AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function

Abstract

The aim of the present study was to clarify the role of the basal forebrain (BF)-cortical cholinergic system in visual attentional function by investigating the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced lesions of the basal forebrain on performance of a five-choice serial reaction time task. AMPA lesions in the present study produced a profound effect on performance of the task, as measured by choice accuracy and correct response latency. This deficit was significantly greater than that observed in earlier studies following ibotenate- or quisqualate-induced lesions of the BF. However, detailed histological and biochemical analysis revealed three rather different BF lesions depending upon the batch of AMPA supplied. In one group of animals (BF/1) the deficits in task performance were substantially greater and longer lasting compared to another group of lesioned animals (BF/2), which showed behavioral recovery several months following the lesion. The former sustained severe pallidal damage in addition to marked reductions in cortical ChAT activity. Support for the attentional nature of these deficits was obtained by the ability to improve task performance in BF/1 lesioned animals by increasing the duration of the visual stimulus and thus reducing the attentional load placed on these animals. In contrast, performance deficits could be reinstated in those animals showing behavioral recovery (BF/2) by reducing the duration of the visual stimulus and thus increasing attentional load. In the second experiment more discrete lesions of the magnocellular cholinergic neurons were made, resulting in extensive reduction of cortical ChAT activity with considerably less neuronal loss from the dorsal pallidum compared to the BF/1 lesion group. Once again, deficits on the task were substantially greater than observed previously following either quisqualate- or ibotenate-induced BF lesions. Furthermore, the cholinergic specificity of these deficits was supported by the attenuation of behavioral impairments following administration of the anti-cholinesterase physostigmine. Taken together with our earlier work, which has failed to demonstrate mnemonic deficits following lesions to the magnocellular neurons of the nucleus basalis of Meynert, these results suggest that the most consistent deficit produced following lesions of the BF-cortical cholinergic system is attentional dysfunction Analogous deficits in visual attention are also seen in patients with Alzheimer's disease, which can also be improved by anti-cholinesterase treatment.

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

“…Other brain regions that have important significance in correct performance of the 5-CSR task include the anterior cingulate cortex, striatum and the thalamus (Muir et al, 1994;Muir et al, 1996;Rogers et al, 2001;Robbins, 2002;Chudasama et al, 2003) Baviera et al, (2008) used the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP), which was injected directly into the mPFC of male Lister Hooded rats (50 ng/side) trained in the 5-choice task. This experiment demonstrated that selective blockade of NMDA receptors specifically located within the mPFC produced a profound impairment in the rat's ability to perform in the task.…”

Input-specific effects of acetylcholine on sensory and intracortical evoked responses in the “barrel cortex” in vivo

“…Ach is an important neuromodulator in the cerebral cortex. It has been implicated in Many important brain functions, such as arousal (Celesia & Jasper, 1966), attention (Muir et al, 1994; for a review see Saner & Bruno, 2000) and sensory discrimination (Jacobs & Juliano, 1995). It is projected from the nucleus basalis of the basal forebrain (Eckenstein· et al, 1988;Mesulam et al, 1983;Mesulan & Van Hoesen, 1976) and terminates diffusely tbroughout the cerebral cortex.…”

Disruption of Decrements in Conditioned Stimulus Processing by Selective Removal of Hippocampal Cholinergic Input

“…On the basis of the effects of nonselective neurotoxic and electrolytic lesions of basal forebrain nuclei, distinct functions have been proposed for cholinergic projections to the neocortex and hippocampus. The cholinergic neurons that project to neocortex are thought to be involved primarily in the regulation of attentional function (Robbins et al, 1989;Muir et al, 1992Muir et al, , 1994Voytko et al, 1994), whereas cholinergic basal forebrain neurons projecting to the hippocampus are thought to play an important role in learning and memory (Hagan et al, 1988;Kelsey and Landry, 1988;Decker et al, 1992;Kelsey and Vargas, 1993).…”

“…Attentional disruption produced by nonselective neurotoxic basal forebrain lesions (Chiba et al, 1994;Muir et al, 1994;Voytko et al, 1994) also is apparent after selective cholinergic lesions of the basal forebrain (Chiba et al, 1995(Chiba et al, , 1997J. J. Waite, personal communication).…”