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The Relationship between Stress and Anxiety Disorders
The following excerpt is taken from the chapter Stress and Anxiety Disorders by C.V. Chen, S.A. George and I. Liberzon and is included in both the multivolume set Hormones, Brain and Behavior (Third Edition) and the Reference Module in Neuroscience and Biobehavioral Psychology
The Relationship between Stress and Anxiety Disorders
Careful examination of the relationship between stress, anxiety, and fear reveals an often-confusing picture due to both the degree of conceptual overlap and the liberal use of these definitions in the literature. To minimize potential confusion, we will be using these concepts in the following manner: stress represents an interaction between a particular type of environmental stimuli (stressors) and specific stress response systems, namely hypothalamic–pituitary–adrenal (HPA) axis and/or catecholamines. Anxiety and fear, on the other hand, constitute a set of behavioral, cognitive, and physiologic responses to threatening situations or uncertainty. While fear often constitutes a normal response to a well-defined threat, anxiety is often dissociated from the external stimulus and is not necessarily associated with a well-defined physiological response. From these definitions one can appreciate the potential for conceptual overlap and confusion, stemming from two sources: (1) anxiety and fear can be a part of the stress response, and (2) anxiety and fear, in turn, can constitute a component of a potential stressor. In this chapter we focus on the long-lasting effects of stress on anxiety symptoms and behaviors, usually examining the relationship between stress exposure and symptoms of anxiety that are dissociated in time.
An additional important distinction is between normal or adaptive fear and anxiety, and the pathological conditions. These processes evolved to promote survival of an organism and, under normal functioning, serve advantageous and adaptive purposes. While the character of behavioral, cognitive, and autonomic responses might not differ between the normal and pathological conditions, the context in which they occur, their intensity, and the extent to which they exert their effects on overall behavior, defines the extent of the pathology. This phenomenological overlap, at times, leads to erroneous assumptions of identical neurophysiology underlying both normal and pathological anxiety.
A particularly interesting example of stress/anxiety interaction comes from examining posttraumatic stress. Posttraumatic stress disorder (PTSD) is, per definition, a stress disorder (induced or triggered by trauma) and the clinical picture includes multiple manifestations of pathological anxiety (among other symptoms). The most recent DSM-V-based nosology recognizes the unique character of PTSD, by no longer characterizing it as anxiety disorder; nevertheless, in the chapter we address PTSD extensively, as a prototypical disorder linking stress exposure, fear systems, and anxiety symptomatology. Furthermore, laboratory findings in PTSD also suggest changes in hormonal systems involved in the stress response. Traditionally, stress studies have primarily been focused on the investigation of particular neuroendocrine axes, while studies of fear and anxiety focused on cognitive and psychophysiologic responses, in humans, and on behavioral responses, in animals. A combination of these diverse modalities and both clinical and basic science approaches have contributed to substantial growth of knowledge in these fields of late, and even more integrative research will be needed in the future to further elucidate complex interactions between these systems.
Description of Basic Stress and Anxiety Systems
The HPA Axis and Its Regulation
Stress activates secretion of a number of hormones, and the main stress hormone system is the hypothalamic–pituitary–adrenal (HPA) axis. Stress-sensitive pathways in multiple areas of the brain are activated by stress and integrated at the hypothalamus resulting in a hormonal cascade leading to cortisol secretion by the adrenal cortices. Specifically, in response to a stressor, hypophysiotropic neurons from the medial parvocellular subdivision of the paraventricular nucleus of the hypothalamus (PVN) synthesize corticotropin-releasing hormone (CRH). Stressors known to activate CRH secretion in humans are novelty (Mason, 1968), exercise, insulin-induced hypoglycemia, and infection (Hellhammer and Wade, 1993). CRH is secreted into the hypophyseal portal system via the median eminence (Swanson et al., 1983) to act on receptors in cells of the anterior pituitary gland. This hormone is believed to be the primary secretagogue driving pituitary corticotrophs to release adrenocorticotropic hormone (ACTH) into the circulatory system. Circulating ACTH principally targets the adrenal cortex and stimulates glucocorticoid synthesis and secretion from the zona fasciculata (Smith and Vale, 2006; Herman and Cullinan, 1997; Miyashita and Williams, 2006).
Glucocorticoids, cortisol in humans and corticosterone in rodents, affect targets throughout the brain and periphery, and their primary function is to suppress immune activity and maintain or increase glucose in the blood. An increase in glucose prevents glucose-dependent tissue such as the heart and brain from starvation when their activity is high. In addition, it provides the organism with enough energy to maintain its alert state in case the danger persists. The released corticosterone can also facilitate memory consolidation of emotionally laden information. This process is regulated by the basolateral amygdala, which projects to several regions where new memories are stored, such as the caudate nucleus, nucleus accumbens, and cortex (McGaugh, 2004; Roozendaal and McGaugh, 2011). For instance, administration of cortisol to humans during presentation of emotionally arousing pictures enhanced long-term recall performance a week later (Buchanan and Lovallo, 2001). These effects of glucocorticoids on memory and higher cognitive functions, however, are quite complex and dose-, time-, tissue- and potentially context-specific, as illustrated by studies on glucocorticoid-mediated effects on extinction memory (for recent review see Maren and Holmes, 2016).
