Nucleus incertus promotes cortical desynchronizati

Authors: Sherie Ma Giancarlo Allocca Emma K E OngPålsson Caitlin E Singleton David Hawkes Stuart J McDougall Spencer J Williams Ross A D Bathgate Andrew L Gundlach

Publish Date: 2016/05/20

Volume: 222, Issue: 1, Pages: 515-537

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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 longrange 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—clozapineNoxide CNO activation of virally delivered excitatory hM3DqDREADDs—to activate the NI in rats and examined the behavioral and physiological effects relative to effects in naïve rats and appropriate viraltreated controls hM3Dq activation by CNO resulted in longlasting depolarization of NI neurons with action potentials in vitro Peripheral injection of CNO significantly increased cFos 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 headscanning 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 behaviorsThe authors would like to thank Prof Bryan Roth University of North Carolina NC USA and Dr Melanie White ARMI Monash University VIC Australia for access to the DREADD construct and assistance in establishing the approach in our laboratory respectively and Prof Neil McNaughton University of Otago Dunedin NZ for valuable comments on the manuscript This research was supported by project grants from the National Health and Medical Research Council NHMRC of Australia 1005988 and 1067522 A L G and R A D B a Grant from The Florey Institute of Neuroscience and Mental Health Foundation A L G and S M a Grant from the Besen Family Foundation A L G and by the Victorian Government Operational Infrastructure Support Program S J W is an Australian Research Council ARC Future Fellow R A D B and A L G are NHMRC Australia Senior Research Fellows GA is the recipient of a Commonwealth of Australia International Postgraduate Research Scholarship IPRS and E K E OP is the recipient of a University of Melbourne International Research Scholarship MIFRS/MRS

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