Population Health: Behavioral and Social Science Insights

By Bruce S. McEwen

Abstract

The brain is the central organ of stress and adaptation. Brain circuits are remodeled by stress so as to change the ability to self-regulate anxiety and mood and to perform working and episodic memory, as well as executive function and decisionmaking. The brain regulates the body via the neuroendocrine, autonomic, immune, and metabolic systems, and the mediators of these systems and those within the brain and other organs activate epigenetic programs that alter expression of genetic information so as to change cellular and organ function. While the initial active response to stressors promotes adaptation ("allostasis"), there can be cumulative change (e.g., body fat, hypertension) from chronic stress and a resulting unhealthy lifestyle ("allostatic load"), which may lead to disease, e.g. diabetes, cardiovascular disease ("allostatic overload"). Besides early life experiences, the most potent of stressors are those arising from the social and physical environment, and these can affect both brain and body. Gradients of socioeconomic status generally reflect the cumulative burden of coping with limited resources, toxic environments, and negative life events, as well as health-damaging behaviors that result in chronic activation of physiological systems and lead to allostatic load and overload. Can we intervene to change this progression? After describing the new view of epigenetics that negates the old notion that "biology is destiny" and opens new avenues for collaboration between the biological and the behavioral and social sciences, I summarize some of the underlying cellular, molecular, and neuroendocrine mechanisms of stress effects on brain and body. I then discuss integrative or "top down" approaches involving behavioral interventions at the individual level that take advantage of the increasing ability to reactivate plasticity in the brain. At the societal level, virtually all policies of government and the private sector affect health directly or indirectly and must be redirected to allow people to make choices that improve their chances for a healthy life.

Introduction

Stress is a condition of the mind and a factor in the expression of disease that differs among individuals and reflects not only major life events, but also the conflicts and pressures of daily life that elevate physiological systems so as to cause a cumulative chronic stress burden on brain and body. This burden reflects not only the impact of life experiences, but also of genetic variations; individual health-related behaviors such as diet, exercise, sleep patterns, and substance abuse; and epigenetic modifications in development and throughout life that set life-long patterns of behavior and physiological reactivity through both biological embedding and cumulative change. Epigenetics is the now popular way to describe gene x environment interactions via molecular mechanisms that do not change the genetic code but rather activate, repress, and modulate expression of the code.¹ Indeed, epigenetics denies the notion that "biology is destiny" and opens new opportunities for collaboration between the biological and behavioral and social sciences.

Acting epigenetically, hormones associated with stress protect the body in the short term and promote adaptation (allostasis), but in the long run, the burden of chronic stress causes changes in the brain and body that lead to cumulative change—such as accumulation of body fat (allostatic load)—or disease, such as diabetes or cardiovascular disease (allostatic overload). Brain circuits are plastic and appear to be continuously remodeled by stress, as well as by other experiences, so as to change the balance between anxiety and self-regulatory behaviors, including mood control and impulsivity, memory, and decisionmaking. Such changes may have adaptive value in danger, but their persistence and lack of reversibility in brains that are not resilient can be maladaptive.

Besides developmental influences associated with parent-infant interactions and the quality of early experiences, the most potent of stressors that influence adult life are those arising from the family, neighborhood, workplace, and exposure to local, national, and international events in the media that can affect both brain and body health and progression toward a variety of diseases. Social ordering in human society is associated with gradients of disease, with an increasing frequency of mortality and morbidity along a gradient of decreasing income and education (socioeconomic status, SES).^a Although the causes of these gradients of health are very complex, they likely reflect, with increasing frequency going down the SES ladder, the cumulative burden of coping with limited resources, toxic and otherwise stressful living environments, and negative life events, as well as differences in health-related behaviors (aka "lifestyle") that result in chronic activation of physiological systems involved in adaptation leading to allostatic overload.²

