Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response.

TLDR

The hippocampus, rich in glucocorticoid receptors, normally inhibits adrenocortical activity, but aged rats lose these receptors and neurons, leading to impaired termination of corticosterone secretion during stress. We investigated whether loss of hippocampal neurons or loss of glucocorticoid receptors drives corticosterone hypersecretion in aged rats. Using two reversible hippocampal glucocorticoid receptor depletion models, we showed that receptor loss alone, without neuronal death, induces corticosterone hypersecretion. Restoring receptor levels normalizes corticosterone secretion, underscoring the hippocampus as a key glucocorticoid sensor and revealing its receptor system’s plasticity under corticosterone and vasopressin control.

Abstract

The hippocampus is the principal target site in the brain for adrenocortical steroids, as it has the highest concentration of receptor sites for glucocorticoids. The aged rat has a specific deficit in hippocampal glucocorticoid receptors, owing in large part to a loss of corticoid-sensitive neurons. This deficit may be the cause for the failure of aged rats to terminate corticosterone secretion at the end of stress, because extensive lesion and electrical stimulation studies have shown that the hippocampus exerts an inhibitory influence over adrenocortical activity and participates in glucocorticoid feedback. We have studied whether it is the loss of hippocampal neurons or of hippocampal glucocorticoid receptors in the aged rat that contributes most to this syndrome of corticosterone hypersecretion. To do this, we used two model systems for producing reversible glucocorticoid receptor depletion in the hippocampus, and we found that depletion of receptors without inducing cell loss results in corticosterone hypersecretion. Furthermore, correction of the receptor deficit results in normalization of corticosterone secretion. These results focus attention on the hippocampus as an important glucocorticoid sensor in relation to the stress response. They also provide important new physiological correlates for the remarkable plasticity of the hippocampal glucocorticoid receptor system, which is under independent control by corticosterone and by vasopressin.