Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons

We have used Golgi-impregnated tissue to demonstrate that exposure to excess glucocorticoids alters dendritic morphology in a specific population of neurons in the adult rat hippocampus. Daily injection of 10 mg of corticosterone for 21 days resulted in decreased numbers of apical dendritic branch points and decreased total apical dendritic length measured in a 100-microns-thick section in CA3 pyramidal cells compared to sham-injected and non-injected controls. In contrast, no changes were observed in CA3 pyramidal cell basal dendritic morphology. Furthermore, no changes were observed in the dendritic morphology of CA1 pyramidal cells or granule cells of the dentate gyrus. Cross-sectional cell body area of any of the 3 cell types examined in this study was unaffected by corticosterone treatment. Finally, qualitative analysis of Nissl-stained tissue from the same brains revealed increased numbers of darkly staining, apparently shrunken CA3 pyramidal cells in corticosterone treated compared to control brains. The changes in dendritic morphology we have observed may be indicative of neurons in the early stages of degeneration, as prolonged exposure to high levels of corticosterone has been shown by others to result in a loss of CA3 pyramidal cells. Additionally, these results suggest possible structural alterations which may occur under physiological conditions in which corticosterone levels are chronically elevated such as in aged animals.

[1]  P. E. Gold,et al.  Changes in Learning and Memory During Aging , 1975 .

[2]  K. Knigge,et al.  Evidence of Inhibitive Role of Hippocampus in Neural Regulation of ACTH Release.∗ , 1963, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[3]  R. Sapolsky,et al.  Glucocorticoid toxicity in the hippocampus: in vitro demonstration , 1988, Brain Research.

[4]  R. Hauger,et al.  Differential regulation of brain and pituitary corticotropin-releasing factor receptors by corticosterone. , 1987, Endocrinology.

[5]  F. Gaarskjaer.  The organization and development of the hippocampal mossy fiber system , 1986, Brain Research Reviews.

[6]  G. Lynch,et al.  Hippocampal aging and adrenocorticoids: quantitative correlations. , 1978, Science.

[7]  B. Horwitz.  Neuronal plasticity: how changes in dendritic architecture can affect the spread of postsynaptic potentials , 1981, Brain Research.

[8]  R. Sapolsky,et al.  Hippocampal damage associated with prolonged and fatal stress in primates , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  J. Silver,et al.  Changing role of forebrain astrocytes during development, regenerative failure, and induced regeneration upon transplantation , 1986, The Journal of comparative neurology.

[10]  R. S. Sloviter.  “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies , 1983, Brain Research Bulletin.

[11]  J. Nadler,et al.  Kainic acid neurotoxicity toward hippocampal formation: Dependence on specific excitatory pathways , 1980, Brain Research.

[12]  S. Feldman,et al.  Participation of the dorsal hippocampus in the glucocorticoid feedback effect on adrenocortical activity. , 1980, Neuroendocrinology.

[13]  D. Choi.  Ionic dependence of glutamate neurotoxicity , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  E. R. Kloet,et al.  Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. , 1985, Endocrinology.

[15]  R. Sapolsky.  Glucocorticoid toxicity in the hippocampus. Temporal aspects of synergy with kainic acid. , 1986, Neuroendocrinology.

[16]  R. Sapolsky,et al.  Chemical adrenalectomy reduces hippocampal damage induced by kainic acid , 1988, Brain Research.

[17]  B. McEwen,et al.  Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Swanson,et al.  The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. , 1988, Neuron.

[19]  R. Sousa,et al.  In situ hybridization mapping of glucocorticoid receptor messenger ribonucleic acid in rat brain. , 1989, Molecular endocrinology.

[20]  R. Sapolsky.  A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  K. Fuxe,et al.  Mapping of glucocorticoid receptor immunoreactive neurons in the rat tel- and diencephalon using a monoclonal antibody against rat liver glucocorticoid receptor. , 1985, Endocrinology.

[22]  M. Kadekaro,et al.  Local cerebral glucose utilization is increased in acutely adrenalectomized rats. , 1988, Neuroendocrinology.

[23]  T. A. Pitler,et al.  Brain aging correlates: retardation by hormonal-pharmacological treatments. , 1981, Science.

[24]  B. McEwen,et al.  Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  R. S. Sloviter.  Calcium‐binding protein (calbindin‐D28k) and parvalbumin immunocytochemistry: Localization in the rat hippocampus with specific reference to the selective vulnerability of hippocampal neurons to seizure activity , 1989, The Journal of comparative neurology.

[26]  B. McEwen,et al.  Stress down-regulates corticosterone receptors in a site-specific manner in the brain. , 1984, Endocrinology.

[27]  S Levine,et al.  Behavioral stress impairs long-term potentiation in rodent hippocampus. , 1987, Behavioral and neural biology.

[28]  R. Sapolsky.  Glucocorticoid toxicity in the hippocampus: reversal by supplementation with brain fuels , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  J. V. Van eekelen,et al.  Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus , 1988, Journal of neuroscience research.

[30]  F. Tang,et al.  Some age-related changes in pituitary-adrenal function in the male laboratory rat. , 1978, Journal of gerontology.

[31]  Paul Leonard Gabbott,et al.  The ‘single’ section Golgi-impregnation procedure: methodological description , 1984, Journal of Neuroscience Methods.

[32]  C. Woolley,et al.  Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus , 1990, Neuroscience.

[33]  D. Carpenter,et al.  Kainic acid responses and toxicity show pronounced Ca2+ dependence , 1985, Brain Research.

[34]  J. Kiss,et al.  Immunocytochemical study on the intracellular localization of the type 2 glucocorticoid receptor in the rat brain , 1987, Brain Research.

[35]  B. McEwen,et al.  The adrenocorticol stress-response in the aged male rat: Impairment of recovery from stress , 1983, Experimental Gerontology.

[36]  P. Landfield,et al.  Corticosteroid modulation of hippocampal potentials: increased effect with aging. , 1989, Science.