Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets.

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex.

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en-passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.

Cortical cholinergic input is required for normal auditory perception and experience-dependent plasticity in adult ferrets.

The nucleus basalis (NB) in the basal forebrain provides most of the cholinergic input to the neocortex and has been implicated in a variety of cognitive functions related to the processing of sensory stimuli. However, the role that cortical acetylcholine release plays in perception remains unclear. Here we show that selective loss of cholinergic NB neurons that project to the cortex reduces the accuracy with which ferrets localize brief sounds and prevents them from adaptively reweighting auditory localization cues in response to chronic occlusion of one ear. Cholinergic input to the cortex was disrupted by making bilateral injections of the immunotoxin ME20.4-SAP into the NB. This produced a substantial loss of both p75 neurotrophin receptor (p75(NTR))-positive and choline acetyltransferase-positive cells in this region and of acetylcholinesterase-positive fibers throughout the auditory cortex. These animals were significantly impaired in their ability to localize short broadband sounds (40-500 ms in duration) in the horizontal plane, with larger cholinergic cell lesions producing greater performance impairments. Although they localized longer sounds with normal accuracy, their response times were significantly longer than controls. Ferrets with cholinergic forebrain lesions were also less able to relearn to localize sound after plugging one ear. In contrast to controls, they exhibited little recovery of localization performance after behavioral training. Together, these results show that cortical cholinergic inputs contribute to the perception of sound source location under normal hearing conditions and play a critical role in allowing the auditory system to adapt to changes in the spatial cues available.

Neural circuits underlying adaptation and learning in the perception of auditory space.

Sound localization mechanisms are particularly plastic during development, when the monaural and binaural acoustic cues that form the basis for spatial hearing change in value as the body grows. Recent studies have shown that the mature brain retains a surprising capacity to relearn to localize sound in the presence of substantially altered auditory spatial cues. In addition to the long-lasting changes that result from learning, behavioral and electrophysiological studies have demonstrated that auditory spatial processing can undergo rapid adjustments in response to changes in the statistics of recent stimulation, which help to maintain sensitivity over the range where most stimulus values occur. Through a combination of recording studies and methods for selectively manipulating the activity of specific neuronal populations, progress is now being made in identifying the cortical and subcortical circuits in the brain that are responsible for the dynamic coding of auditory spatial information.