Effects on hippocampus of lifelong absence of glucocorticoids in the pro-opiomelanocortin null mutant mouse reveal complex relationship between glucocorticoids and hippocampal structure and function

In humans changes in serum cortisol levels have been observed with aging, stress, and with affective disorders such as major depression and post-traumatic stress disorder. Corticosteroids are known to influence hippocampal structure and function; specifically, plasma corticosteroid levels have been inversely correlated with hippocampal cell proliferation, cell death, and impaired memory function. The relationship between corticosteroids and structure and function of the hippocampus has been studied in experimental systems in adult animals by increasing or decreasing corticosterone levels through pharmacological supplementation and through surgical removal of the adrenal gland. Here, we utilized the genetically engineered pro-opiomelanocortin (POMC) null mutant mouse, which because of the lack of all POMC peptides has no corticosterone from birth throughout life. The effect of this lifelong absence of corticosterone on the dentate gyrus of the hippocampus is a decrease in granule cell density, which correlated with a decrease in cell proliferation but not an increase in cell degeneration. Fine morphology of granule cells was unaltered. Analyses of gene expression revealed no changes in POMC null mutant vs wild-type hippocampus with respect to levels of expression of corticoid receptor genes or genes known to be regulated by corticosterone. Spatial learning as tested by the Morris water maze was not altered in the POMC null mutant mouse. Taken together with findings from other studies of the effects of altered levels of corticosteroids on the hippocampus, our results argue for a complex homeostasis in which disturbances of any one factor can offset the system in varying ways.