Thus, the behavioral and social sciences have increasingly important roles in the evolution of our knowledge about brain-body interactions over the life course in the area known now as "social neuroscience." Because of the multiple levels of interaction from the physical and social environment down to individual health behaviors and the impact of all of these upon the physiology of the body and internal workings of the brain, interventions must occur at multiple levels. This topic will be discussed in relation to our increasing knowledge of the potential for brain plasticity as influenced by "top down," that is, integrative, behavioral, and societal interventions facilitated by activities like exercise that increase the potential for plasticity. This is particularly important in discussions about understanding the origins of diseases and improving health and health care in view of the "lifecourse health development" perspective that is now superseding the "biopsychosocial" and "germs, genes, and biomedical" models of the past.³ Indeed, what happens at each stage of development, with particular potency early in life, has influences upon the trajectory that brain and body development take as the life course unfolds.

Determinants of Physical and Mental Health

There are many aspects of life experiences that influence physical and mental health, and the brain is central to all of them (Figure 1).⁴ Social stressors include trauma and abuse, major life events, and the daily experiences of work, family, neighborhood, and ongoing events in one's city, State, nation, and world. The brain processes all of this and determines the behavioral and physiological responses. Behavioral responses include quality and quantity of sleep and health- damaging behaviors, such as eating too much, smoking and substance abuse, including alcohol, as well as health promoting behaviors, such as regular physical activity and social integration and social support. Physiological responses that are normally adaptive ("allostasis"—see below) can lead to pathophysiology ("allostatic load and overload") when overused or dysregulated, as will be discussed below. Health behaviors feed into the network of allostasis and can lead to allostatic load (AL) and overload, sleep deprivation being a good example.⁵ Socioeconomic status (SES), including both education and income, are reflected in AL and overload and gradients of disease.^b Again, the brain with its influence on the rest of the body is key because subjective SES, reflecting perceived social position, is reflected in many aspects of physical and mental health.^6,7 The gradient of income in many societies is reflected not only in the frequency of diseases, but also in abnormal behavior, including depression, aggression, and violence and the degree of incarceration.^8,9 Next, we will consider in more detail the concepts of allostasis and allostatic load/overload and how experiences over the life course interact with the brain and body to cause disease.

Figure 1. Central role of the brain in the protective and damaging effects of the mediators of stress and adaptation

Source: McEwen BS. Protective and damaging effects of stress mediators. NEJM 1998;338(3):171-9. Used with permission.

The brain regulates neuroendocrine, autonomic, immune, and metabolic systems and the mediators of these systems interact in a non-linear manner.¹⁰ The concepts of allostasis and allostatic load/overload concern the protective, as well as potentially damaging, effects of the mediators of stress and adaptation, and they reflect a life course perspective that recognizes the power of the social environment and the health behaviors adopted by individuals. These concepts also include genetic contributions, and they recognize the central role of the brain and the importance of reciprocal brain-body interactions.^4,11

The distinction between AL and overload is based on the severity of the outcome—allostatic load refers to cumulative change in biomarkers, whereas allostatic overload signifies cumulative change that has pathophysiological consequences.² In the natural world, bears putting on fat for the winter develop an AL in terms of body fat that they burn off during hibernation; a bear in a zoo, overfed and physically inactive, can develop an allostatic overload that involves diabetes and cardiovascular disease. Migrating salmon present another example of AL in the natural world; they die after spawning due, in part, to a massive over-secretion of glucocorticoids.²

Measuring allostasis and allostatic load/overload requires biomarkers that tap into multiple interactive systems and look at the brain, as well as systemic physiology.^12–14 These biomarkers tap into measures of the multiple interacting mediators that affect many body systems concurrently, including measures of blood pressure, metabolic parameters (glucose, insulin, lipid profiles, and waist circumference), markers of inflammation (interleukin-6, C-reactive protein, and fibrinogen), heart rate variability, sympathetic nervous system activity (12-hour urinary norepinephrine and epinephrine), and hypothalamic-pituitary-adrenal axis activity (diurnal salivary free cortisol).¹⁴ Dehydroepiandrosterone (DHEA) and insulin-like growth factor 1 (IGF-1) have been used as positive markers of health. Choice of markers is limited by their cost and accessibility in studies involving large numbers of subjects. Telomeres and telomerase have been added as another endpoint of cumulative effect.^15,16

