Use of Mice in Studies of Brain Microcirculation

To the Editor:

The report by Dalkara et al. (1995) in the November issue of Journal of Cerebral Blood Flow and Metabolism is of great interest. The current interest in transgenic mice and the potential for their use in studies of cerebral circulation/stroke led Dalkara et al. to develop a mouse model in which expired CO₂ is continuously monitored in paralyzed, artificially respired mice, thus permitting constant monitoring and control of intraarterial CO₂ and pH. The article implies that prior lack of this control capacity has led to neglect of the mouse as an experimental subject for cerebrovascular research. This may be so, but it need not have been so. As Dalkara et al. point out, I began studies of mouse pial microcirculation in 1963 (Rosenblum and Zweifach, 1963). This has been followed by ∼150 papers over a 32-year period of research in my laboratory. We generally used spontaneously respiring mice. By concentrating on studies involving topically applied agents rather than using drugs or routes of administration that might change systemic conditions, by vigorously controlling local pH, and by reporting only consistently reproducible results, we have established a body of murine data that should stand the test of time. Indeed, the qualitative similarity between our data and those gathered from other species both in vivo and in vitro is readily apparent in a recent comprehensive review (Edvinsson et al., 1993). This similarity has been apparent for 30 years, and for that reason we have consistently advocated the use of mice in cerebrovascular studies.

In addition, there is qualitative agreement between our data and the limited data from paralyzed, respired mice reported thus far by Dalkara et al. We also showed the expected increase of regional CBF with increasing inspiratory CO₂ (Rosenblum, 1977). Much more recent, unpublished data from our laboratory, using the same laser-Doppler flowmetry as Dalkara et al., again showed the effects of increasing CO₂ with a CO₂ reactivity of 2.7, slightly higher than the value of 2 they report. We observed rather large differences between the responses of different mice to CO₂. This is not emphasized in the report of Dalkara et al., but is readily apparent in a comparison of Figs. 3 and 4 from their paper, presumably illustrating responses in two different mice.

There is, in the excellent article of Dalkara et al., an implication, perhaps unintended, that only the recent availability of equipment for continuously monitoring CO₂, permits the gathering of valid data from mice. This in turn implies that all prior studies will have to be repeated to establish baselines for use of genetically manipulated mice. The similarities, remarked upon herein, between our data gathered over a 30-year period and those gathered in many species by others indicate that this is not correct. It is my hope that needless repetition of prior studies is not a result, perhaps unintended, of the report by Dalkara et al.