Mouse Models

The technical challenges of surgery and physiologic monitoring and control in mice have limited global ischemia studies in this species, but mouse equivalents of the common rodent models have been described. Complete global ischemia can be produced by cardiac arrest, but, in normothermic animals, it fails to result in hippocampal damage (99) or produces only slight injury (100) after insult durations compatible with long-term survival. Another study noted more than 50% CA1 injury after cardiac arrest in Balb/c mice, but comparable loss of the usually resistant DG cells was also reported (101). Very recent work combined body cooling with normothermic or even hyperthermic head temperature during cardiac arrest in an attempt to increase brain injury, while avoiding systemic complications (102,103), but only partial CA1 loss could be achieved.

Bilateral carotid artery occlusion results in strikingly strain-dependent effects (104-108), with greater susceptibility of C57BL/6 and BALB/c strains that, like the gerbil, show frequent insufficiency in communication between carotid and posterior circulations. However, long insults are required to observe neuronal injury in these mouse models, and increasing insult duration produces surprisingly little impact on the extent of hippocampal damage, even with progressive injury to striatum and cortex (106,109), which may be suggestive of incomplete ischemia and/or significant postischemic brain cooling, as will be considered in detail below. Robust CA1 damage has been reported for individual C57BL/6 mice subjected to relatively long (15 min) occlusions that resulted in documented severe perfusion deficits under conditions of maintained head temperature (107). Generally comparable results have been obtained in ventilated animals of the same strain (110,111). An inverse correlation was also noted between histopathologic damage and the extent of posterior communicating artery development for individual hemispheres in CD-1 mice (112 ).

A model of 2-VO with hypotension has also been established in mice (113,114). Histopathol-ogy was strain dependent, with significant damage in C57Bl/6, but not in SV129 mice, despite severe and equivalent CBF reduction demonstrated autoradiographically (114). Surprisingly, the efficacy of carotid artery occlusion alone was identical in the 2 strains, and it was suggested that a smaller caliber basilar artery could have restricted perfusion in the SV129 strain.

The functional equivalent of the rat 4-VO model is a 3-VO method, combining bilateral carotid artery occlusion with targeting of the basilar artery to disrupt the posterior circulation (115,116). An initial study noted striking vulnerability of hippocampal CA1 neurons, essentially equivalent to that occurring in rat and gerbil models, with no difference between C57Bl/6 and SV129 strains (115). More recent results indicate a requirement for longer insult durations and evident strain differences (116), remarkably consistent with reported 2-VO results in mice. Figure 2 shows the comparison of insult thresholds for CA1 damage identified in representative mouse studies with those of rat and gerbil.

Significant inconsistencies in outcome remain among mouse global ischemia models, as well as notable differences in histopathology in comparison with rat and gerbil. For example, in contrast to most other models, cardiac arrest with head hyperthermia results in somewhat more severe damage in SV129 than in C57Bl/6 mice (102). These strains differ in pial vasomotor responses (117), which could conceivably influence brain heat exchange. The greater vulnerability of striatum relative to hippocampus, a frequent finding in mice (102,106,109), precludes straightforward comparison with other rodent models. Mortality is high in many studies, and histology is often assessed at survival times of only a few days. Whether this relative lack of CA1 vulnerability reflects a fundamental biologic difference or a modeling issue (e.g., temperature control or survival time) remains to be determined, but the latter remains likely.

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