Bidirectional modulation of basal forebrain N-methyl-d-aspartate receptor function differentially affects visual attention but not visual discrimination performance

Basal forebrain neuronal circuits, specifically the corticopetal cholinergic system, mediate attentional abilities. The effects of infusions of N-methyl-D-aspartate (NMDA) and the competitive NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) into the basal forebrain were assessed in rats trained in an operant task designed to generate measures of sustained attention performance. Control animals were trained in a cued visual discrimination task devoid of explicit demands on attentional performance, but involving similar basic operant components as the sustained attention task. The effects of intrabasalis infusions of NMDA (1, 3 and 6nmol) and APV (3, 10 and 20nmol) were tested in separate groups of animals. Infusion of neither drug affected the animals' response accuracy in the cued visual discrimination task, indicating that performance in this task remains insufficient to activate basal forebrain NMDA receptors. Infusions of APV in sustained attention task-performing animals selectively decreased the animals' ability to detect visual signals, but spared their ability to reject non-signal events. Conversely, infusions of NMDA into the basal forebrain did not affect the animals' hit rate but increased their number of false alarms, i.e. "claims" for signals in non-signal trials. The concentrations of NMDA infused into the basal forebrain did not result in neurotoxic effects as demonstrated by a separate experiment, which indicated neurodegeneration following the infusion of 30 nmol NMDA as visualized by the Fluoro-Jade method.The effects of APV correspond with the attentional consequences of other manipulations known to impair the functions of cortical cholinergic input. Conversely, the effects of NMDA infusions agree with the hypothesis that overactivity of cortical cholinergic inputs mediates an abnormal overprocessing of the stimulus situation. Basal forebrain NMDA receptor manipulations assist in determining the role of this neuronal system in cognitive processes.

[1]  D. Rasmusson.  The role of acetylcholine in cortical synaptic plasticity , 2000, Behavioural Brain Research.

[2]  Peter W. Frey,et al.  Sensitivity and responsivity measures for discrimination learning , 1973 .

[3]  William Slikker,et al.  Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration , 1997, Brain Research.

[4]  J. Thayer,et al.  The continuing problem of false positives in repeated measures ANOVA in psychophysiology: a multivariate solution. , 1987, Psychophysiology.

[5]  R. Beninger,et al.  Excitotoxic lesions of rat basal forebrain: Differential effects on choline acetyltransferase in the cortex and amygdala , 1992, Neuroscience.

[6]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[7]  M. Sarter,et al.  Effects of repeated administration of amphetamine on behavioral vigilance: evidence for “sensitized” attentional impairments , 1998, Psychopharmacology.

[8]  Failure of a chlordiazepoxide to reproduce the behavioral effects of muscimol administered into the basal forebrain , 1992, Behavioural Brain Research.

[9]  M. Sarter,et al.  Operant performance and cortical acetylcholine release: role of response rate, reward density, and non-contingent stimuli. , 1997, Brain research. Cognitive brain research.

[10]  M. Sarter,et al.  Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release , 2000, Psychopharmacology.

[11]  M. Sarter,et al.  Bidirectional modulation of cortical acetylcholine efflux by infusion of benzodiazepine receptor ligands into the basal forebrain , 1995, Neuroscience Letters.

[12]  T. Robbins,et al.  Central cholinergic systems and cognition. , 1997, Annual review of psychology.

[13]  L. Schmued,et al.  Characterizing cortical neuron injury with fluoro‐jade labeling after a neurotoxic regimen of methamphetamine , 1998, Synapse.

[14]  M. Sarter,et al.  Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats , 1999, Psychopharmacology.

[15]  John H. Martin.  Autoradiographic estimation of the extent of reversible inactivation produced by microinjection of lidocaine and muscimol in the rat , 1991, Neuroscience Letters.

[16]  M. Sarter,et al.  Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density. , 1996, Behavioral neuroscience.

[17]  L. Schmued,et al.  Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain , 2000, Brain Research.

[18]  L. Hersh,et al.  Prefrontal cortical projections to the cholinergic neurons in the basal forebrain , 1991, The Journal of comparative neurology.

