Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli.

The effects of the cholinergic immunotoxin 192 IgG-saporin (SAP) (0.0, 0.15, or 0.45 microg/microl; 0.5 microl/hemisphere) infused into the area of the nucleus basalis magnocellularis (NBM) of rats were tested in a five-choice serial reaction time task (5CSRTT) designed to assess visual attention. The effects of this manipulation on acetylcholine efflux in the medial frontal cortex were determined using in vivo microdialysis during the 5CSRTT. Rats with extensive lesions of the NBM (SAP HIGH) showed an array of behavioral deficits in the 5CSRTT hypothesized to represent deficits in central executive function that were associated with severe deficits in accuracy. Lengthening the stimulus duration ameliorated these deficits. Rats with restricted lesions of the NBM (SAP LOW) showed impairments over time on task when tested under standard conditions that were exacerbated by increases in the event rate. The number of choline acetyltransferase-immunoreactive cells in the area of the NBM but not the vertical limb of the diagonal band correlated significantly with accuracy in the task. SAP HIGH rats had significantly lower levels of cortical acetylcholine (ACh) efflux relative to SHAM both before and during the 5CSRTT. SAP LOW rats showed significantly higher levels of cortical ACh efflux before but not during the 5CSRTT. Cortical ACh efflux increased in all rats with the onset of the attentional task. These data provide the first direct evidence for a relationship between selective damage in the basal forebrain with decreased cortical ACh efflux and impaired attentional function.

Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradrenergic systems. This investigation dissociates functions of cortical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional performance. The five-choice serial reaction time task was used to provide a continuous assessment of visuospatial attention. Previous studies using this task have established a critical role for the cortical cholinergic system in the detection of visual targets. However, selective lesions of the locus coeruleus noradrenergic system impair performance only when additional attentional demands are placed on the subject by distractors or temporally unpredictable targets. To test the hypothesis that the cortical noradrenergic system is particularly sensitive to novel task contingencies, we also assessed NA and ACh efflux in rats that been trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished. Cortical ACh efflux showed a robust and task-related increase during established contingent performance. This response was significantly attenuated in noncontingent subjects, although it still exceeded pretask values. In contrast, NA efflux only increased transiently in contingent subjects after task onset but showed sustained elevations in noncontingent subjects on the first day when contingencies were changed. These data also implicate cortical ACh in aspects of attentional functioning but highlight a specific involvement of the cortical noradrenergic system in detecting shifts in the predictive relationship between instrumental action and reinforcement.

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.

Female ovariectomized (OVX) and sham-OVX rats were trained in a task designed to assess sustained attention. After achieving asymptotic performance, OVX rats did not exhibit the impairment in performance over blocks of trials (i.e., the vigilance decrement) observed in sham-OVX rats. Furthermore, OVX rats' performance over blocks of trials was unaffected by the normally detrimental effects of a visual distractor. 192 IgG-saporin-induced lesions of basal forebrain cholinergic neurons resulted in similar impairments in the performance of OVX and sham-OVX rats. The acute, but not chronic, administration of 17beta-estradiol attenuated the lesion-induced decrease in the relative number of hits to longest signals exclusively in rats with intact ovaries. These findings indicate that the variables contributing to the potential therapeutic effects of estradiol remain poorly understood.

RATIONALE: Loss of telencephalic cholinergic projections has been postulated to contribute significantly to the cognitive decline associated with aging and dementia. OBJECTIVE: The effects of the nicotinic acetylcholine receptor agonist ABT-418, a potential therapeutic drug for the treatment of the age- and dementia-associated cognitive disorders, were tested in an animal model of the cortical cholinergic deafferentation-induced impairments in sustained attention. METHODS: Animals were trained in an operant task designed to test sustained attention performance. A partial loss of cortical cholinergic inputs was produced by infusions of 192 IgG-saporin into the basal forebrain. The effects of the systemic administration of ABT-418 (0.04, 0.13, 0.39 mg/kg) and the psychostimulant methylphenidate (0.2, 0.4, 0.8 mg/kg) were assessed. RESULTS: Compared with sham-lesioned animals, this lesion resulted in a decrease in the relative number of hits while the relative number of correct rejections remained unaffected. Administration of ABT-418 significantly improved the relative number of hits. Furthermore, this effect of ABT-418 interacted with the effects of the lesion. Unexpectedly, this interaction was based on a significant enhancement of the performance of sham-lesioned animals while no effects were found in 192 IgG-saporin-lesioned animals. Administration of methylphenidate did not affect performance. CONCLUSIONS: While these data do not support the hypothesis that administration of ABT-418 attenuates the impairments in attentional performance that result from loss of cortical cholinergic inputs, they support previous notions about this drug's ability to enhance cognitive processes in intact subjects.

Rats with extensive lesions of cortical cholinergic afferents as a result of infusions of 192 IgG-saporin into the basal forebrain show persistent impairments in sustained attention performance (J. McGaughy, T. Kaiser, & M. Sarter, 1996). However, the administration of neither the cholinesterase inhibitor physostigmine nor the benzodiazepine receptor partial inverse agonist FG 7142 attenuated the lesion-induced impairments in performance. The present study demonstrated that less extensive cortical cholinergic deafferentation, produced by intracortical infusions of a relatively small concentration of 192 IgG-saporin, resulted in a significant impairment in sustained attention. However, the administration of neither physostigmine (0.01-0.1 mg/kg) nor FG 7142 (0.1-1.0 mg/kg) benefited the performance of the animals. Because neither compound selectively augments performance-associated increases in acetylcholine release from residual neurons, beneficial effects on cortical cholinergic deafferentation-based impairments in attention may remain limited.

