Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental demands on the individual, be they physical, physiological, or psychosocial. The impact of this overload is deleterious to brain health, and it results in vulnerability to a range of brain disorders, including major depression and cognitive deficits. Thus, stress biology is one of the best understood systems in affective neuroscience and is an ideal target for addressing the pathophysiology of many brain-related diseases. The story we present began with the discovery of glucocorticoid receptors in hippocampus and has extended to other brain regions in both animal models and the human brain with the further discovery of structural and functional adaptive plasticity in response to stressful and other experiences.
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