Biomarkers for allostasis and allostatic load/overload fall into different classes: primary, secondary, tertiary.¹⁷ Primary mediators include cortisol, sympathetic and parasympathetic activity, pro- and anti-inflammatory cytokines, metabolic hormones, and neurotransmitters and neuromodulators in the nervous system. Secondary mediators are those that reflect the cumulative actions of the primary mediators in a tissue/organ-specific manner, often reflecting the actions of more than one primary mediator, such as those described above: e.g. those that reflect abnormal metabolism and risk for cardiovascular disease, such as waste-hip ratio, blood pressure, glycosylated hemoglobin, cholesterol/high-density lipoprotein (HDL) ratio, and HDL cholesterol, as well as telomere length and telomerase activity.

In the realm of neuroimaging, secondary outcomes include functional activation of a set of brain regions that appear to define subtypes of anxiety disorder¹⁸ and hypo- or hyperactivation of the insula region of the brain that defines antidepressant responsiveness.¹⁹ In the case of telomeres and telomerase, which are secondary outcomes, oxidative stress and inflammatory processes are primary mediators that appear to cause these changes.¹⁵

Tertiary outcomes are actual diseases or disorders that are the result of AL that is predicted from the extreme values of the secondary outcomes and of the primary mediators.¹⁷ Cardiovascular disease, decreased physical capacity, and severe cognitive decline have been used as outcomes in successful aging studies.¹⁷ However, as noted by McEwen and Seeman,¹⁷ "...cognitive function could be classified as a secondary outcome, although Alzheimer's disease or vascular dementia would be a tertiary outcome when there is clearly a serious and permanent disease. By the same token, cancer would be a tertiary outcome, whereas the common cold would be a secondary outcome and an indirect measure, in part, of immune system efficacy."

Both simple and more complex mathematical approaches have been used to analyze the biomarker data to create an "allostatic load battery."¹² Regardless of the analysis used, the AL battery has revealed relationships with behavioral and other outcomes, including predictions of outcomes over time.^13,14,20 In the MacArthur Successful Aging Study, for example, higher AL scores predicted increased mortality 7 years later.²¹ Higher education was consistently associated with lower AL scores, while African Americans, in general, have higher AL scores and a flatter gradient across education. Neighborhood poverty has been found to be associated with higher AL scores among the residents.²² As might be expected, higher AL is associated with increased social conflict, whereas positive social support and social connectedness is linked to lower AL scores.^13,23 Allostatic load concepts have also been applied to begin to elucidate the systemic consequences of psychiatric disorders such as bipolar illness, major depression, and schizophrenia^24,25

In a recent review of the history of AL in relation to health disparities, Beckie concludes: "There is.... empirical substantiation for the relationships between AL and socioeconomic status, social relationships, workplace, lifestyle, race/ethnicity, gender, stress exposure, and genetic factors. The literature also demonstrated associations between AL and physical and mental health and all- cause mortality."²⁶ And, Beckie adds: "Targeting the antecedents of AL during key developmental periods is essential for improving public health. Priorities for future research include conducting prospective longitudinal studies, examining a broad range of antecedent allostatic challenges, and collecting reliable measures of multisystem dysregulation explicitly designed to assess AL, at multiple time points, in population-representative samples." Beckie, however, notes: "The results (of her systematic review) revealed considerable heterogeneity in the operationalization of AL and the measurement of AL biomarkers, making interpretations and comparisons across studies challenging, and therefore, future work should standardize the allostatic load battery along the lines used by Seeman and colleagues¹⁴ so as to make easier comparisons across studies."²⁶

