Abstract
Functional magnetic resonance imaging (fMRI) has revolutionized neuroscience by opening a unique window that allows neurocircuitry function and pathological alterations to be probed non-invasively across brain disorders. Here we report a novel sustainable anesthesia procedure for small animal neuroimaging that overcomes shortcomings of anesthetics commonly used in rodent fMRI. The significantly improved preservation of cerebrovascular dynamics enhances sensitivity to neural activity changes for which it serves as a proxy in fMRI readouts. Excellent cross-species/strain applicability provides coherence among preclinical findings and is expected to improve translation to clinical fMRI investigations. The novel anesthesia procedure based on the GABAergic anesthetic etomidate was extensively validated in fMRI studies conducted in a range of genetically engineered rodent models of autism and strains commonly used for transgenic manipulations. Etomidate proved effective, yielded long-term stable physiology with basal cerebral blood flow of ~0.5 ml/g/min and full recovery. Cerebrovascular responsiveness of up to 180% was maintained as demonstrated with perfusion- and BOLD-based fMRI upon hypercapnic, pharmacological and sensory stimulation. Hence, etomidate lends itself as an anesthetic-of-choice for translational neuroimaging studies across rodent models of brain disorders.
Highlights
To date, α -chloralose, isoflurane and medetomidine are widely used anesthetics for Functional magnetic resonance imaging (fMRI) studies in rats and mice[3,7]
We report on studies in which we used continuous arterial spin labelling (CASL)-based fMRI to quantitatively assess and benchmark local brain perfusion, cerebrovascular reserve capacity (CVRC) and functional responses to pharmacological intervention in freely breathing mice and rats anesthetized with either isoflurane, medetomidine or according to our newly introduced protocol based on etomidate
We show that etomidate-based anesthesia overcomes the shortcomings of anesthetics commonly used in rodent fMRI related to compromised hemodynamic responses and limited cross-species/strain applicability, and we report findings in six different mouse models of autism spectrum disorder
Summary
Α -chloralose, isoflurane and medetomidine are widely used anesthetics for fMRI studies in rats and mice[3,7]. The volatile anesthetic isoflurane excels with ease of use and rapid reversibility of its anesthetic effect but causes neural, cardiovascular and respiratory depression[9,10,11,12] It raises basal cerebral blood flow (CBF) in a dose-dependent manner[11] that potentially limits neurovascular reactivity and would leave only a narrow window for hemodynamic imaging readouts. Basal CBF values ascertained by different modalities were found to be substantially lower compared to isoflurane and cerebrovascular autoregulation was preserved[22,23] This pharmacological profile putatively renders etomidate suitable for fMRI studies in small rodents. Etomidate anesthesia provides long-term stable physiological conditions and full recovery, lending itself as an anesthesia-of-choice for comparative and repeated fMRI-based endophenotyping and imaging genetics studies across rodent models
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