Global Ischemia Models Gerbil Carotid Artery Occlusion

The Mongolian gerbil provides, in principle, the technically simplest global ischemia model. Most gerbils lack robust communication between the carotid and vertebral arteries (44,45), and a significant proportion of the animals shows limited anastomoses between anterior cerebral arteries (46,47). This combination of vascular configurations permits production of unilateral forebrain ischemia by occlusion of a single common carotid artery (47-49), albeit at a success rate of only approximately 40%. Efficacy of unilateral occlusion can be predicted at the time of surgery by the reduction of arterial caliber distal to the occlusion site (50,51) or by behavioral observations after recovery from anesthesia in the case of longer occlusions (45). Study of such unilateral ischemia led to an initial description of the more rapid "maturation" of postischemic neuropathology with increasing insult duration (4). However, this model of hemispheric focal ischemia is now rarely applied. Rather, occlusion of both carotid arteries achieves severe bilateral forebrain ischemia in perhaps 90% of animals, and this has evolved into a widely used model of transient global ischemia (6). Conversely, although little studied, the vascular anatomy of the gerbil also permits production of selective hindbrain ischemia by bilateral occlusion of the vertebral arteries (30,31). Early dye perfusion studies sometimes demonstrated residual filling of forebrain vasculature after carotid artery occlusions (52 ), but quantitative cerebral blood flow (CBF) estimates are typically at the lower limit of the methodologies (53,54). Therefore, as is the intended result for most contemporary surgical occlusions in rodents, the gerbil is considered to model "severe incomplete" ischemia.

The carotid arteries of the gerbil are more accessible than those of the rat and the surgery itself can be completed in a matter of minutes, but this procedural simplicity is counterbalanced by several complications. A long recognized but sometimes still ignored feature of the gerbil model is the pronounced hyperthermic response (to 39°C or more) that can emerge in postischemic animals during the initial hours of recovery from anesthesia (55), presumably because of effects on hypothalamic signaling. Although sufficiently long insults can produce robust CA1 neuronal loss in the absence of hyperthermia (56,57), amplification of insult severity is apparent after short occlusions (55,58) . This almost certainly contributes to the striking neuronal injury sometimes reported following very brief (e.g., 3 min) insults under conditions of aggressive, unmonitored postischemic warming (59 ) . This makes the gerbil model particularly sensitive to artifacts that arise from intervention-induced hypothermia, as treated animals maintained at 37°C could still experience significant cooling relative to an untreated ischemic group. Such hyperthermia can be avoided if animals are maintained under anesthesia through approximately 90-min recirculation (58). The additional effort clearly lessens the convenience of the model, but it is a practical necessity if results in the gerbil are to be compared with those obtained in other species. Temperature issues in model control will be considered more generally below.

Successful ischemia in the gerbil model is determined entirely by the vascular anatomy, which varies considerably among animals (52) . Unilateral lesions occur with appreciable frequency (58,60), although such inconsistencies can be identified using electrophysiologic recording approaches (60). Seizure susceptibility has been raised as an issue in this species (61) but is largely a property of specific substrains independent of variations in vascular anatomy that impact ischemia (49). In addition, it has been argued that those seizures observed following forebrain ischemia involve spinal cord, rather than the cortical circuitry implicated in spontaneous seizures (62). A more fundamental disadvantage is that the genomic sequence information and related tools that are increasingly available for mouse and rat remain lacking for the gerbil, which restricts the utility of the model for basic research. Commercially available gerbils are not inbred, although it should be noted that most commonly used rats are also outbred strains. Importantly, with proper temperature control, there appears to be no intrinsic difference in hippocampal CA1 neuronal vulnerability between rats and gerbils (Fig. 2), and the gerbil should therefore continue to be considered a reliable screening tool for intervention studies.

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