Elsevier

Physiology & Behavior

Volume 99, Issue 2, 9 February 2010, Pages 186-193
Physiology & Behavior

Review
The effects of chronic glucocorticoid exposure on dendritic length, synapse numbers and glial volume in animal models: Implications for hippocampal volume reductions in depression

https://doi.org/10.1016/j.physbeh.2009.09.008Get rights and content

Abstract

Glucocorticoids (GCs) are hormones secreted by the adrenal glands as an endocrine response to stress. Although the main purpose of GCs is to restore homeostasis when acutely elevated, animal studies indicate that chronic exposure to these hormones can cause damage to the hippocampus. This is indicated by reductions in hippocampal volume, and changes in neuronal morphology (i.e., decreases in dendritic length and number of dendritic branch points) and ultrastructure (e.g., smaller synapse number). Smaller hippocampal volume has been also reported in humans diagnosed with major depressive disorder or Cushing's disorder, conditions in which GCs are endogenously and chronically elevated. Although a number of studies considered neuron loss as the major factor contributing to the volume reduction, recent findings indicated that this is not the case. Instead, alterations in dendritic, synaptic and glial processes have been reported. The focus of this paper is to review the GC effects on the cell number, dendritic morphology and synapses in an effort to better understand how these changes may contribute to reductions in hippocampal volume. Taken together, the data from animal models suggest that hippocampal volumetric reductions represent volume loss in the neuropil, which, in turn, under-represent much larger losses of dendrites and synapses.

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.

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