Brain as Central Organ of Stress and Adaptation

The brain is the key organ of the response to stress because it determines what is threatening and therefore stressful, as well as the physiological and behavioral responses that can be either protective or damaging.⁴ The brain is a target of stress, and the hippocampus was the first brain region besides the hypothalamus to be recognized as a target of glucocorticoids.²⁷ Stress and stress hormones produce both adaptive and maladaptive effects on the hippocampus throughout the life course. Early life events influence lifelong patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The amygdala is an important target of stress and is important in fear and strong emotions, and the prefrontal cortex is involved in attention, executive function, and working memory.²⁸ The hippocampus and amygdala show an opposite response to repeated stress, involving remodeling of dendrites, whereas the prefrontal cortex shows both types of responses.²⁹ Hippocampal and medial prefrontal cortical neurons become shorter and less branched, and dentate gyrus neurogenesis is suppressed by repeated stress, whereas amygdala and orbitoprefrontal cortical neurons show signs of hypertrophy after repeated stress.^30,31 Repeated stress promotes impairment of hippocampal-dependent memory and enhances fear and aggression, as well as impairing attention set shifting, a form of executive function that indicates cognitive flexibility.³¹ In the human brain, magnetic resonance imaging (MRI) has shown amygdala enlargement and overactivity and hippocampal and prefrontal cortical shrinkage in a number of mood disorders.³² Hippocampal atrophy is also reported in Cushing's disease, post-traumatic stress disorder, recurrent depressive illness, and borderline personality disorder.^29,33 Knowledge of underlying anatomical changes and the mechanism of neuronal shrinkage or growth may help in developing treatment strategies to either reverse or prevent them, as will be discussed later in this chapter.

Early Life Adverse Experiences and Epigenetics

Early life events related to maternal care in animals, as well as parental care in humans, play a powerful role in later mental and physical health,^34,35 as demonstrated by the adverse childhood experiences (ACE) studies³⁶ and recent work that will be noted below. Animal models have contributed enormously to our understanding of how the brain and body are affected, starting with the "neonatal handling" studies of Levine and Denenberg³⁷ and the recent, elegant work of Meaney and Syzf.³⁸ Epigenetic, transgenerational effects transmitted by maternal care are central to these findings. Besides the amount of maternal care, the consistency over time of that care and the exposure to novelty are also very important, not only in rodents,^39,40 but also in monkey models.⁴¹ Prenatal stress impairs hippocampal development in rats, as does stress in adolescence.⁴² Abusive maternal care in rodents and the surprising attachment shown by infant rats to their abusive mothers appear to involve an immature amygdala,⁴³ activation of which by glucocorticoids causes an aversive conditioning response to emerge. Maternal anxiety in the variable foraging demand (VFD) model in rhesus monkeys leads to chronic anxiety in the offspring, as well as signs of metabolic syndrome.^44,45

In studies of ACE in human populations, there are reports of increased inflammatory tone, not only in children, but also in young adults related to early life abuse, which includes family instability, use of chronic harsh language, and physical and sexual abuse.^46–48 Chaos in the home is associated with development of poor self-regulatory behaviors, as well as obesity.⁴⁹ It should be noted that the ACE study was carried out in a middle-income population,⁵⁰ highlighting that poverty is not the only source of early life stressors.

Nevertheless, low SES does increase the likelihood of stressors in the home and neighborhood, including toxic chemical agents such as lead and air pollution.⁵¹ Without a determination of exact causes, it has been reported that low SES children are more likely than other children to be deficient in language skills and self-regulatory behaviors and also in certain types of memory that are likely to be reflections of impaired development of perisylvian gyrus language centers, prefrontal cortical systems, and temporal lobe memory systems.^52,53 Low SES and family poverty are reported to correlate with smaller hippocampal volumes,⁵⁴ overall smaller gray matter volume,⁵⁵ and impaired development in children of reduced prefrontal control of amygdala activity resulting in impaired self-regulatory behavior.^29,31,56 Neglect is associated with impaired white matter development and integrity.⁵⁷ Lower subjective SES, an important index of objective SES, is associated with reduction in prefrontal cortical gray matter.⁵⁸ Moreover, individuals reared in a lower SES environment tend to show greater amygdala reactivity to angry and sad faces,⁵⁹ which, as noted above, may be a predisposing factor for early cardiovascular disease that is known to be more prevalent at lower SES levels.⁶⁰ Finally, depression is often associated with low SES, and children of depressed mothers, followed longitudinally, have shown increased amygdala volume, while hippocampal volume was not affected.⁶¹

