Abstract
Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.
Highlights
Recent technical and procedural developments in mouse functional magnetic resonance imaging (fMRI) with subcutaneous electrostimulation have achieved blood oxygenation level-dependent (BOLD) sensitivities comparable to human fMRI8–11
We provide a detailed comparison of the thermal condition of anesthetized mice in two experimental Magnetic resonance imaging (MRI) setups: i) a common animal cradle customized for a conventional mouse head RF coil array (CONV), and ii) a cradle tailored for a state-of-the-art high sensitivity mouse head RF coil (CryoProbe, CRYO) (Fig. 1a)
To achieve a uniform normothermic body temperature distribution for anesthetized mice placed in the MR bore, we developed a novel setup that provides convective, non-contact body warming: a mouse bed customized for the geometry of the CryoProbe setup, which we call the ROdent Convective Keg-shaped Environment for Thermostimulation (ROCKET) (Fig. 1b; Online Methods)
Summary
Recent technical and procedural developments in mouse fMRI with subcutaneous electrostimulation have achieved BOLD sensitivities comparable to human fMRI8–11. Pioneering studies have demonstrated the proof-of-principle for mouse fMRI with nociceptive heat stimuli[12,13,14]. In these studies, the BOLD sensitivity was an order of magnitude below that reported for electrostimulation, www.nature.com/scientificreports/. Our method includes (i) a mouse cradle that generates uniform and physiological body temperatures in anesthetized mice, (ii) an MRI-compatible stimulation device permitting controlled thermal stimulation, (iii) the application of a high sensitivity radio-frequency (RF) probe[8], and (iv) data processing tools to enhance the detection of the BOLD signal. The precise influence of MABP on the BOLD signal remains to be determined
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