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Journal of Neuroscience, Vol 5, 1222-1227, Copyright © 1985 by Society for Neuroscience
Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging
RM Sapolsky, LC Krey and BS McEwen
The hippocampus of the rat loses neurons with age, a loss which may
eventuate in some of the functional impairments typical of senescence.
Cumulative exposure to corticosterone (CORT) over the lifespan may be a
cause of this neuronal loss, as it is prevented by adrenalectomy at mid-
age. In this study, we demonstrate that prolonged exposure to CORT
accelerates the process of cell loss. Rats were injected daily with
sufficient CORT to produce prolonged elevations of circulating titers
within the high physiological range. Animals treated for 3 months (chronic
subjects) resembled aged rats in a number of ways. First, both groups had
extensive and persistent depletions of CORT receptors in the hippocampus;
in the case of chronic rats, no recovery of receptor concentrations
occurred 4 months after the end of steroid treatment. Second,
autoradiographic analysis revealed that the receptor depletion was due, in
part, to a loss of CORT-concentrating cells, especially in the CA3 cell
field. Remaining cells bound significantly less [3H]corticosterone than did
those of control rats. Finally, analysis of size distributions of
hippocampal cell bodies indicated that chronic subjects lost neurons of the
same size as those lost in the aged hippocampus. Furthermore, chronic
subjects also had increased numbers of small, darkly staining cells of CA3;
these corresponded in size to the dark glia whose numbers increase in the
aged hippocampus, and which are thought to infiltrate in response to
neuronal damage or destruction. Thus, this study supports the hypothesis
that cumulative exposure to CORT over the lifespan may contribute to
age-related loss of neurons in the hippocampus, and that prolonged stress
or exposure to CORT accelerates this process.
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