Yet, on the positive side, there are the "reactive or context-sensitive alleles"⁶² that, in nurturing environments, lead to beneficial outcomes and even better outcomes compared to less reactive alleles, even though those same alleles can enhance adverse outcomes in a stressful early life environment.^63-65 Regarding adverse outcomes and "good and bad environments," allostatic processes are adjusted via epigenetic influences to optimize the individual's adaptation to, and resulting fitness for, a particular environment, whether more or less threatening or nurturing.⁶⁶ Yet, there are "trade-offs" in terms of physical and mental health that, on the one hand, may increase the likelihood of passing on one's genes by improving coping with adversity and enhancing mental health and overall reproductive success, but on the other hand, may impair later health, e.g., by eating of "comfort foods" (for example Jackson, et al).⁶⁷ Moreover, when an individual faces a new challenge, there is the question of resilience in terms of the ability to show experience-related adaptation, for example, when an individual from a safe environment is placed into a dangerous one or vice versa. This brings up the question of plasticity, particularly in brain architecture that is so fundamental to brain and body health, and there is both old and new evidence that glucocorticoids, often thought of in a negative sense in relation to stress effects, play an important role in the ability of the brain to adapt to new challenges and possibly also to remediate deficits associated with stress over the life course.

Role of Glucocorticoids and Other Mediators in Brain Plasticity

The discovery of receptors for glucocorticoids in the hippocampus has led to many investigations in animal models and translation to the human brain using modern imaging methods that show the degree to which the brain, on the one hand, may be damaged by excessive glucocorticoids, but on the other hand, the beneficial role that they play in adaptive plasticity together with other mediators.³⁰ Glucocorticoids thus provide insights into brain plasticity, as well as the more negative side related to AL and overload.

The most striking findings from animal models have identified structural plasticity in the hippocampus, consisting of ongoing neurogenesis in the dentate gyrus⁶⁸ and remodeling of dendrites and synapses in the major neurons of Ammon's horn.¹⁷ The mediators of this plasticity include excitatory amino acids⁶⁹ and glucocorticoids, along with a growing list of other mediators, such as oxytocin, corticotrophin releasing factor, brain derived neurotrophic factor (BDNF), lipocalin-2, and tissue plasminogen activator (tPA).^30,33 Moreover, glucocorticoid actions involve both genomic and non-genomic mechanisms that implicate mineralocorticoid, as well as glucocorticoid, receptors and their translocation to mitochondria, as well as to cell nuclei, and an as-yet unidentified G-protein coupled membrane receptor related to endocannabinoid production.^70–72

Studies of the human hippocampus have demonstrated shrinkage of the hippocampus not only in mild cognitive impairment and Alzheimer's,⁷³ but also in Type 2 diabetes,⁷⁴ prolonged major depression,⁷⁵ Cushing's disease,⁷⁶ and posttraumatic stress disorder (PTSD).⁷⁷ Moreover, in non-disease conditions, such as chronic stress,⁷⁸ chronic inflammation,⁷⁹ lack of physical activity,⁸⁰ and jet lag,⁸¹ smaller hippocampal or temporal lobe volumes have been reported.

