Hypothalamic–pituitary–adrenal axis
The HPA axis is a major neuroendocrine system[1] that controls reactions to stress and regulates many body processes, including digestion, immune responses, mood and emotions, sexual activity, and energy storage and expenditure.
[2] While steroid hormones are produced mainly in vertebrates, the physiological role of the HPA axis and corticosteroids in stress response is so fundamental that analogous systems can be found in invertebrates and monocellular organisms as well.
[1] The key elements of the HPA axis are:[3] CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence.
[5] Important to the function of the HPA axis are some of the following feedback loops: Release of corticotropin-releasing hormone (CRH) from the hypothalamus is influenced by stress, physical activity, illness, by blood levels of cortisol and by the sleep/wake cycle (circadian rhythm).
The HPA axis integrates physical and psychosocial influences in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival.
[6] Anatomical connections between brain areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the HPA axis.
Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids.
[12][13] During an immune response, proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through the blood–brain barrier where they can interact with the brain and activate the HPA axis.
[13][14][15] Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes.
[13][14] Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
The drug LY354740 (also known as Eglumegad, an agonist of the metabotropic glutamate receptors 2 and 3) has been shown to interfere in the HPA axis, with chronic oral administration of this drug leading to markedly reduced baseline cortisol levels in bonnet macaques (Macaca radiata); acute infusion of LY354740 resulted in a marked diminution of yohimbine-induced stress response in those animals.
[31] Additionally, they require a longer time for their stress hormone levels to return to baseline following exposure to both acute and prolonged stressors.
Prenatally stressed animals also show abnormally high blood glucose levels and have fewer glucocorticoid receptors in the hippocampus.
[32] In humans, prolonged maternal stress during gestation is associated with mild impairment of intellectual activity and language development in their children, and with behavior disorders such as attention deficits, schizophrenia, anxiety and depression; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems.
Exposure to mild or moderate stressors early in life has been shown to enhance HPA regulation and promote a lifelong resilience to stress.
There may be a critical period during development during which the level of stress hormones in the bloodstream contribute to the permanent calibration of the HPA axis.
For example, increased maternal licking and grooming has been shown to alter expression of the glucocorticoid receptor gene implicated in adaptive stress response.
Though animal models allow for more control of experimental manipulation, the effects of early life stress on HPA axis function in humans has also been studied.
[41] In one study, adult survivors of childhood abuse that are not depressed show increased ACTH response to both exogenous CRF and normal cortisol release.
Heim and colleagues have proposed that early life stress, such as childhood abuse, can induce a sensitization of the HPA axis, resulting in particular heightened neuronal activity in response to stress-induced CRH release.
The HPA axis was present in the earliest vertebrate species, and has remained highly conserved by strong positive selection due to its critical adaptive roles.
[44][45] Widely studied in animal models (e.g. licking and grooming/LG in rat pups),[47] the consistency of maternal care has been shown to have a powerful influence on the offspring's neurobiology, physiology, and behavior.
Whereas maternal care improves cardiac response, sleep/wake rhythm, and growth hormone secretion in the neonate, it also suppresses HPA axis activity.
Although the primary mediators of the HPA axis are known, the exact mechanism by which its programming can be modulated during early life remains to be elucidated.
Various hypotheses have been proposed, in attempts to explain why early life adversity can produce outcomes ranging from extreme vulnerability to resilience in the face of later stress.
Conversely, if an individual is exposed to significant early life adversity, heightened HPA axis reactivity may "mismatch" them in an environment characterized by low stress.
Ultimately, the conservation of the HPA axis has underscored its critical adaptive roles in vertebrates, so, too, various invertebrate species over time.
The HPA axis plays a clear role in the production of corticosteroids, which govern many facets of brain development and responses to ongoing environmental stress.
