Chronic stress: Implications for neuronal morphology, function and neurogenesis

Abstract

In normal life, organisms are repeatedly exposed to brief periods of stress, most of which can be controlled and adequately dealt with. The presently available data indicate that such brief periods of stress have little influence on the shape of neurons or adult neurogenesis, yet change the physiological function of cells in two time-domains. Shortly after stress excitability in limbic areas is rapidly enhanced, but also in brainstem neurons which produce catecholamines; collectively, during this phase the stress hormones promote focused attention, alertness, vigilance and the initial steps in encoding of information linked to the event. Later on, when the hormone concentrations are back to their pre-stress level, gene-mediated actions by corticosteroids reverse and normalize the enhanced excitability, an adaptive response meant to curtail defense reactions against stressors and to enable further storage of relevant information. When stress is experienced repetitively in an uncontrollable and unpredictable manner, a cascade of processes in brain is started which eventually leads to profound, region-specific alterations in dendrite and spine morphology, to suppression of adult neurogenesis and to inappropriate functional responses to a brief stress exposure including a sensitized activation phase and inadequate normalization of brain activity. Although various compounds can effectively prevent these cellular changes by chronic stress, the exact mechanism by which the effects are accomplished is poorly understood. One of the challenges for future research is to link the cellular changes seen in animal models for chronic stress to behavioral effects and to understand the risks they can impose on humans for the precipitation of stress-related disorders.

Introduction

For optimal survival of the individual it is important that bodily functions are subject to homeostatic control. Hence there is a continuous effort to contain these functions within a certain range—variable to demand—, a process referred to as allostasis [178]. Potential disturbances from internal or external sources (stressors), which collectively are perceived by the individual as “stress”, will activate two systems that serve to normalize the disturbed functions: the sympatho-adrenomedullar system and the hypothalamo–pituitary–adrenocortical (HPA) axis. Activation of the former rapidly results in enhanced release of adrenaline, which through activation of the vagal nerve indirectly increases the activity of noradrenergic neurons in the nucleus tractus solitairus and the locus coeruleus [180]. As a consequence noradrenaline (NA) levels elsewhere in the brain—in regions which receive projections from these nuclei—will be temporarily elevated leading to functional changes in neurons carrying NA receptors. Activation of the HPA system gives rise to increased release of corticosterone (the prevailing hormone in most rodents; cortisol in humans) which due to its lipophilic nature easily enters the brain. Within the brain the hormone acts at those sites where receptors are enriched.

Two types of corticosteroid receptors have been recognized within the brain: The high-affinity mineralocorticoid receptor (MR) which is highly expressed in limbic areas like the hippocampal subfields, lateral septum and central amygdala; and the more ubiquitously distributed glucocorticoid receptor (GR) which has a 10-fold lower affinity for corticosterone [58], [59]. These receptors belong to the family of nuclear receptors [66], [206]. In their inactivated state they reside in the cytoplasm, bound to other molecules like heat shock proteins and immunophilins. Upon binding of the ligand to the receptor, these chaperon molecules dissociate, enabling the receptor to translocate to the nucleus, dimerize and bind to response elements in the promoter region of responsive genes; this process is referred to as transactivation. In addition, activated receptor monomers can interact with other transcription factors, in this way leading to transrepression of specific genes. Through both pathways, corticosteroid hormones can exert a delayed but long-lasting control over neuronal function. More recently, it has been recognized that corticosteroid hormones can also affect brain function through rapid nongenomic pathways [54], [110], [260].

In addition to NA and corticosterone, stress exposure also leads to enhanced release of neuropeptides in the brain, such as vasopressin and corticotrophin releasing hormone (CRH) [15], [70], [152]. Collectively, catecholamines, neuropeptides and corticosterone change (among other things) the electrical properties, shape and proliferative capacity of cells in the brain, thus giving rise to the central and behavioral aspects of a stress response. In the next section of this review we will summarize the current views on the cellular effects induced by a brief period of stress, focusing particularly on the role of corticosterone. It should be kept in mind that stress and stress hormones also affect other aspects of brain function, such as bio-availability of neurotransmitters (see e.g. [230]) and metabolic processes [73], each contributing to the dynamic range of cellular effects of stress; these, however, are beyond the scope of the present review. The emphasis in this review will be on stress-induced changes in cell function/shape of the hippocampus, an area which (i) forms a target for noradrenergic as well as peptidergic pathways, (ii) highly expresses both MR and GR, and (iii) has been extensively investigated. We will only briefly allude to cellular effects of stress in other parts of the brain. How these changes in cellular activity translate into behavioral effects will be discussed at the end of the section; for more extensive reviews of behavioral stress effects, e.g. on memory, we refer to excellent reviews [163], [246].

While cellular changes in brain and their consequences for behavioral and peripheral functions after brief stress exposure serve to restore homeostatic control and therefore are beneficial for survival of the organism, it is important that the cellular changes are eventually terminated, as they ‘wear out’ cells and potentially make them vulnerable to (other) adverse situations [177], [178], [240]. The latter could happen when the organism is repeatedly exposed to stressful situations. Repetitive stress exposure will gradually change the electrical characteristics, morphology and proliferative capacity of brain cells, so that after several weeks the basal as well as (acute) stress-induced properties of brain cells are altered. The nature of the stress paradigm plays a role in the eventual effects on brain activity. In the third part of this chapter we will briefly discuss the various models that have been used to study the cellular consequences of long-lasting stress exposure. In the fourth part, we will give an overview of the cellular changes that have been reported after chronic stress, again with emphasis on the hippocampal formation. Subsequently, we will discuss the possibility to reverse effects of chronic stress and the mechanisms that could lead to changes in brain function after chronic stress exposure.

Repetitive exposure to uncontrollable stressors is known to be a risk factor for the precipitation of psychiatric disorders in vulnerable individuals [58], [201], [258]. In the final part we will summarize the current evidence for this view and discuss how the changes in shape, proliferative capacity and electrical properties of brain cells seen in animal models could explain the increased risk on precipitation of clinical symptoms in major depression.