Abstract
.Significance: Cerebrovascular reactivity (CVR), defined as the ability of the cerebral vasculature to dilate or constrict in response to a vasoactive stimulus, is an important indicator of the brain’s vascular health. However, mechanisms of cerebrovascular dysregulation are poorly understood, and no effective treatment strategies for impaired CVR exist. Preclinical murine models provide an excellent platform for interrogating mechanisms underlying CVR dysregulation and determining novel therapeutics that restore impaired CVR. However, quantification of CVR in mice is challenging.Aim: We present means of assessing CVR in awake mice using intraperitoneal injection of acetazolamide (ACZ) combined with continuous monitoring of cerebral blood flow.Approach: Measurements of cerebral blood flow were made with a minimally invasive diffuse correlation spectroscopy sensor that was secured to an optical window glued to the intact skull. Two source–detector separations (3 and 4.5 mm) per hemisphere were used to probe different depths. CVR was quantified as the relative increase in blood flow due to ACZ. CVR was assessed once daily for 5 days in 5 mice.Results: We found that CVR and the response half-time were remarkably similar across hemispheres and across 3- versus 4.5-mm separations, suggesting a homogenous, whole brain response to ACZ. Mean(std) intra- and intermouse coefficients of variations were 15(9)% and 19(10)%, respectively, for global CVR and 24(15)% and 27(11)%, respectively, for global response half-time.Conclusion: In sum, we report a repeatable method of measuring CVR in free-behaving mice which can be used to screen for impairments with disease and to track changes in CVR with therapeutic interventions.
Highlights
Cerebrovascular reactivity (CVR), defined as the ability of the cerebral vasculature to dilate or constrict in response to a vasoactive stimulus, is an important indicator of the brain’s vascular NeurophotonicsDownloaded From: https://www.spiedigitallibrary.org/journals/Neurophotonics on 01 Mar 2022 Terms of Use: https://www.spiedigitallibrary.org/terms-of-useJan–Mar 2021 Vol 8(1)Brothers et al.: Cerebrovascular reactivity measured in awake mice using diffuse correlation spectroscopy health.[1]
At the 3-mm separation, baseline blood flow index (BFI) on the left hemisphere (BFIleft) trended higher than BFI on the right hemisphere (BFIright, p 1⁄4 0.06), whereas at the 4.5-mm separation, BFIright trended higher than BFIleft (p 1⁄4 0.08)
Intravenous ACZ is commonly used in humans to assess CVR,[54] it is less common in mice due to difficulties with drug administration
Summary
Cerebrovascular reactivity (CVR), defined as the ability of the cerebral vasculature to dilate or constrict in response to a vasoactive stimulus, is an important indicator of the brain’s vascular NeurophotonicsDownloaded From: https://www.spiedigitallibrary.org/journals/Neurophotonics on 01 Mar 2022 Terms of Use: https://www.spiedigitallibrary.org/terms-of-useJan–Mar 2021 Vol 8(1)Brothers et al.: Cerebrovascular reactivity measured in awake mice using diffuse correlation spectroscopy health.[1]. In the case of ACZ, intravenous tail vein injection is possible, longitudinal assessment of CVR with this approach is challenging because repeated tail vein injections without the use of a catheter cause inconsistent drug delivery and increase risk of infection and vein collapse.[26] Alternatively, hypercapnia requires anesthesia for gas delivery in mice, which can induce significant confounding effects on the cerebrovasculature that lead to errors in the estimation of CVR.[27,28,29,30,31,32] monitoring the amount of carbon dioxide that has reached the blood stream to accurately estimate CVR during hypercapnia requires either invasive insertion of an arterial catheter to sample blood or intubation to measure end tidal carbon dioxide concentrations Both interventions to assess CVR (ACZ/hypercapnia) require quantification of cerebral blood flow, which is non-trivial in mice due to their small size. Challenges in both stimulus delivery and monitoring response to the stimulus make CVR measurements in murine models technically challenging, time consuming, and preclude longitudinal assessment
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