Characterization of brain-wide somatosensory BOLD fMRI in mice under dexmedetomidine/isoflurane and ketamine/xylazine

Abstract

Mouse fMRI under anesthesia has become increasingly popular due to improvement in obtaining brain-wide BOLD response. Medetomidine with isoflurane has become well-accepted for resting-state fMRI, but whether this combination allows for stable, expected, and robust brain-wide evoked response in mice has yet to be validated. We thus utilized intravenous infusion of dexmedetomidine with inhaled isoflurane and intravenous infusion of ketamine/xylazine to elucidate whether stable mouse physiology and BOLD response are obtainable in response to simultaneous forepaw and whisker-pad stimulation throughout 8 h. We found both anesthetics result in hypercapnia with depressed heart rate and respiration due to self-breathing, but these values were stable throughout 8 h. Regardless of the mouse condition, brain-wide, robust, and stable BOLD response throughout the somatosensory axis was observed with differences in sensitivity and dynamics. Dexmedetomidine/isoflurane resulted in fast, boxcar-like, BOLD response with consistent hemodynamic shapes throughout the brain. Ketamine/xylazine response showed higher sensitivity, prolonged BOLD response, and evidence for cortical disinhibition as significant bilateral cortical response was observed. In addition, differing hemodynamic shapes were observed between cortical and subcortical areas. Overall, we found both anesthetics are applicable for evoked mouse fMRI studies.

Whole-brain mapping of effective connectivity by fMRI with cortex-wide patterned optogenetics

“…To verify our simulation results with in vivo studies, we performed ofMRI in Thy1-ChR2 mice under light anesthesia with three different irradiance levels on nine different atlas-based cortical regions: unilateral motor (primary, MOp; secondary, MOs) areas, primary somatosensory (barrel field, SSp-bfd; upper and lower limb, SSp-ul/ll) areas, visual (primary, VISp; anterior and rostrolateral, VISa/rl) areas, auditory (AUD) areas, medial (antero- and posteromedial visual, VISam/pm) areas and bilateral retrosplenial areas (dorsal and ventral, RSPd/v) 30 ( Fig. 3f-m ).…”

“…For MRI experimental preparation, mice were initially kept in a chamber with 4% ISO for ~4 min for anesthesia induction. In the case of ketamine/xylazine anesthesia 5 , a ketamine (100 mg/kg) and xylazine (10 mg/kg) mixture was first injected intraperitoneally (IP) and maintained by intravenous (IV) continuous infusion of ketamine (35-45 mg/kg/hr) and xylazine (1.75-2.25 mg/kg/hr) into the tail vein during experiments. For the ISO experimental group, 1% ISO was maintained throughout the preparation and experiment.…”

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“…These results indicate that low-dose anesthesia can be useful to investigate the abnormality of the functional network in resting state, although the limitation of interpretation of fMRI under light anesthesia still exists. Despite common functional connectivity between awaked and lightly anesthetized state ( Grandjean et al, 2020 ; Tsurugizawa and Yoshimaru, 2021 ), fMRI signal changes to the physiological stimuli are significantly disturbed by the anesthetic ( Peeters et al, 2001 ; Tsurugizawa et al, 2010 , 2016 ; Aksenov et al, 2015 ; Tokunaga et al, 2021 ; You et al, 2021 ). As an alternative, awake mouse fMRI is developed using habituation training to reduce stress during MRI experiments ( Tsurugizawa et al, 2013 , 2020 , 2021 ; Bergmann et al, 2016 ; Yoshida et al, 2016 ; Madularu et al, 2017 ; Chen et al, 2020 ; Russo et al, 2021 ).…”

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“…Nevertheless, anesthesia drug- and dose-dependently modulated the neural activity triggering changes in BOLD signal intensity. Many studies suggested the dexmedetomidine plus low-dose isoflurane anesthesia was conducted on the rodent to result in the boxcar-like BOLD response with consistent hemodynamic patterns in the contralateral sensorimotor cortical regions induced by the somatosensory stimulation 51 – 53 . In this study, the mice were anesthetized with 0.03 mg/kg dexmedetomidine hydrochloride subcutaneously after induction with 3% isoflurane (Attane, Minrad Inc., Bethlehem, PA, USA) mixed with 20% O 2 , 75% N 2 , and 5% CO 2 for 5 min for sedation under anesthesia.…”

“…A biphasic electrical current with a pulse width of 0.2 ms was delivered and applied by using an isolated stimulator (S48, Grass Technologies, West Warwick, RI, USA) with an isolated constant-current unit (PSIU6, Grass Technologies, West Warwick, RI, USA). The intensity and frequency of the electrical stimulation were 1 mA and 12 Hz, respectively, as commonly used to evoke the contralateral sensorimotor cortical BOLD activation in dexmedetomidine sedated rodents 53 , 54 .…”