Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging

Abstract

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.

Hippocampal neuroplasticity induced by early-life stress: Functional and molecular aspects

“…Therefore, stress may perturb gene expression transiently, perhaps via epigenetic effects [97,143], but the withdrawal of the inciting stimulus leads to re-instatement of the original, fully programmed 'steady state.' In addition, whereas neuronal loss has been suspected to occur upon chronic stress in the adult [125,90], most current evidence supports the notion that the structural effects of chronic stress on hippocampal neurons involve dendritic modifications, without cell loss or profound dendritotoxicity. Thus, upon withdrawal of the molecular processes initiated by stress, recovery of both function and structure occurs in mature hippocampus [109,56,114].…”

“…Indeed, LTP was impaired in both CA3 and CA1 hippocampal areas of 12-month old rats stressed early in life [31]. In area CA3, the hippocampal field considered most vulnerable to chronic stress in adults [125,100], both LTP as well as basic synaptic physiology were abnormal [31]. Interestingly, abnormal LTP, although normal synaptic physiology, was found in area CA1 [31].…”

“…GC are released from the adrenal glands by stress, cross the blood-brain barrier readily, and activate hippocampal GC receptors (GRs) [99,44]. Indeed, saturation of GRs by 'stresslevels' of GC can lead to hippocampal neuronal injury [125,140] but these receptors reside primarily in rodent CA1 [115,62, but see primate data in 122], whereas stress-induced structural changes involve mainly CA3 [125,99,100]. In addition, GC administration early in life does not reproduce the effects of stress on hippocampal function and integrity when given in a nonstressful manner [87], suggesting that other factors may also contribute to the mechanisms by which early-life stress influences hippocampal development and function throughout life.…”

Gray Matter Changes in Late Life Depression—a Structural MRI Analysis

“…These results can be interpreted according to the two most prevalent hypotheses, the toxic stress, and the dementia prodrome. According to the toxic-stress hypothesis of depression, high levels of glucocorticoids (McEwen, 1997;Sapolsky, 1993) induce shrinking of the highly sensitive hippocampal gray matter (Sapolsky et al, 1985;Sheline et al, 1999;Steffens et al, 2000;Videbech and Ravnkilde, 2004). According to the prodromal dementia hypothesis of LLD, a subgroup of subjects develops LLD as a very early clinical presentation of dementia (Alexopoulos et al, 1993;O'Brien et al, 2004;Steffens et al, 2000).…”

Increased Temporal Cortex ER Stress Proteins in Depressed Subjects Who Died by Suicide

“…A number of studies have found evidence of neuronal atrophy and loss of hippocampal neurons in response to stress (Magarinos et al 1996;Uno et al 1989;Sapolsky et al 1985), and a report of reduced hippocampal volumes in elderly patients with histories of depression suggests that analogous processes may occur in individuals with depression (Sheline et al 1996). Some models of mood disorders (Hyman and Nestler 1996; Post 1992) have attempted to incorporate the notion of compensatory processes into an understanding of the pathophysiologic changes that occur in patients with mood disorders, but few studies have tested these notions empirically (Post 1992).…”