Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC58
Extensive cortical cholinergic innervation is required for normal auditory processing and perceptual learning in adult ferrets
N. D. Leach1, V. M. Bajo Lorenzana1, P. M. Cordery1, F. R. Nodal1, D. S. Burke1, A. J. King1
1. Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
Cholinergic modulation of cortical activity has been implicated in a number of cognitive functions, including the induction of experience-dependent plasticity, processing of sensory inputs and the potential mechanisms underlying attention. Given the clear role for acetylcholine in altering cortical activity, and the knowledge that an intact auditory cortex is critical for many aspects of auditory processing, including the perception of sound source location, we investigated the role cortical acetylcholine efflux plays in modulating auditory processing in adult ferrets. Anatomical studies revealed the distribution of cholinergic cells in the nucleus basalis (NB), the main source of cholinergic innervation to the cortex, while tracing studies confirmed that neurons within this region project unilaterally to the auditory cortex. Cortical cholinergic input was subsequently disrupted by selectively destroying cholinergic projections from the NB, prior to testing animals on a free-field sound localization task. Ferrets were anaesthetized with ketamine (5 mg/kg i.m.) and medetomidine (0.022 mg/kg i.m.) prior to bilateral injections of either the cholinergic neurotoxin ME20.4-SAP (n=6), or ACSF (n=2), in the NB. ME20.4-SAP injections produced a decrease in the number of cholinergic cells in the nucleus basalis (Controls, 1144±253; Lesion, 550±415), and in acetylcholinesterase positive fibre density throughout the auditory cortex (Controls, density (fibres/mm3) = 0.738±0.069; Lesion, 0.622±0.162). Animals with cholinergic lesions of the NB were significantly impaired in their ability to localize short duration sounds in azimuth (linear mixed-effects (lme) model, 40-500 ms; F(18)=19.57, p<0.01). Performance impairments manifested as a decrease in correct responses, and an increase in mean error magnitude, over all speaker locations, and an increase in front-back errors, or mislocalizations to the incorrect anteroposterior hemifield. The degree of performance impairment positively correlated with the extent of cholinergic cell loss in NB (linear model, 40-500 ms; F(1,12)=172.72, p<0.001), with more extensive cell loss producing greater performance impairments. Furthermore, the ability to adapt to perturbations in spatial cue composition induced by unilateral earplugging was impaired. Recovery of function was less complete (unpaired t-test, t(6)=-2.388, p=0.054), and occurred at a significantly reduced rate (lme, F(77)=37.513, p<0.01), relative to controls. These results suggest that cortical acetylcholine plays an important role in modulating sensory processing, potentially by altering the way in which auditory cues are integrated, or by less well-defined attentional mechanisms. However, whether such effects are mediated via the auditory cortex alone, or whether other, more frontal, cortical regions are involved, remains unclear.
Where applicable, experiments conform with Society ethical requirements