Modulation of neurobiological correlates of hippocampal aging by corticosteroids and chronic stress

Previous studies have shown that a number of neurobiological variables are consistently altered in the aged rodent hippocampus. Due to the nature of these alterations, disturbed Ca{dollar}sp{lcub}2+{rcub}{dollar} homeostasis has been suggested to be a critical factor underlying brain aging. In addition, the hippocampus is rich in two types of cytosolic corticosteroid (CORT) receptors, and it has been demonstrated that long-term adrenalectomy (ADX) spares neuronal loss and reactive gliosis in the aged rodent hippocampus, whereas prolonged glucocorticoid administration induces neuronal loss and glial proliferation in young rats. These latter studies strongly implicate corticosteroids in the modulation of hippocampal aging processes.; Work described in this dissertation has focused on the nature of these phenomena by examining (1) whether or not relatively physiological alterations in endocrine processes (e.g. by chronic stress) can also modulate patterns of hippocampal aging, and (2) the nature of corticosteroid effects on cellular physiological processes, and changes in this with aging. Various paradigms involving chronic stress, adrenalectomy, and in vivo or in vitro CORT administration have been employed in the assessment of cellular mechanisms underlying electrophysiological correlates of hippocampal aging.; The results of these studies indicate that chronic stress can accelerate or exaggerate the development of several of the neurobiological correlates of normal hippocampal aging, including impaired frequency potentiation, reduced synaptic thresholds, diminished field EPSP amplitudes, and neuronal loss in aged animals. Acceleration of electrophysiological age correlates by stress is most notable in young and mid-aged animals, but is not different in aged subjects, indicating possible "floor" effects (that is, the aged subjects might already have been as impaired as is possible). At the cellular level, both the Ca{dollar}sp{lcub}2+{rcub}{dollar}-dependent, slow afterhyperpolarization (AHP{dollar}sb{lcub}rm Ca{rcub}{dollar}) and isolated Ca{dollar}sp{lcub}2+{rcub}{dollar} action potentials (which are prolonged with aging) are reduced following adrenalectomy; moreover, the AHP{dollar}sb{lcub}rm Ca{rcub}{dollar} can be restored after in vivo or in vitro administration of CORT to slices from ADX animals. These findings suggest that corticosteroids modulate Ca{dollar}sp{lcub}2+{rcub}{dollar}-mediated potentials across the cell membrane following CORT activation. In addition, the effect of ADX on the AHP{dollar}sb{lcub}rm Ca{rcub}{dollar} is greatest in aged animals, indicating that there is an increased impact of corticosteroid activation with aging.; These findings extend, as well as bring together, two previously unrelated areas in the field of brain aging; namely, the acceleration of brain aging by chronic stress and glucocorticoids, and the appearance of disturbed Ca{dollar}sp{lcub}2+{rcub}{dollar} homeostasis during brain aging. As such, a mechanism is now proposed by which glucocorticoids modulate G{dollar}sb{lcub}rm Ca{rcub}{dollar}, which in turn modulate both acute intracellular physiology as well as long-term structural integrity of the cell.