Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging

There is increasing evidence that experimental interventions that alter adrenal corticosteroid plasma concentrations can modulate aging changes in the rodent hippocampus. However, there still is very little evidence that elevation of endogenous corticosteroid levels within physiological ranges, such as occurs during chronic stress, can accelerate hippocampal aging-like changes. In addition, almost all prior intervention studies of corticosteroid effects on brain biomarkers of aging have utilized morphologic measures of aging, and it is not yet clear whether electrophysiologic biomarkers of hippocampal aging can also be accelerated by conditions that elevate corticosteroids. In the present studies, specific pathogen-free rats of three ages (4, 12, and 18 months at the start) were trained for 6 months (4 hr/d, 5 d/week) in a two-way shuttle escape task, using low intensity foot shock. This task induces "anxiety" stress, because animals receive little actual shock, but chronic training in the task has been shown to elevate plasma corticosteroids and to downregulate hippocampal corticosteroid receptors. At the end of 6 months, animals were allowed to recover for 3 weeks and were then assessed in acute, anesthetized preparations on a battery of hippocampal neurophysiological markers known to separate young from aged animals (frequency potentiation, synaptic excitability thresholds, EPSP amplitude). The brains were then fixed and sectioned for quantification of neuronal density in field CA1 (a highly consistent anatomic marker of hippocampal aging). The pattern of stress effects differed considerably across age groups. The two younger stress groups exhibited increased evidence of aging-like neurophysiologic change, but exhibited no indications of accelerated neuronal loss. Conversely, the oldest stress group did not show additional aging-like electrophysiologic changes (possibly because of a "floor" effect in the already-impaired aged controls), but did exhibit additional cell loss. These results suggest that electrophysiologic aging changes can be accelerated by moderate stress relatively early in life, whereas structural brain aging changes are more resistant to such stress until some other aging process develops sufficiently to act as a cofactor and increase susceptibility. Aging-dependent resistance of hippocampal corticosteroid receptors to down-regulation by stress has been reported, as have alterations in calcium homeostasis. These or other molecular/cellular aging changes could act as cofactors to increase the susceptibility of aged individuals to stress-induced brain cell degeneration.