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.

Rats were trained in a previously validated behavioral vigilance task that required them to detect visual signals of variable length and to discriminate signal from nonsignal events. Baseline performance was characterized by a signal length-dependent ability to score hits, a decline in hits over time, and a correct rejection rate of approximately 70%. After the rats reached criterion performance in this task, the immunotoxin 192 IgG-saporin or its vehicle was infused into the area of the nucleus basalis/substantia innominata of the basal forebrain. Postoperative performance in lesioned rats was characterized by a decrease in their ability to detect signals while their ability to correctly reject nonsignals remained unaffected. The effect of the lesion did not recover in the course of over 180 sessions of postlesion testing. The overall performance of the rats correlated with acetylcholinesterase (AChE)-positive fiber density in all cortical areas measured except the cingulate and pyriform cortex. These findings help to elucidate the nature of the attentional impairments resulting from the loss of cortical cholinergic inputs.

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simultaneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.

An operant task for the measurement of sustained attention or vigilance in rats was characterized. The task requires the animals to respond to the presentation of visual signals (presented for 25, 50, or 500 ms) by operating one lever ("hits") and to the absence of a signal by operating the opposite lever ("correct rejection"). Incorrect responses ("misses" and "false alarms", respectively) were not rewarded. Performance in this task is a function of signal length, i.e., the shorter the signals the higher the number of misses. An increase in "background noise" by flashing the chamber houselight (at 0.5 Hz) impaired the animals' ability to discriminate between signal and non-signal events. Also flashing the houselight augmented the vigilance decrement observed for shortest signals. An increase in the event-rate also resulted in a vigilance decrement. Finally, the inability of the animals to time signals was examined by testing the effects of an increase in event asynchrony. In a second experiment, the performance of differently aged rats (6- and 20 month-old male BNNia/F344 rats) was studied. Compared to young animals, 20-month-old rats showed a decrease in their ability to discriminate between shortest signals (25 ms) and non-signal events but did not differ in their ability to correctly reject non-signal trials. Administration of the benzodiazepine receptor (BZR) agonist chlordiazepoxide (CDP; 3, 5, 8 mg/kg) resulted in an impairment of the animals' ability to discriminate between signal and non-signal events and, similar to the effects of age, this effect was exclusively due to an increase in the number of misses. CDP generally produced potent effects while affecting the aged animals to a greater degree. BZR-ligands with weak or "selective" inverse agonist properties (ZK 93426; beta-CCtB) did not affect vigilance performance. The BZR partial inverse agonist RU 33965 (0.1, 0.5 mg/kg) dose-dependently impaired vigilance performance. The administration of amphetamine (0.4, 0.8 mg/kg) also impaired performance, but these impairments were possibly based on effects unrelated to attentional mechanisms. The finding that performance in this task revealed the interactions between the effects of age and BZR agonists on attentional abilities further supports the validity of measures of performance generated by this task.

Our previous studies revealed impairments in the ability of aged rats to detect brief, rarely and unpredictably occurring stimuli. The failure of these impairments to interact with the effects of benzodiazepine receptor (BZR) ligands was attributed to low demands on stimulus-related information processing. Thus, in the present experiment, rats of different ages were trained to detect visual stimuli that were flashing at 20 Hz, or were constantly illuminated, for 8, 3, or 5 sec. Additionally, selection of the correct lever to report detection required the processing of propositional rules (e.g., flashing-go left; constant-go right), i.e., the identification of the stimulus. All measures of performance varied with stimulus duration. Subsedative doses of the BZR agonist chlordiazepoxide (CDP; 3.13, 4.69 mg/kg), similar to the effects of the muscarinic antagonist scopolamine (.025, 0.1 mg/kg), impaired response accuracy, increased the number of errors of omission and decreased response latencies. Animals aged 28 months omitted more trials following the administration of CDP than 12-month-old rats. Age did not produce main effects and did not interact with the effects of the drugs on response accuracy. It is speculated that, as stimuli had to be presented for relatively long periods of time (to maintain above chance-level discrimination performance), demands on detection remained too low to replicate previously documented effects of age. The demonstration of interactions between the effects of age and of BZR-ligands appears to depend on combined demands for stimulus detection and identification.

"Divided attention" is a psychological construct that hinges on assumptions about a fixed finite capacity of subjects to simultaneously process multiple sets of information. A model of a crossmodal divided attention task was developed in rats. Initially, rats were trained consecutively in operant auditory and visual conditional discrimination tasks. The final task consisted of two successive blocks of 20 trials per modality (modality certainty), followed by 60 trials comprising a semi-randomized sequence of stimuli of both modalities (auditory or visual) and qualities (flashing/pulsing or constantly turned on; modality uncertainty). In comparison to unimodal blocks of trials, performance in the mixed condition was assumed to reflect the demands on the parallel processing of two sets of stimulus-response rules. While response accuracy remained unchanged, response latencies were generally longer in the bimodal condition. Administration of scopolamine (0.03, 0.06, 0.1 mg/kg) or chlordiazepoxide (1, 3, 5, 8 mg/kg) dose-dependently increased response latencies. The scopolamine-induced increase in response latencies was greater in the mixed condition. Cost-benefit analyses demonstrated that the absolute divided attention costs (in ms) were generally higher for visual than for auditory stimuli. Both drugs produced qualitatively similar effects; however, scopolamine was more potent in increasing the absolute divided attention costs than chlordiazepoxide. These data are discussed in terms of the validity of this animal paradigm, and of hypotheses about the effects of benzodiazepine receptor agonists and muscarinic antagonists on brain information processing capacity.