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Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress
remain reactive and produce catecholamines for many years. That is commonly seen in people with anxiety disorders who have increased heart rates and blood pressure. Long-term increase in catecholamines can produce chronic inflammation, as discussed later in the chapter.
The Hypothalamus-Pituitary-Adrenal Axis
In the peripheral stress pathway, the hypothalamus secretes corticotropin-releasing hormone (CRH), which acts on the pituitary to secrete corticotropin (also known as adrenocorticotropic hormone). Corticotropin enters the bloodstream and acts on the adrenal cortex to induce release of the glucocorticoid hormone cortisol. This pathway is known as the HPA axis or peripheral stress response (Chrousos and Gold 1992; Selye 1956).
Cortisol is distributed to body tissues where it serves several functions, such as replenishing energy lost to the epinephrine surge, increasing cardiovascular tone; enhancing memory for avoiding danger in the future; preserving energy; and, if necessary, activating immune-cell migration to areas of the body where there is infection or injury (McEwen and Lasley 2002). Cortisol also has key functions in the brain: it acts to increase arousal, vigilance, attention, and formation of memories (Charney 2004). It can also act in the amygdala and BNST to increase production and release of CRH from the hypothalamus. Cortisol also facilitates fear conditioning (Roozendaal et al. 2006). However, if the cortisol surge is large and prolonged, it can suppress growth, tissue repair, reproduction, digestion, and inflammation (Sapolsky 2003).
When cortisol reaches the brain it exerts a negative feedback on the HPA axis. First, it binds to glucocorticoid receptors in the hippocampus (McEwen et al. 1968), which projects into the hypothalamus, and binds to glucocorticoid receptors in the hypothalamus. Cortisol binding in both the hippocampus and the hypothalamus acts to turn off CRH production and release by the hypothalamus (Herman et al. 1989; McEwen et al. 1992). The net effect is that high cortisol concentrations reaching the brain inhibit the HPA axis (McEwen 2002b; Vermetten and Bremner 2002). Thus, glucocorticoids, such as cortisol, enhance CRH in the amygdala and help to turn on the HPA axis when activated by stress, and a feedback mechanism turns the HPA axis off at the level of the hypothalamus and pituitary (see Figure 4-1). It is the balance between activation via the amygdala and inhibition via the hypothalamus, prefrontal cortex, and hippocampus that determines HPA activity and how rapidly it is turned on and off.
The hippocampus plays a key role in shaping memories; it forms explicit memory, which is the ability to recollect an event consciously and to assemble its pieces to form a coherent memory of the whole event. The opposite, nondeclarative memory, refers to memories not consciously recalled, for example, such skills as playing the piano and reading. For fearful memories, the hippocampus works with the amygdala and the prefrontal cortex of the brain. The prefrontal cortex modulates the actions of the amygdala, usually through inhibition, and thus can control cortisol secretion and activation of the parasympathetic and sympathetic nervous systems (Radley et al. 2006; Thayer and Brosschot 2005). The prefrontal cortex also participates in attention, decision making and sense of control, working memory, extinction of fear memories, and other aspects of cognitive flexibility (Hariri et al. 2006; McDougall et al. 2004).
The effects of cortisol (peripheral pathway) and epinephrine (central pathway) are not restricted to the central nervous system (CNS). Many other tissues respond to cortisol and communicate with the CNS in a bidirectional manner. Of particular concern for the stress response is the immune system. In the acute phase of the stress response, the immune system fights infection and repairs wounds by boosting immunity. Some immune cells (such as leukocytes, white blood cells) are rapidly deployed from the circulation to the skin, where they