ReviewThe effects of chronic glucocorticoid exposure on dendritic length, synapse numbers and glial volume in animal models: Implications for hippocampal volume reductions in depression
Introduction
A primary endocrine response to stress is the secretion of glucocorticoids (corticosterone in rats and cortisol in humans). Although glucocorticoids are normally elevated as a neuroendocrine response to acute threats to maintain homeostasis [1], [2], they are chronically elevated in a number of neuropsychiatric disorders (e.g., depression, Cushing's syndrome) [3], [4] as well as during chronic stress [5], [6]. In addition to endogenous elevations, glucocorticoids are also elevated through the use of prescription drugs, which serve to reduce immune responses such as inflammation [7]. The variety of conditions in which glucocorticoids are chronically elevated raises concerns about the accumulating effects of the prolonged exposure to this hormone. Systemic effects of long-term glucocorticoid elevations include heart disease, osteoporosis, and muscle wasting [7]. The finding that glucocorticoid receptors are also expressed in the brain [8] raised the possibility that elevated GCs may affect brain structure and function.
Glucocorticoids act on the brain through two known receptor types, the mineralocorticoid (MR) and glucocorticoid (GR) receptors. The rodent hippocampus has a high density of both GR and MR, whereas in primates the hippocampus has a high density of MR [9], [10]. The hippocampus, a structure important for learning and memory [11], mediates the regulation of glucocorticoid release through its indirect action on the Hypothalamic–Pituitary–Adrenal axis activity [12], [13]. The hippocampus is not the sole structure providing negative feedback; additional structures have been involved in the regulation of the Hypothalamic–Pituitary–Adrenal axis activity [14], [15], the high expression of glucocorticoid receptors in the hippocampus may render this brain structure a target of glucocorticoid elevations. For this reason, the effects of elevated glucocorticoids have been studied extensively in the hippocampus, and many investigators have questioned the effects of both acute and chronic glucocorticoid elevations on hippocampal structure and function. These studies have been performed by testing for relationships, correlational or causal, between glucocorticoids and hippocampal structure, and between glucocorticoids and behaviors dependent upon hippocampal integrity. This review focuses on the relationship between glucocorticoids and hippocampal structure.
The first studies to address whether high glucocorticoid levels damage the hippocampus were carried out on animals [16], [17], [18]. The initial findings of pyknosis or cell loss [16], [19], [20], [21] and dendritic atrophy [22], [23], [24] as a result of glucocorticoid elevations led to the assumption that these losses would be reflected by a reduction in hippocampal volume. Only a few studies in animals, which will be discussed below, have directly measured hippocampal volume. In contrast, brain imaging techniques allow for the study of hippocampal volume in clinical populations with disorders associated with elevated plasma glucocorticoids (e.g., Cushing's syndrome, depression). These studies have caused a surge of interest in the association between prolonged exposure to glucocorticoids and hippocampal volume. The focus of this review is primarily on the relationship between chronic glucocorticoid elevations and their effects on hippocampal volume, cell number and synapses, specifically exploring the relationship between these three variables in an effort to better inform the interpretation of volumetric differences reported in clinical conditions that include elevated glucocorticoids. Specifically, we will briefly review the reports of smaller hippocampal volume in major depressive disorder and Cushing's syndrome, and then discuss animal research that addresses the causal relationship between glucocorticoids and hippocampal volume. The latter studies also address glucocorticoid effects on neuron number, dendritic atrophy, synapse numbers and how well the glucocorticoid effects on volume reflect changes in these tissue constituents.
Section snippets
Effects on hippocampal volume
The use of brain imaging techniques has allowed investigators to explore whether hippocampal damage occurs in individuals who suffer from disorders associated with high plasma glucocorticoids, two of which are Cushing's syndrome (CS) and major depressive disorder. Patients with Cushing's syndrome (CS) are exposed to elevated levels of endogenous cortisol for months to years due to adrenal pathology or hypersecretion of pituitary adrenocorticotropin hormone (ACTH) (Cushing's disease). Because of
Glucocorticoid-induced morphological alterations in hippocampus: animal models
The intriguing possibility that sustained cortisol elevations may decrease hippocampal volume is difficult to fully investigate in human subjects. The studies cited thus far have the advantage of measuring volume in humans at the time of a depression episode, and in some studies over time. The limitations, however, are the inability to investigate cells and ultrastructure at a time point close to volumetric measurement in order to understand how such changes contribute to volume reductions.
