Mouse model of diffuse brain damage following anoxia, evaluated by a new assay of generalized arousal

Abstract

Diffuse brain damage following anoxia due to cardiac failure, drowning, carbon monoxide exposure or other accidents constitutes a major medical problem. We have created a novel mouse model using the breathing of pure nitrogen, followed by a recently developed assay that reflects an operational definition of generalized arousal. The operational definition is precise, complete, and leads to quantitative, physical measures in a genetically tractable animal. Exposure to pure nitrogen for controlled periods had a surprising bifurcate effect: about half the mice survived with neurological measures that were virtually normal while the other half died. The new assay detected behavioral deficits unrevealed by neurological screening. Two important features of the results were that (i) deficits were not equal across the circadian cycle, and (ii) deficits were not equal across all the measures within the operational definition of arousal. Specific voluntary motor measurements were decreased in a manner that depended on the phase of the circadian cycle. Sensory responses were also decreased, with an emphasis on vertical movement responses; but, interestingly, fear learning was not damaged. This study establishes the first useful approach to diffuse brain damage in a genetically tractable animal. The model and its outcome measurements will be useful during future attempts at amelioration of acquired neurological disabilities following hypoxic-ischemic injuries.

Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates

“…Hippocampal neurons of the naked mole-rat consistently tolerate oxygen deprivation for over 5 hours, and show no signs of neural degradation even 24 hours after exposure, suggesting evidence of hypoxia tolerance in the adult brain of naked mole-rats [134]. Further, naked mole-rat brains maintain synaptic function much longer than mice in reduced oxygen, and recover from 30-minute periods of no oxygen [124], an experiment that would routinely kill a mouse [135]. The naked mole-rat maintenance of the neonatal, hypoxia tolerant NMDA receptor subunit, GluN2D, may contribute to this extreme hypoxia tolerance [136] and likely is an adaptation to living in environments with variable partial pressures of oxygen.…”

Definition of Arousal and Mechanistic Studies in Intact and Brain‐Damaged Mice

“…In an attempt to render mice brain‐damaged and study the consequences of generalized arousal, we developed an anoxia protocol 21 and used it. All mice were examined neurologically preanoxia and postanoxia treatment.…”

“…Values are expressed as percentages postanoxia treatment ( black bar ) compared to their own preanoxia values ( white bar ) normalized at 100%. (Adapted with permission from Arrieta‐Cruz et al 21 )…”

“…Significant differences were confirmed by Bonferroni's posttests used to make pairwise comparisons (preanoxia vs. postanoxia). (Adapted with permission from Arrieta‐Cruz et al 21 ).…”

Estrogens, androgens and generalized behavioral arousal in gonadectomized female and male C57BL/6 mice

“…The hormones were administered in a fast acting preparation as well as in the classical oil vehicle and Silastic capsule. The subjects’ arousal level following hormone treatment was determined in a previously validated assay of general arousal [29–31]. It is based on continuous recording of several behavioral parameters, including locomotion and rearing as well as the reaction to sensory stimuli, i.e.…”