Enhanced cell death in hippocampus and emergence of cognitive impairments following a localized mini‐stroke in hippocampus if preceded by a previous episode of acute stress

Abstract

This series of experiments represents a test of a theory concerning the etiology of age-related cognitive decline, including Alzheimer's disease (AD). The theory suggests that multiple combinations of cofactors produce variants of these disorders. Two factors that have been linked to the etiology of AD, that are of interest to our laboratories, are stress and vascular strokes. The current experiments tested the cofactors theory by evaluating the neuronal and functional effects of localized subthreshold strokes in the hippocampus of different groups of rats. One group experienced episodes of stress prior to stroke induction while the other did not. The results showed that a low dose of endothelin-1 (ET-1) injected into the hippocampus of groups of rats that had previously experienced stressful episodes showed enhanced hippocampal cell death and neurodegeneration that did not occur in the rats that did not experience stress prior to stroke induction. The results also showed that the stressed rats given subthreshold ET-1 injections into the hippocampus showed hippocampal-based learning and memory deficits that were not present in the non-stressed group given the same injections. This pattern of results suggests that individuals that are under stress are more vulnerable to insults to the hippocampus that have little effect on an individual that is not stressed. This vulnerability might be due to the actions of stress hormones, like the glucocorticoids, that have been previously shown to endanger hippocampal neurons.

Revisiting the cholinergic hypothesis in the development of Alzheimer's disease

“…I predict that I would have found minimal damage to the hippocampus in the low dose group and extensive cell death in groups receiving the higher doses. Additional experiments in our laboratory confirmed this prediction by finding minimal damage surrounding the infusion site (Driscoll et al, 2007;McDonald et al, 2008), or a moderate amount of neuronal cell The lowest dose (7.5 pmol) of ET-1 used in the current study did not impair acquisition of the water maze task. I chose this dose for future studies to better model the 'silent' infarcts commonly observed in the elderly (Snowden et al, 1997;Vermeer et al, 2007).…”

“…Alternatively, if I increased the daily duration of stress (vary between one to six hours) I may be able to observe an impairment in spatial memory. Although the number of animals used in this pilot was low, additional studies in our laboratory have consistently reported no effect of either one or two weeks of this variable restraint stress schedule on water maze performance providing further support for my sub-threshold stress model McDonald et al, 2008).…”

“…Additional support for this model has been provided combining a number of other risk factors for AD such as aging and mild ischemia (Driscoll et al, 2007), stress and mild ischemia as well as cholinergic depletion and stress . While the effect of these combinations on hippocampal pathology can vary between dramatically ramping up lesion size (Driscoll et al, 2007;McDonald et al, 2008), to no obvious damage , the appearance of a deficit on hippocampal based tasks remains constant. Taken together, these studies suggest that although the many risk factors for AD are all capable of producing cognitive impairment, the underlying mechanism or extent of neuronal damage varies depending on the risk factors present.…”

“…This method of analysis has been used previously and produces an accurate estimate of hippocampal damage following focal stroke in the rat (Driscoll et al, 2007;McDonald et al, 2008).…”

Letter by Griebe et al Regarding Article, “Jugular Veins in Transient Global Amnesia: Innocent Bystanders”

“…A recent experimental study demonstrated that cell death in the hippocampus caused by moderate ischemia was dramatically amplified in rats that experienced stressful episodes before the ischemic event. 5 The animals also displayed a pronounced increase in corticosterone levels and hippocampus-related learning and memory deficits. These findings indicate that prior stress sensitizes hippocampal neurons to the damaging effects of hypoperfusion.…”