[19]  M. Sarter,et al.  Cortical acetylcholine and processing capacity: effects of cortical cholinergic deafferentation on crossmodal divided attention in rats. , 1997, Brain research. Cognitive brain research.

[20]  M. Sarter,et al.  Basal forebrain glutamatergic modulation of cortical acetylcholine release , 2001, Synapse.

[21]  J. Price,et al.  Sources of presumptive glutamatergic/aspartatergic afferents to the magnocellular basal forebrain in the rat , 1990, The Journal of comparative neurology.

[22]  D. Rasmusson,et al.  Modification of neocortical acetylcholine release and electroencephalogram desynchronization due to brainstem stimulation by drugs applied to the basal forebrain , 1994, Neuroscience.

[23]  K. Berridge,et al.  Opioid site in nucleus accumbens shell mediates eating and hedonic ‘liking’ for food: map based on microinjection Fos plumes , 2000, Brain Research.

[24]  M. Fanselow,et al.  N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats , 1996 .

[25]  N. Weinberger.  Dynamic regulation of receptive fields and maps in the adult sensory cortex. , 1995, Annual Review of Neuroscience.

[26]  M. Sarter,et al.  Cognitive functions of cortical acetylcholine: toward a unifying hypothesis , 1997, Brain Research Reviews.

[27]  D. Rasmusson,et al.  Differential effects of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-d-aspartate receptor antagonists applied to the basal forebrain on cortical acetylcholine release and electroencephalogram desynchronization , 1996, Neuroscience.

[28]  M. Sarter,et al.  Cognitive functions of cortical ACh: lessons from studies on trans-synaptic modulation of activated efflux , 1994, Trends in Neurosciences.

[29]  R. Beninger,et al.  Nucleus basalis injections of N-methyl-D-aspartate enhance memory of rats in the double Y-maze , 1999, Brain Research Bulletin.

[30]  M. Sarter,et al.  Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders , 1999, Trends in Neurosciences.

[31]  M. Sarter,et al.  The cognitive neuroscience of sustained attention: where top-down meets bottom-up , 2001, Brain Research Reviews.

[32]  I. Eyüpoglu,et al.  Entorhinal cortex lesion studied with the novel dye Fluoro-Jade , 2000, Brain Research.

[33]  M. Sarter,et al.  Increases in cortical acetylcholine release during sustained attention performance in rats. , 2000, Brain research. Cognitive brain research.

[34]  T. Robbins,et al.  Comparative effects of quisqualic and ibotenic acid-induced lesions of the substantia innominata and globus pallidus on the acquisition of a conditional visual discrimination: Differential effects on cholinergic mechanisms , 1989, Neuroscience.

[35]  R. Gaykema,et al.  Cortical input to the basal forebrain , 1997, Neuroscience.

[36]  ML Voytko,et al.  Basal forebrain lesions in monkeys disrupt attention but not learning and memory [published erratum appears in J Neurosci 1995 Mar;15(3): following table of contents] , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[37]  M. Sarter,et al.  Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents , 1999, Neuroscience.

[38]  A. Routtenberg.  Intracranial chemical injection and behavior: a critical review. , 1972, Behavioral biology.

[39]  R. Beninger,et al.  Differential action of NMDA antagonists on cholinergic neurotoxicity produced by N‐methyl‐D‐aspartate and quinolinic acid , 1996, British journal of pharmacology.

[40]  M. Sarter,et al.  Effects of intra-accumbens infusions of amphetamine or cis-flupenthixol on sustained attention performance in rats , 2000, Behavioural Brain Research.

[41]  R. Beninger,et al.  N-Methyl-d-asparate unilaterally injected into the dorsal striatum of rats produces contralateral circling: antagonism by 2-amino-7-phosphonoheptanoic acid and cis-flupenthixol , 1992, Brain Research.

[42]  B. Everitt,et al.  AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[43]  M. Sarter,et al.  Sustained Visual Attention Performance-Associated Prefrontal Neuronal Activity: Evidence for Cholinergic Modulation , 2000, The Journal of Neuroscience.