Association between hippocampal volume, cell number, morphology and ultrastructure: concluding remarks
By studying hippocampal volume differences in rats following treatment conditions that elevate glucocorticoids, we can address the causal relationships that may explain the differences in hippocampal volume reported in clinical populations without confounding factors such as differences in treatment parameters, age, duration and severity of illness. Volume reduction is often assumed to reflect a loss of cells without the understanding that packing density may increase, thus all cells may be
Acknowledgement
This work was supported by MH62075.
References (113)
Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome
Biol Psychiatry
(1992)- et al.
The effects of olfactory bulbectomy and chronic psychosocial stress on serum glucocorticoids and sexual behavior in female rats
Physiol Behav
(1992) Effects of chronic stress on plasma corticosterone. ACTH and prolactin
Physiol Behav
(1987)Changes of plasma and adrenal catecholamines and corticosterone in stressed rats with septal lesions
Physiol Behav
(1982)Stress induces neuronal death in the hippocampus of castrated rats
Neurosci Lett
(1992)- et al.
Anabolic–androgenic steroid and adrenal steroid effects on hippocampal plasticity
Brain Res
(1995) - et al.
Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons
Brain Res
(1990) - et al.
Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons
Brain Res
(1992) Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement
Neuroscience
(2000)Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease
Biol Psychiatry
(1999)
Improvement in learning associated with increase in hippocampal formation volume
Biol Psychiatry
The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex
Behav Brain Res
Abnormal size of the amygdala predicts impaired emotional memory in major depressive disorder
J Affect Disord
Amygdala and hippocampal volumes in familial early onset major depressive disorder
Biol Psychiatry
Hippocampal volume and incident dementia in geriatric depression
Am J Geriatr Psychiatry
Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects
Biol Psychiatry
Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study
Biol Psychiatry
Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment
Biol Psychiatry
3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity
Biol Psychiatry
Anatomical MRI study of hippocampus and amygdala in patients with current and remitted major depression
Psychiatry Res
Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans
Neuroimage
Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure
Am J Pathol
Cognitive impairment in depression is not associated with neuropathologic evidence of increased vascular or Alzheimer-type pathology
Biol Psychiatry
Cellular changes in the postmortem hippocampus in major depression
Biol Psychiatry
Chronic corticosterone affects brain weight, and mitochondrial, but not glial volume fraction in hippocampal area CA3
Neuroscience
Effects of corticosterone treatment and rehabilitation on the hippocampal formation of neonatal and adult rats. An unbiased stereological study
Brain Res
Chronic psychosocial stress does not affect the number of pyramidal neurons in tree shrew hippocampus
Neurosci Lett
Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox
Brain Res
Ligand and subfield specificity of corticoid-induced neuronal loss in the rat hippocampal formation
Neuroscience
The glucocorticoid hormone: from pedestal to dust and back
Eur J Pharmacol
Salivary cortisol patterns and cognitive speed in major depression: a comparison with allergic rhinitis and healthy control subjects
Biol Psychol
Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons
Brain Res
Glial cells express both mineralocorticoid and glucocorticoid receptors
J. Steroid Biochem. Mol. Biol.
Mapping and computer assisted morphometry and microdensitometry of glucocorticoid receptor immunoreactive neurons and glial cells in the rat central nervous system
Neuroscience
Transition between immature radial glia and mature astrocytes studied with a monoclonal antibody to vimentin
Brain Res
Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain
Brain Res
The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis
Jama
Physiological functions of glucocorticoids in stress and their relation to pharmacological actions
Endocr Rev
Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients
Arch Gen Psychiatry
Selective retention of corticosterone by limbic structures in rat brain
Nature
Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation
Endocrinology
Brain corticosteroid receptor balance in health and disease
Endocr Rev
Magnetic resonance imaging of the hippocampal formation and mammillary nuclei distinguish medial temporal lobe and diencephalic amnesia
J Neurosci
Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response
Proc Natl Acad Sci U S A
Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis
J Neurosci
Glucocorticoid negative feedback and glucocorticoid receptors after hippocampectomy in rats
Horm Metab Res
Morphologische veranderungen'im diencephalon und telencephalon nach storungen des regelkreises adenohypophyse-nebennierenrinde. III. Ergebnisse beim meerschweinchen nach verabreichung von cortison und hydrocortison
Z. Zellforsch
Brain aging correlates: retardation by hormonal–pharmacological treatments
Science
Hippocampal aging and adrenocorticoids: quantitative correlations
Science
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