title: Acute modulation of the cholinergic system in the mouse brain detected by pharmacological resting-state functional MRI.
abstract: BACKGROUND
  The cholinergic system is involved in learning and memory and is affected in neurodegenerative disorders such as Alzheimer's disease. The possibility of non-invasively detecting alterations of neurotransmitter systems in the mouse brain would greatly improve early diagnosis and treatment strategies. The hypothesis of this study is that acute modulation of the cholinergic system might be reflected as altered functional connectivity (FC) and can be measured using pharmacological resting-state functional MRI (rsfMRI).
  
  
  METHODS
  Pharmacological rsfMRI was performed on a 9.4T MRI scanner (Bruker BioSpec, Germany) using a gradient echo EPI sequence. All mice were sedated with medetomidine. C57BL/6 mice (N = 15/group) were injected with either saline, the cholinergic antagonist scopolamine, or methyl-scopolamine, after which rsfMRI was acquired. For an additional group (N = 8), rsfMRI scans of the same mouse were acquired first at baseline, then after the administration of scopolamine and finally after the additional injection of the cholinergic agonist milameline. Contextual memory was evaluated with the same setup as the pharmacological rsfMRI using the passive avoidance behavior test.
  
  
  RESULTS
  Scopolamine induced a dose-dependent decrease of FC between brain regions involved in memory. Scopolamine-induced FC deficits could be recovered completely by milameline for FC between the hippocampus-thalamus, cingulate-retrosplenial, and visual-retrosplenial cortex. FC between the cingulate-rhinal, cingulate-visual and visual-rhinal cortex could not be completely recovered by milameline. This is consistent with the behavioral outcome, where milameline only partially recovered scopolamine-induced contextual memory deficits. Methyl-scopolamine administered at the same dose as scopolamine did not affect FC in the brain.
  
  
  CONCLUSIONS
  The results of the current study are important for future studies in mouse models of neurodegenerative disorders, where pharmacological rsfMRI may possibly be used as a non-invasive read-out tool to detect alterations of neurotransmitter systems induced by pathology or treatment.
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: Disha.Shah@uantwerpen.be.
authors.forename: Disha
authors.initials: D
authors.lastname: Shah
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Ines
authors.initials: I
authors.lastname: Blockx
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: Guns
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Lindendreef 1, 2020 Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Debby
authors.initials: D
authors.lastname: Van Dam
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jonckers
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Rafael
authors.initials: R
authors.lastname: Delgado Y Palacios
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Verhoye
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van der Linden
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D012146:Rest; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018680:Cholinergic Antagonists; D000109:Acetylcholine