title: Reassessment of the structural basis of the ascending arousal system.
abstract: The "ascending reticular activating system" theory proposed that neurons in the upper brainstem reticular formation projected to forebrain targets that promoted wakefulness. More recent formulations have emphasized that most neurons at the pontomesencephalic junction that participate in these pathways are actually in monoaminergic and cholinergic cell groups. However, cell-specific lesions of these cell groups have never been able to reproduce the deep coma seen after acute paramedian midbrain lesions that transect ascending axons at the caudal midbrain level. To determine whether the cortical afferents from the thalamus or the basal forebrain were more important in maintaining arousal, we first placed large cell-body-specific lesions in these targets. Surprisingly, extensive thalamic lesions had little effect on electroencephalographic (EEG) or behavioral measures of wakefulness or on c-Fos expression by cortical neurons during wakefulness. In contrast, animals with large basal forebrain lesions were behaviorally unresponsive and had a monotonous sub-1-Hz EEG, and little cortical c-Fos expression during continuous gentle handling. We then retrogradely labeled inputs to the basal forebrain from the upper brainstem, and found a substantial input from glutamatergic neurons in the parabrachial nucleus and adjacent precoeruleus area. Cell-specific lesions of the parabrachial-precoeruleus complex produced behavioral unresponsiveness, a monotonous sub-1-Hz cortical EEG, and loss of cortical c-Fos expression during gentle handling. These experiments indicate that in rats the reticulo-thalamo-cortical pathway may play a very limited role in behavioral or electrocortical arousal, whereas the projection from the parabrachial nucleus and precoeruleus region, relayed by the basal forebrain to the cerebral cortex, may be critical for this process.
authors.affiliation: Division of Sleep Medicine, Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. pfuller@bidmc.harvard.edu
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fuller
authors.forename: Patrick
authors.initials: P
authors.lastname: Fuller
authors.forename: David
authors.initials: D
authors.lastname: Sherman
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Pedersen
authors.forename: Clifford B
authors.initials: CB
authors.lastname: Saper
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D001143:Arousal / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology; D004569:Electroencephalography; D004576:Electromyography; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006801:Humans; D007051:Ibotenic Acid / Q000494:pharmacology; D008297:Male; D009434:Neural Pathways / Q000033:anatomy & histology* / Q000473:pathology / Q000502:physiology; D016548:Prosencephalon / Q000033:anatomy & histology* / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000502:physiology; D013788:Thalamus / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology
chemical_list: D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; C493475:Slc17a6 protein, rat; D050599:Vesicular Glutamate Transport Protein 2; D007051:Ibotenic Acid