Hibernation in Ground Squirrels Induces State and Species-Specific Tolerance to Hypoxia and Aglycemia: An In Vitro Study in Hippocampal Slices

Hibernation in mammals is associated with a regulated depression of global cellular functions accompanied by reductions of cerebral blood flow that would render the brain profoundly ischemic under normal conditions. Homeostatic control is preserved, however, and brain damage does not occur. We investigated the possibility that hibernation not only confers tolerance to profound hypothermia, but also to hypoxia and aglycemia independent of temperature. Hippocampal slices from ground squirrels Citellus tridecemlineatus in both the active and hibernating states and from rats were subjected to in vitro hypoxia and aglycemia at incubation temperatures of 36°C, 20°C, and 7°C and evaluated histologically. A binary bioassay was used to determine the duration of hypoxia/aglycemia tolerated in each group. At all temperatures, slices from hibernating animals were most tolerant compared with both active squirrels and rats. Slices from active ground squirrels were more tolerant than rat at 20°C and 7°C but not at 36°C indicating a species-specific difference that becomes manifest at lower temperatures. These results indicate that hibernation is associated not only with tolerance to profound hypothermia but also to deprivation of oxygen and glucose. Because tolerance was already demonstrable at the shortest duration of hibernation studied, rapid therapeutic induction of a similar state may be possible. Therefore, identification of the regulatory mechanisms underlying this tolerance may lead to novel neuroprotective strategies.