) mice learn robust CTAs, which extinguish more slowly in the mutants. Further testing to distinguish effects on learning from alterations in memory retention demonstrate that p75-/- mice do in fact learn stronger CTAs than WT mice. These data provide novel evidence for the hypothesis linking ACh and taste learning.