Protective and damaging effects of stress mediators: central role of the brain

Bruce S McEwen, Bruce S McEwen

Abstract

The mind involves the whole body and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals. It is notjust the dramatic stressful events that exact their toll, but rather the many events of daily life that elevate and sustain activities of physiological systems and cause sleep deprivation, overeating, and other health-damaging behaviors, producing the feeling of being "stressed out." Over time, this results in wear and tear on the body which is called "allostatic load," and it reflects not only the impact of life experiences but also of genetic load, individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis, but in the long run allostatic load causes changes in the body that can lead to disease. The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral responses. Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing structural remodeling, which alters behavioral and physiological responses. Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions, such as mild cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low self-esteem. Alterations in amygdala and prefrontal cortex are also reported. Besides pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden.

Figures

Figure 1.. Four types of allostatic load.…
Figure 1.. Four types of allostatic load. The top panel illustrates the normal allostatic response, in which a response is initiated by a stressor, sustained for an appropriate interval, and then turned off. The remaining panels illustrate four conditions that lead to allostatic load: top left- repeated “hits” from multiple stressors; top right- lack of adaptation; bottom left- prolonged response due to delayed shut down; and bottom right - inadequate response that leads to compensatory hyperactivity of other mediators (eg, inadequate secretion of glucocorticoid, resulting in increased levels of cytokines that are normally counter-regulated by glucocorticoids). Reproduced from reference 1 ; McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998; 338:171-179. Copyright © Massachusetts Medical Society 1998.
Figure 2.. Nonlinear network of mediators of…
Figure 2.. Nonlinear network of mediators of allostasis involved in the stress response. Arrows indicate that each system regulates the others in a reciprocal manner, creating a nonlinear network. Moreover, there are multiple pathways for regulation- eg, inflammatory cytokine production is negatively regulated via anti-inflammatory cytokines as well as via parasympathetic and glucocorticoid pathways, whereas sympathetic activity increases inflammatory cytokine production. Parasympathetic activity in turn, restrains sympathetic activity DHEA, dehydroepiandrosterone
Figure 3.. Central role of the brain…
Figure 3.. Central role of the brain in allostasis and the behavioral and physiological response to stressors. Reproduced from reference 1: McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171-179. Copyright © Massachusetts Medical Society 1998.
Figure 4.. Brain regions that are involved…
Figure 4.. Brain regions that are involved in perception and response ress, and which show structural remodeling as a result of stress.

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