title: Nucleus incertus promotes cortical desynchronization and behavioral arousal.
abstract: Arousal and vigilance are essential for survival and relevant regulatory neural circuits lie within the brainstem, hypothalamus and forebrain. The nucleus incertus (NI) is a distinct site within the pontine periventricular gray, containing a substantial population of GABAergic neurons with long-range, ascending projections. Existing neuroanatomical data and functional studies in anesthetized rats, suggest the NI is a central component of a midline behavioral control network well positioned to modulate arousal, vigilance and exploratory navigation, yet none of these roles have been established experimentally. We used a chemogenetic approach-clozapine-N-oxide (CNO) activation of virally delivered excitatory hM3Dq-DREADDs-to activate the NI in rats and examined the behavioral and physiological effects, relative to effects in naïve rats and appropriate viral-treated controls. hM3Dq activation by CNO resulted in long-lasting depolarization of NI neurons with action potentials, in vitro. Peripheral injection of CNO significantly increased c-Fos immunoreactivity in the NI and promoted cortical electroencephalograph (EEG) desynchronization. These brain changes were associated with heightened arousal, and increased locomotor activity in the homecage and in a novel environment. Furthermore, NI activation altered responses in a fear conditioning paradigm, reflected by increased head-scanning, vigilant behaviors during conditioned fear recall. These findings provide direct evidence that the NI promotes general arousal via a broad behavioral activation circuit and support early hypotheses, based on its connectivity, that the NI is a modulator of cognition and attention, and emotional and motivated behaviors.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia. sherie.ma@florey.edu.au.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. sherie.ma@florey.edu.au.
authors.forename: Sherie
authors.initials: S
authors.lastname: Ma
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Allocca
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Emma K E
authors.initials: EK
authors.lastname: Ong-Pålsson
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Singleton
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Hawkes
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: McDougall
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.|Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia. andrew.gundlach@florey.edu.au.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. andrew.gundlach@florey.edu.au.|Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia. andrew.gundlach@florey.edu.au.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gundlach
mesh_terms: D000818:Animals; D001143:Arousal; D001362:Avoidance Learning; D001522:Behavior, Animal / Q000502:physiology*; D058256:Brain Waves; D003214:Conditioning, Classical / Q000502:physiology; D003344:Cortical Synchronization; D004569:Electroencephalography; D005239:Fear / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism; D008297:Male; D009043:Motor Activity; D011903:Raphe Nuclei / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
keywords: Arousal; Cortical desynchronization; Locomotion; Nucleus incertus; Vigilance