In the first half of the 20th century, Hans Selye described a uniform mammalian response to stress. This response is triggered when the homeostasis of the organism is threatened. Selye termed this universal response the “general adaptation syndrome”. It is characterized by an initial “alarm reaction” during which a response is mounted by increasing the activity of neuroendocrine systems initiated by the hypothalamic-pituitary-adrenal (HPA) axis. Enlargement of the adrenal cortex is a typical outcome in this stage. Often, an additional feature of the alarm reaction is the loss of body weight. The second phase, “stage of resistance” is characterized by an adaptive response allowing the organism to cope with the demands of the stress. The manifestations of this stage tend to be opposite to those of the alarm reaction. The body weight reductions that accompany the first stage usually return back to normal in this stage. The third and final phase, “stage of exhaustion” is characterized by a diminished capacity to cope with subsequent stressors that the organism may encounter and is strikingly similar to the alarm reaction stage.
Since Hans Selye first described the general adaptation syndrome, a large number of studies have been conducted investigating various aspects of neuroendocrine responses to stress. Many systems and organs work in concert to bring about the stress response which can be a very complex interaction of various hormones. One such system is the HPA axis. It is the body’s main defense mechanism against stress and is highly involved in the coping response to metabolic and psychological challenges.
The hypothalamic-pituitary-adrenal axis is regulated by factors connected to mood disorders, including circadian rhythms and stress. The HPA axis also exhibits abnormalities in mood disorders that have made it of interest as a biomarker for understanding and treating these diseases. The HPA axis communicates through a relay of hormones. The release of corticotrophin releasing hormone from the paraventricular hypothalamus causes the anterior pituitary to release adrenocorticotropin (ACTH), resulting in the release of glucocorticoids from the adrenal glands. The primary glucocorticoid is cortisol in humans and is corticosterone in rodents, which lack 17-hydroxylase. The HPA axis regulates the secretion of glucocorticoids through negative feedback inhibition, in which the release of glucocorticoids from the adrenal glands inhibits corticotropin releasing hormone and ACTH secretion. When glucocorticoids are released, they can bind to mineralocorticoid receptors, concentrated in limbic regions, and to glucocorticoid receptors (GR), which are widely distributed throughout the brain. Mineralocorticoid receptors are highly expressed in the hippocampus and lateral septum. To a lesser extent mineralocorticoid receptors are also expressed in the cerebral cortex and amygdala. GR are located in the medial prefrontal cortex, hippocampus, amygdala, caudate putamen, nucleus accumbens, lateral septum, bed nucleus stria terminalis, hypothalamus, thalamus, dorsal raphe nucleus, ventral tegmental area, locus coeruleus and cerebellum. Binding of glucocorticoids to their receptors induces receptor translocation to the nucleus, where corticosteroid receptors act as transcription factors to modify gene ex
The HPA axis secretes glucocorticoids in a circadian rhythm. Lower glucocorticoid secretion occurs during the nadir or trough of the circadian rhythm, when an organism is less active. Higher glucocorticoid secretion occurs during the peak of the circadian rhythm, when an organism is more active. In humans, the trough of the circadian rhythm begins in the evening, and the peak of the circadian rhythm begins during the morning. Since rodents are nocturnal animals, the trough of the circadian rhythm is during the morning and the peak of the circadian rhythm is during the evening. In general, the circadian rhythm is known to regulate sleeping and feeding patterns in humans and animals, and is thought to function to conserve energy. In addition to the circadian release of glucocorticoids, a variety of stressors can activate the HPA axis to release glucocorticoids, helping to maintain homeostasis during stress.
Brain corticosteroid receptors differentially regulate circadian and stress-induced HPA activity. Since endogenous glucocorticoids have a higher affinity for mineralocorticoid receptors than for GR, mineralocorticoid receptors are thought to be saturated when glucocorticoid levels are low. Therefore, mineralocorticoid receptors have traditionally been thought to be important for controlling basal HPA activity during the nadir of the circadian rhythm when glucocorticoid levels are low. However, there is some evidence that mineralocorticoid receptors can also participate in feedback inhibition during mild stress when glucocorticoid levels are elevated. In contrast, GR are occupied during the peak of the circadian rhythm and following stressful events, when glucocorticoid levels are high.
When glucocorticoids are released, they can act directly on the anterior pituitary gland, the paraventricular hypothalamus and on non-hypothalamic brain regions to mediate the negative feedback of glucocorticoids. However, the brain is more sensitive to glucocorticoid negative feedback than is the anterior pituitary. The forebrain areas that have been shown to mediate HPA negative feedback via indirect projections to the paraventricular hypothalamus include the prefrontal cortex, hippocampus, amygdala, and the bed nucleus stria terminalis. Both the prefrontal cortex and hippocampus have been implicated in feedback regulation of HPA activity through studies in which glucocorticoid implants in these regions were found to inhibit ACTH or corticosterone secretion. In contrast, the amygdala and bed nucleus stria terminalis have been found to enhance HPA activity and glucocorticoid release. This difference in function is supported by studies showing that amygdala damage results in decreased ACTH and corticosterone release and that stimulation of bed nucleus stria terminalis increases corticosterone secretion. Therefore, forebrain regions have been shown to have roles in both stimulating and inhibiting glucocorticoid release.
Of interest, many of the forebrain regions expressing GR have also been implicated in depression or anxiety pathology. For example, decreased hippocampus volume correlates with memory impairment in depressed patients. Altered brain activity, measured either by changes in glucose uptake or cerebral blood flow in positron emission tomography, or by changes in blood oxygen levels in functional magnetic resonance imaging, has been identified in both depression and anxiety. Although anxiety is not associated with hippocampal changes, a common observation in depression and anxiety includes decreased and increased brain activity in the prefrontal cortex and amygdala, respectively. It has been hypothesized that decreased activity in the prefrontal cortex results in the loss of inhibitory control over the amygdala, resulting in increased amygdala activity. Consequently, the increased amygdala activity could lead to uncontrollable or exaggerated responses to stress that can lead to or exacerbate depression and anxiety.