The effects of chronic stress on health: new insights into the molecular mechanisms of brain–body communication

Today’s life rhythms and demands are often challenging and require intense physical and psychological efforts in order to be sustained. An individual reacts to physical and mental strain that is potentially health threatening by activating interconnected neuroendocrine circuits. This response allows the body to face and deal with the challenge and re-establish homeostatic equilibrium. If the individual perceives a noxious stimulus as too intense, or its duration as too long, he may fail coping with it, and incur maladaptation. In this case, the stress response does not resolve into a state of balance (either similar or new, i.e., adapted, compared with the state before stress hits), neuroendocrine parameters remain altered, and illness may ensue. It is clear that stress has both a physical (objective) and a psychological (subjective) component: the latter, as described by Koolhaas and colleagues, depends on the individual perception of its predictability and controllability [1]. The way a person can anticipate a certain stressor and then control it, largely defines the resulting stress response, how promptly and efficiently it is activated promoting adaptation, and how fast it is turned off once equilibrium has been recovered. The time course of the stress response, characterized by measurable neuroendocrine and behavioral indexes, thus reveals whether a destabilizing stimulus is manageable, or conversely, cannot be handled and consequently becomes harmful. This implies that not all stimuli that elicit strong neuroendocrine responses are real stressors, but only those that exceed the individual’s ability to change and adapt. Cortical centers in the brain sense a disturbing stimulus and respond by activating pathways that through the limbic system stimulate peripheral networks, including the sympathetic–adrenal–medullary axis and the renin-angiotensin system, and later the hypothalamic–pituitary–adrenal (HPA) axis [2]. A cascade of events follows that results in the orchestration of a complex response. Adrenaline and other hormones, and neuropeptides are produced and regulate cardiovascular and metabolic functions (inducing, for instance, increases in heart rate, breath frequency, glucose release) for a prompt response concerted to overcome the challenge. If the distressing stimulus persists, the HPA axis kicks in to sustain the immediate reaction mediated by the centrally activated peripheral systems. The HPA response starts with the hypothalamus delivering corticotropin-releasing hormone to the pituitary and culminates with the stimulation of the adrenal cortex by the pituitary-derived adreno corticotropic hormone to produce glucocorticoids (GCs). Most organs and tissues, including sympathetic nerves, immune cells and several brain regions express GC receptors and are responsive to GCs induced by stress. Consequently, these hormones participate in the regulation of disparate stressassociated processes, from the modulation of cardiovascular effects and the immune function, to the eventual dampening of the stress response through inhibition of the HPA axis when adaptation is attained. In situations in which the stressor is overwhelming and cannot be resolved, stress becomes chronic. In this case, the Commentary