The role of cortical cholinergic afferent projections in cognition: impact of new selective immunotoxins

Abstract

Previous investigations aimed at determining the role of corticopetal cholinergic afferents in cognition have relied upon human psychopharmacological studies, neuropsychological analyses of Alzheimer's patients, or psychopharmacological manipulations and excitotoxic lesions in animals. Unfortunately, each approach has its limitations. The interpretation of neuropsychological data relies upon correlations of post-mortem assessments of cholinergic degeneration that may be quite temporally distant from the time of cognitive assessment. In contrast, the use of animals allows direct manipulations of the cholinergic system and the establishment of causal relationships between acetylcholine and cognitive function but is limited by the selectivity of the toxins and drugs available to manipulate the system. The recent introduction of immunotoxins to lesion cortical cholinergic pathways with greater selectivity has allowed the effective testing of these hypotheses of cholinergic functions in cognition. Previous neuropsychological, psychopharmacological and excitotoxic lesion data are reviewed and compared to results produced using the more selective immunotoxins to provide an update to the current hypotheses of the role of corticopetal cholinergic afferents in cognitive function. Additionally, the conceptual and methodological cost and benefits of the methods of infusion used to produce lesions with these immunotoxins is assessed.