The Brain on Stress

Abstract

The discovery of stress-hormone receptors in the hippocampal formation has fostered research showing that the brain, including its higher cognitive centers, is the key organ of the response to stressors, in terms of both perception of what is stressful and its ability to determine the consequences of stress for brain and body via the neuroendocrine, autonomic, immune, and metabolic systems. These systems, in turn, are responsible for either successful adaptation or pathophysiology as a result of the cumulative burden of adaptation to stress and maladaptive lifestyle, which is known as “allostatic load.” The brain itself is also a target of stress and stress-related hormones, and it undergoes structural and functional remodeling and significant changes in gene expression. These changes are adaptive under normal circumstances but can lead to damage when stress is excessive. The growing recognition of the adaptive plasticity and stress vulnerability of the brain itself, which began with research on the hippocampus, now includes other brain regions such as the amygdala and prefrontal cortex and fear-related memories, working memory, and self-regulatory behaviors. The interactions between these brain regions during the biological embedding of experiences over the life course determines whether events in the social and physical environment will lead to successful adaptation or to maladaptation and impaired mental and physical health, with implications for understanding health disparities and the impact of early life adversity and for intervention and prevention strategies.

Keywords

neuroscience disorders anxiety stress development child aging memory

The Behavioral Science Program at The Rockefeller University in 1966 included as senior members Neal Miller and Carl Pfaffman, William Estes and George Miller, and Peter Marler and Donald Griffin, a who’s who of physiological psychology, cognitive psychology and animal behavior, respectively. The atmosphere was exciting; these specialists in different aspects of cutting-edge behavioral science educated one another and provided a rich training ground for students, postdoctoral scholars, and young faculty, including me and my current Rockefeller colleagues Donald Pfaff and Fernando Nottebohm.

Neal Miller played a major role in defining the field of behavioral medicine through work that led to the widespread use of biofeedback and by calling attention to mechanisms by which the nervous system and body interact. My own research on brain-body interactions, involving the neuroendocrine system, began in the Miller laboratory. This research was shaped by his interest in stress, which inspired our 1968 discovery of stress hormone receptors in the hippocampal formation (McEwen, Weiss, & Schwartz, 1968), a brain region involved in episodic, spatial, and contextual memory and mood regulation. As we now know, stress hormones act in the hippocampus and in other brain regions involved in cognition and affect regulation rather than affecting only the hypothalamus. This knowledge has triggered a large number of studies on animal models; more and more results from these studies have been translated to human stress-related disorders (such as depression) and changes associated with the aging process. This line of research has reinforced the notion that the brain is the key organ of the stress response in terms of both perception of what is stressful and its ability to determine the consequences of stress for brain and body.

Stress Through the Lifespan

Stress hormones progressively impair brain function, which further increases cortisol levels, which promotes further impairment. This concept, called the glucocorticoid cascade hypothesis, has fostered considerable research on the “weathering” of the brain and body during aging, including effects on longevity and on decline of cognitive function. It was also a stimulus for the allostatic load concept described later in the text (Sapolsky, 1992; Sapolsky, Krey, & McEwen, 1986). One very productive direction of this research has been the investigation of maternal care and early-life stress as a determinant of stress vulnerability by Meaney, Plotsky, and others (Liu et al., 1997), following on the pioneering work of Levine and Denenberg (Levine, Haltmeyer, Kara, & Denenberg, 1967) on effects of “handling” of newborn rats. This work, in turn, provided an experimental foundation for recent translational research on gene-environment interactions, now called “epigenetics,” and, in particular, for the effects of abuse and trauma in childhood on depression and antisocial behavior as well as cardiovascular disease and obesity (Caspi et al., 2002; Felitti et al., 1998). This work also shows positive effects of a nurturing environment in improving brain function and promoting a healthy body (Center on the Developing Child, n.d.; Shonkoff, Boyce, & McEwen, 2009).

Indeed, stress and stress hormones can have positive effects. Along with investigating the damaging effects of chronic stress, a second direction of our research has been to elaborate the notion that the mediators of the biological and behavioral stress responses exert positive, adaptive effects in the aftermath of stress (McEwen, 1998; McEwen & Gianaros, 2011). The concepts of allostasis (active process of adaptation and maintaining homeostasis) and allostatic load (deterioration produced by too much stress and a resulting unhealthy lifestyle) emphasize the protective as well as damaging effects of these mediators, which act in a nonlinear manner and simultaneously influence brain and multiple body systems (McEwen & Gianaros, 2011). For example, acute stress enhances immune function and improves certain types of memory, whereas chronic stress has the opposite effect; moreover, disorders such as depression, diabetes, and mild cognitive impairment in aging share comorbidities (McEwen & Gianaros, 2011).

