Elsevier

Biological Psychiatry

Volume 48, Issue 8, 15 October 2000, Pages 721-731
Biological Psychiatry

Molecular and cellular hypotheses of antidepressant action
Effects of adverse experiences for brain structure and function

https://doi.org/10.1016/S0006-3223(00)00964-1Get rights and content

Abstract

Studies of the hippocampus as a target of stress and stress hormones have revealed a considerable degree of structural plasticity in the adult brain. Repeated stress causes shortening and debranching of dendrites in the CA3 region of the hippocampus and suppresses neurogenesis of dentate gyrus granule neurons. Both forms of structural remodeling of the hippocampus appear to be reversible and are mediated by glucocorticoid hormones working in concert with excitatory amino acids (EAA) and N-methyl-d-aspartate (NMDA) receptors, along with transmitters such as serotonin and the GABA-benzodiazepine system. Glucocorticoids, EAA, and NMDA receptors are also involved in neuronal damage and death that is caused in pyramidal neurons by seizures and by ischemia. A similar mechanism may be involved in hippocampal damage caused by severe and prolonged psychosocial stress. Studies using magnetic resonance imaging have shown that there is a selective atrophy of the human hippocampus in a number of psychiatric disorders, as well as during aging in some individuals, accompanied by deficits in declarative, spatial, and contextual memory performance. It is therefore important to appreciate how hippocampal dysfunction may play a role in the symptoms of the psychiatric illness and, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible remodeling to develop treatment strategies to prevent or reverse deficits. Remodeling of the hippocampus may be only the tip of the iceberg; other brain regions may also be affected.

Introduction

The adult brain is more plastic than previously believed. Remodeling of synaptic contacts and dendrites in the hypothalamus with the onset of lactation Michaloudi et al 1997, Stern and Armstrong 1998 and growth and branching of dendrites of cerebrocortical neurons in an enriched environment and after training Greenough and Bailey 1988, Withers and Greenough 1989 are two examples of such plasticity. Recent studies on the hippocampal formation of the brain provides further examples of adult brain plasticity, which is regulated by hormones in adult life and during brain development. The hippocampus is involved in memory and in episodic, declarative, contextual, and spatial learning, as well as being a component in the control of autonomic and vegetative functions such as corticotropin secretion Eichenbaum and Otto 1992, Jacobson and Sapolsky 1991, Phillips and LeDoux 1992. The hippocampus is also vulnerable to damage by stroke and head trauma and susceptible to damage during aging and repeated stress (Sapolsky 1992), and hippocampal atrophy has been reported in a number of psychiatric disorders, as will be discussed below.

Hippocampal neurons express receptors for circulating adrenal steroids (McEwen et al 1968), and work in many laboratories has shown that the hippocampus has two types of adrenal steroid receptors, Type I (mineralocorticoid) and Type II (glucocorticoid), that mediate a variety of effects on neuronal excitability, neurochemistry, and structural plasticity (DeKloet et al 1998). Many of these hormone effects do not occur alone but rather in the context of ongoing neuronal activity. In particular, excitatory amino acids and NMDA receptors, as well as serotonin, play an important role in the functional and structural changes produced in the hippocampal formation by steroid hormones. This article reviews the adaptive plasticity in the hippocampus produced by circulating adrenocortical hormones acting in many cases in concert with excitatory amino acid neurotransmitters, and it also considers some of the ways in which adaptive plasticity gives way to permanent damage. The implications for hippocampal function and its role in the pathophysiology of psychiatric illnesses is discussed.

Section snippets

An overview of hormonally regulated plasticity in the hippocampus

There are three types of plasticity in the hippocampal formation in which adrenal steroids play a role. First, adrenal steroids participate along with excitatory amino acids in regulating neurogenesis of dentate gyrus granule neuron (Gould et al 2000) in which acute stressful experiences can suppress the ongoing neurogenesis (for reviews, see Gould et al 2000, McEwen 1999). We believe that these effects may be involved in fear-related learning and memory because of the anatomic and functional

Reversible remodeling of dendrites

Investigating the process of dendritic remodeling in the hippocampus of rats and tree shrews (formerly called atrophy; see next paragraph for explanation) provides one potential explanation of the hippocampal shrinkage that is seen in human subjects using magnetic resonance imaging (MRI; see below). Furthermore, the neurochemistry and neuroendocrinology of this process offers possibilities for pharmacologic intervention and either blocking or reversing hippocampal atrophy. In animal models

Neurogenesis in the dentate gyrus

Neurogenesis in the dentate gyrus of adult rodents was reported several decades ago (for a review, see Gould et al 2000) but never fully appreciated until recently, and the reactivation of this topic occurred in an unusual manner (McEwen 1999). First, bilateral adrenalectomy of an adult rat was shown to increase granule neuron death by apoptosis (Gould et al 1990). Subsequently, neurogenesis was also found to increase following adrenalectomy in adults rats, as well as in the developing dentate

Stress, glucocorticoids, and cognition

Stress and glucocorticoids have specific effects on cognitive function in humans and in animal models. Adrenal steroids and stressful experiences produce short-term and reversible deficits in episodic and spatial memory in animal models and in humans de Quervain et al 2000, Lupien and McEwen 1997, whereas repeated stress also impairs cognitive function in animal models and repeated glucocorticoid elevation or treatment in humans is accompanied by cognitive dysfunction (McEwen and Sapolsky 1995)

Atrophy of the hippocampus and other brain structures in psychiatric disorders

The human brain shows signs of atrophy as a result of elevated glucocorticoids and severe, traumatic stress (e.g., holocaust survivors; Sapolsky 1992). Advances in brain imaging techniques have allowed for a regional analysis of the atrophy of various brain structures. Recent evidence indicates that the human hippocampus is particularly sensitive in this respect and tends to show greater changes than do other brain areas, especially in Cushing’s syndrome, recurrent depressive illness,

Acknowledgements

Research in the author’s laboratory on the topic of this article is supported by National Institutes of Health Grant Nos. MH 41256 and Center Grant No. MH58911, as well as by funding from the Health Foundation (New York) and Servier (France).

Aspects of this work were presented at the conference “Depression in the Twenty-First Century: New Insights into Drug Development and Neurobiology,” February 21–22, 2000, Dana Point, California. The conference was sponsored by the Society of Biological

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