Glucocorticoid secretion is tightly controlled and limited by the negative feedback effects of glucocorticoids at both pituitary and brain sites. The ability of glucocorticoids to inhibit their own release has formed the basis for challenge studies such as the dexamethasone suppression test. Negative feedback of glucocorticoids on CRH and ACTH secretion can occur very rapidly, within 5–10 min (Russell et al., 2010 and Russell et al., 2016), and provides real-time inhibition to limit the stress response and prevent oversecretion of glucocorticoids (Smith and Vale, 2006; Keller-Wood and Dallman, 1984).
Apart from glucocorticoid negative feedback, afferent inputs to the PVN from different regions also modulate HPA axis activity. For instance, circulating epinephrine in the periphery increases vagal activation and, through cranial nerves, stimulates catecholamine release from the nucleus of solitary tract (NTS) to the PVN, enhancing HPA activity (Smith and Vale, 2006; Miyashita and Williams, 2006). In addition, the lamina terminalis (composed by the subfornical organ (SFO), median preoptic nucleus (MePO) and the vascular organ of the lamina terminalis) has cells outside the blood–brain barrier (BBB) and conveys information to the PVN about the osmotic composition of the blood. Particularly, angiotensinergic neurons in the SFO project to the PVN, amplifying CRH synthesis and release. Furthermore, the amygdala regulates HPA activity. In fact, constant high levels of glucocorticoids due to chronic stress upregulate the number of glucocorticoid receptors (GR) potentiating its effects. More specifically, the medial amygdala (MeA) responds to emotional stressors and projects to the MePO, the bed nucleus of the stria terminalis (BNST) and directly to the PVN. The central amygdala (CeA), on the other hand, responds to physical stressors and projects to the NTS, increasing the enhancing actions of the NTS in the PVN (Smith and Vale, 2006; Jankord and Herman, 2008; Herman et al., 2003).
Downregulation of the HPA axis is mediated mainly by three brain regions. First, stressors activate neurons containing gamma-aminobutyric acid (GABA) in the dorsomedial (DMH) and preoptic area (POA) of the hypothalamus that project to the PVN, inhibiting further secretion of glucocorticoids. In fact, lesioning these areas results in an increase in HPA activity (Smith and Vale, 2006; Herman et al., 2003; Jankord and Herman, 2008). Second, abundant GR in the hippocampus responds to glucocorticoid increase by activating GABAergic neurons in the BNST and peri-PVN that project to the PVN, dampening HPA activity. Lesions to the subiculum and CA1 region of the hippocampus eliminate this inhibitory function, increasing HPA activity (Smith and Vale, 2006; Herman et al., 2003; Jankord and Herman, 2008). Finally, the medial prefrontal cortex (mPFC) sends projections to the amygdala, BNST, and NTS from the infralimbic cortex, and to the DMH and POA from the prelimbic/anterior cingulate cortex to reduce HPA activation. Infusion of glucocorticoids to the mPFC decreases ACTH, supporting the existence of this pathway (Smith and Vale, 2006; Herman et al., 2003; Jankord and Herman, 2008).
In addition to stress as an activator of CRH/ACTH/glucocorticoid secretion, intrinsic rhythmic elements in the suprachiasmatic nucleus (SCN) drive secretion from the HPA axis in a circadian pattern. In fact, vasopressin synthesizing cells in the SCN project directly and indirectly to the PVN (Vrang et al., 1995; Kalsbeek et al., 1992, Kalsbeek et al., 1996 and Kalsbeek et al., 2004; Saper et al., 2005) to regulate HPA activity. In nocturnal mammals, the daily peak in HPA axis activity occurs at the end of the light period (Kalsbeek et al., 1996). In diurnal animals, including humans, the daily rise starts at the end of the night and peaks before waking (Lemos et al., 2006). In this sense, increased HPA axis activity is thought to prepare the organism for the upcoming increase in activity. Interestingly, SCN characteristics such as neuronal firing rate, metabolic activity, clock gene expression, and vasopressin release are similarly phased in nocturnal and diurnal species (Kalsbeek et al., 1996 and Kalsbeek et al., 2004; Sato and Kawamura, 1984; Dardente et al., 2004).
This excerpt is taken from the chapter Stress and Anxiety Disorders by C.V. Chen, S.A. George and I. Liberzon and is included in both the multivolume set Hormones, Brain and Behavior (Third Edition) which provides an authoritative reference on hormonally-mediated behaviors in insects, amphibians, fish, rodents, and more. The chapter is also included in the Reference Module in Neuroscience and Biobehavioral Psychology, a one-stop, interdisciplinary and authoritative resource containing over 3,400 articles in Neuroscience and Psychology. It is continuously reviewed and updated and new articles are commissioned to cover the latest advancements, essential in the fast-paced fields of Neuroscience and Psychology. Learn more here.
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