Psychosocial Factors and Stress

The concepts of allostasis and allostatic load have helped health psychologists and other social scientists, as well as epidemiologists and researchers in the fields of medicine and psychiatry, to integrate the biology of stress with the psychosocial factors that promote stress-related disorders and pathophysiology (McEwen & Gianaros, 2010, 2011; Seeman, Epel, Gruenewald, Karlamangla, & McEwen, 2010). Measurement of allostatic load, using a battery of biomarkers, developed by Teresa Seeman at UCLA and colleagues in the MacArthur Research Network on Socioeconomic Status and Health, has provided predictive power in understanding how socioeconomic status can “get under the skin” to affect health (Seeman et al., 2010). These allostatic load measures have also provided insights into the protective role of social support on risk factors for disease. Moreover, normalization of levels of individual allostatic load measures have been shown to be related to a positive outlook on life (Steptoe, Wardle, & Marmot, 2005). These results, in turn, encourage the establishment of a biology of resilience and positive health and for expanding the concept of allostasis to include the biology of resilience (Davidson & McEwen, 2012; Ryff & Singer, 1998).

The enormous progress in neuroscience, biomedicine, and behavioral science has created a new view of brain-body science. It has also fostered the introduction of such new measures of cumulative stress as telomere length and telomerase activity, which have been shown to decrease in caregivers of autistic children and in conditions such as obesity and diabetes. The new view of reciprocal influences of brain and body systems has also fostered research in brain involvement in psychological concepts such as self-esteem and locus of control, in which hippocampal volume is correlated with low self-esteem and also to a failure to habituate to, and thereby shut off, cortisol secretion efficiently after a repeated public speaking challenge (Pruessner et al., 2005). The prolongation of cortisol secretion and its chronic effects on brain and body contribute to allostatic load (McEwen, 1998).

Low self-esteem and locus of control are also likely factors in explaining how subjective ratings of socioeconomic status (i.e., where one places oneself on a ladder of income and educational attainment) and objective ratings of socioeconomic status can be equally powerful predictors of health (Seeman et al., 2010). Indeed, lower subjective and objective socioeconomic status have also been linked to systemic inflammation and reductions of brain white matter as well as increased incidence of cardiovascular disease, diabetes, depression, and certain cancers (Gianaros, Marsland, Sheu, Erickson, & Verstynen, 2012; Seeman et al., 2010).

Summary

Finally, as noted, the line of research that we embarked on under the inspiration and guidance of Neal Miller and the Rockefeller Behavioral Science Program has reinforced the notion that the brain is the key organ of the stress response for three principal reasons: (a) The brain interprets what is threatening and therefore stressful; (b) it determines and regulates behavioral and physiological stress responses, the latter through the autonomic, immune, neuroendocrine, and metabolic systems that may result in successful adaptation or lead to allostatic load and disease; and (c) the brain is a target of stress and undergoes structural and functional remodeling and significant changes in gene expression that affect its function (McEwen, 2007; McEwen & Gianaros, 2011; McEwen & Morrison, 2013). This includes the biological embedding of experiences of adversity throughout the life course (Boyce, Sokolowski, & Robinson, 2012). Thus, recognition of the stress vulnerability and plasticity of the brain, which began with investigations of the hippocampus, now includes the amygdala and prefrontal cortex and other brain regions and involves an increasing emphasis on formation and extinction of fear-related memory, attentional mechanisms, executive function, and self-regulatory behaviors (McEwen, 2007; McEwen & Gianaros, 2011). These brain changes, which are reversible in healthy people (McEwen, 2007) and therefore do not constitute damage per se, are not only amenable to alteration by pharmaceutical agents but also influenced by lifestyle factors such as exercise (Erickson et al., 2011), cognitive-behavioral therapies (Davidson & McEwen, 2012), social support (Seeman et al., 2010), good sleep and a prudent diet, and by policies that encourage people to adopt healthier lifestyles and reduce stress (McEwen, 2007; McEwen & Gianaros, 2011). A major challenge for future research and practice is to harness the capacity of the brain and body to show plasticity in situations where adversity has left its mark.

Footnotes

Declaration of Conflicting Interests

The author declared no conflicts of interest with respect to the authorship or the publication of this article.

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