Cognitive-behavioural impairments after forebrain ischemia in rats: Relationship to disruptions in emotionality and neuroendocrine regulation

Abstract

Cognitive deficits observed in rodents subjected to forebrain ischemia (mimicking the cerebral ischemia observed following cardiac arrest) are generally interpreted as produced by neuronal degeneration to discrete regions of the brain, principally the hippocampus. Challenging this view, the presence of ischemia-induced neuronal damage is not always associated with manifestations of cognitive impairment, or conversely, impairments post-reperfusion can originate at times when neuronal damage has yet to occur. The current thesis investigated whether the impairing effects of ischemia on cognitive functioning might in part be attributable to endogenous alterations of emotional systems regulating anxiety, stress, and/or arousal, thus not exclusively to discrete neuronal damage. The behavioural findings of Experiment 1, 2 and 3 suggested that hyperactivity in response to novel testing contexts in ischemic animals (as measured in the open field) is modulated by changes in emotional reactivity, and demonstrated time-dependent alterations of anxiety and behavioural activation at discrete reperfusion delays following a 10 minute forebrain ischemia. In Experiment 4, we demonstrated that cerebral ischemia is a significant stressor having lasting impact on HPA axis reactivity, effects associated to spatial memory impairments at delayed post-reperfusion intervals. Specifically, the testing-induced elevations in plasma corticosterone observed in ischemic rats (to a greater extent than sham-operated rats) was elicited after a return to pre-surgery resting levels, suggesting that increased neuroendocrine response was the result of behavioural testing and closely associated with cognitive deficits. Finally, Experiment 5 showed that excessive central noradrenergic reactivity in ischemic rats mediated some of the observed cognitive impairments or behavioural alterations. Overall, the thesis experiments suggest that cognitive-behavioural outcome after forebrain ischemia in rats is associated with impaired emotional regulation and/or arousal. These findings are not compatible with the common hippocampal-based interpretation of cognitive deficits after ischemia, and question the ecological validity (and generlizability) of functional outcome measurements of rats subjected to cerebral ischemia given that cognitive impairments in human survivors of ischemic episodes are not considered the result of arousal deficits.