Cholinergic optimization of cue-evoked parietal activity during challenged attentional performance.

The detection of salient or instrumental stimuli and the selection of cue-evoked responses are mediated by a fronto-parietal network that is modulated by cholinergic inputs originating from the basal forebrain. Visual cues that guide behavior are more strongly represented in the posterior parietal cortex (PPC) than are similar cues that are missed or task-irrelevant. Although the crucial role of cholinergic inputs in cue detection has been demonstrated by lesion studies, the role of PPC neurons in the cholinergic modulation of cue detection is unclear. We recorded extracellular spikes from PPC neurons of rats performing a sustained attention task, before and after selective removal of cholinergic inputs to the recording site. Visual cues that were subsequently detected evoked significant increases in the PPC firing rate. In the absence of cholinergic input, the activation of PPC neurons by detected cues was greatly diminished. When a visual distractor was introduced during task performance, a population of PPC neurons selectively responded to the distractor. As a result of cholinergic deafferentation, distractor-related neuronal activity was enhanced, and the detection-related activity was further suppressed. Thus, in deafferented subjects, the distractor lowered the signal-to-noise ratio of cue-evoked responses. This impairment in cue-evoked neuronal activity may have mediated the increased response latencies observed for detected cues in the presence of the distractor. Additional experiments demonstrated that the effects of cholinergic deafferentation were not confounded by extended practice or electrode depth. Collectively, these findings indicate that cholinergic inputs to PPC neurons amplify cue detection, and may also act to suppress irrelevant distractors.

Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection.

Neurophysiological studies demonstrated that increases in cholinergic transmission in sensory areas enhance the cortical processing of thalamic inputs. Cholinergic activity also suppresses the retrieval of internal associations, thereby further promoting sensory input processing. Behavioral studies documented the role of cortical cholinergic inputs in attentional functions and capacities by demonstrating, for example, that the integrity of the cortical cholinergic input system is necessary for attentional performance, and that the activity of cortical cholinergic inputs is selectively enhanced during attentional performance. This review aims at integrating the neurophysiological and behavioral evidence on the functions of cortical cholinergic inputs and hypothesizes that the cortical cholinergic input system generally acts to optimize the processing of signals in attention-demanding contexts. Such signals 'recruit', via activation of basal forebrain corticopetal cholinergic projections, the cortical attention systems and thereby amplify the processing of attention-demanding signals (termed 'signal-driven cholinergic modulation of detection'). The activity of corticopetal cholinergic projections is also modulated by direct prefrontal projections to the basal forebrain and, indirectly, to cholinergic terminals elsewhere in the cortex; thus, cortical cholinergic inputs are also involved in the mediation of top-down effects, such as the knowledge-based augmentation of detection (see Footnote 1) of signals and the filtering of irrelevant information (termed 'cognitive cholinergic modulation of detection'). Thus, depending on the quality of signals and task characteristics, cortical cholinergic activity reflects the combined effects of signal-driven and cognitive modulation of detection. This hypothesis begins to explain signal intensity or duration-dependent performance in attention tasks, the distinct effects of cortex-wide versus prefrontal cholinergic deafferentation on attention performance, and it generates specific predictions concerning cortical acetylcholine (ACh) release in attention task-performing animals. Finally, the consequences of abnormalities in the regulation of cortical cholinergic inputs for the manifestation of the symptoms of major neuropsychiatric disorders are conceptualized in terms of dysregulation in the signal-driven and cognitive cholinergic modulation of detection processes.

Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory?

The hypothesis that cortical cholinergic inputs mediate attentional functions and capacities has been extensively substantiated by experiments assessing the attentional effects of specific cholinotoxic lesions of cortical cholinergic inputs, attentional performance-associated cortical acetylcholine release, and the effects of pharmacological manipulations of the excitability of basal forebrain corticopetal cholinergic projections on attentional performance. At the same time, numerous animal experiments have suggested that the integrity of cortical cholinergic inputs is not necessary for learning and memory, and a dissociation between the role of the cortical cholinergic input system in attentional functions and in learning and memory has been proposed. We speculate that this dissociation is due, at least in part, to the use of standard animal behavioral tests for the assessment of learning and memory which do not sufficiently tax defined attentional functions. Attentional processes and the allocation of attentional capacities would be expected to influence the efficacy of the acquisition and recall of declarative information and therefore, persistent abnormalities in the regulation of the cortical cholinergic input system may yield escalating impairments in learning and memory. Furthermore, the cognitive effects of loss of cortical cholinergic inputs are augmented by the disruption of the top-down regulation of attentional functions that normally acts to optimize information processing in posterior cortical areas. Because cortical cholinergic inputs play an integral role in the mediation of attentional processing, the activity of cortical cholinergic inputs is hypothesized to also determine the efficacy of learning and memory.