These changes may not be due to neuron loss but rather to volume reduction in dentate gyrus due to inhibited neuronal replacement, as well as dendritic shrinkage and glial cell loss. Autopsy studies on depression-suicide have indicated loss of glial cells and smaller neuron soma size,⁸² which is indicative of a smaller dendritic tree. With regard to type 2 diabetes, it should be emphasized that the hippocampus has receptors for, and the ability to take up and respond to, insulin, ghrelin, insulin-like growth factor-1 (IGF1), and leptin, and that IGF-1 mediates exercise-induced neurogenesis.³⁰ Thus, besides its response to glucocorticoids, the hippocampus is an important target of metabolic hormones that have a variety of adaptive actions in the healthy brain which is perturbed in metabolic disorders, such as diabetes.³⁰

There is a positive side to glucocorticoid action that can be harnessed to promote plasticity and, through that, adaptation and resilience. Glucocorticoid actions involve both genomic and non- genomic mechanisms in mitochondria, as well as in synaptic terminals and dendrites and spines, and interactions with excitatory amino acids and endocannabinoids.^69,71 These actions mediate adaptive neuronal functions, including the ongoing turnover of spine synapses resulting from the ultradian fluctuation of glucocorticoids⁸³ that is involved in the diurnal fluctuations of behavior and is important for efficient motor learning.⁸⁴

These glucocorticoid actions are likely to be involved in the remarkable reversal of amblyopia ("lazy eye" resulting from monocular deprivation during development) that was first shown to be reversed by patterned light exposure in adulthood facilitated by fluoxetine.⁸⁵ This is because, after showing that fluoxetine works, caloric restriction every other day was also shown to be effective.⁸⁶ Then, because caloric restriction elevates glucocorticoids, putting glucocorticoids in the drinking water every other day during visual stimulation was able to mimic the effects of both fluoxetine and food restriction.⁸⁶ Thus, glucocorticoids may play an important role in the re-establishment of a new window of plasticity.⁸⁷ The ultradian fluctuation of glucocorticoids has been shown to be essential for the ongoing turnover of spines on dendrites where excitatory synapses are formed,⁸³ and this turnover plays a role in motor learning and possibly other adaptive functions.⁸⁴

A key mechanism in reactivating plasticity involves reducing inhibitory neuronal activity by GABAergic basket neurons.⁸⁸ One application of reactivation of plasticity is for depressive illness, which is more prevalent in individuals who have had adverse early life experiences.⁵⁰ BDNF may be a key feature of the depressive state, and elevation of BDNF by diverse treatments ranging from antidepressant drugs to regular physical activity may be a key feature of treatment.⁸⁹ Yet, there are other potential applications, such as the recently reported ability of fluoxetine to enhance recovery from stroke.⁹⁰ In both examples, the reactivation of plasticity is accompanied by a behavioral intervention involving behavioral therapy for depression and physical therapy for stroke, since the reactivated plasticity must be directed towards a desired outcome by what I shall refer to as a "top down" or "integrative" intervention. This is to be distinguished from a "bottom up" intervention, such as the use of a pharmaceutical agent targeted at a molecular pathway.

Interventions

What can be done to remediate the effects of chronic stress over the life course at both individual and societal levels? For the individual, the complexity of interacting, non-linear and biphasic actions of the mediators of stress and adaptation, as described above, emphasizes behavioral, or "top-down," interventions (i.e., interventions that involve integrated central nervous system [CNS] activity) that include cognitive-behavioral therapy, physical activity, and programs such as the Experience Corps that promote social support and integration and meaning and purpose in life.^12,30 In contrast, pharmacological agents, which are useful in many circumstances to redress chemical and molecular imbalances, nevertheless run the risk of dysregulating other adaptive pathways, i.e., no pharmaceutical is without side effects. It should also be noted that many interventions that are intended to promote plasticity and slow decline with age, such as physical activity and positive social interactions that give meaning and purpose, are also useful for promoting "positive health" and "eudamonia" ^91-93 independently of any notable disorder and within the range of normal behavior and physiology.

A powerful "top down" therapy (i.e., an activity, usually voluntary, involving activation of integrated nervous system activity, as opposed to pharmacological therapy which has a more limited target) is regular physical activity, which has actions that improve prefrontal and parietal cortex blood flow and enhance executive function.⁹⁴ Moreover, regular physical activity, consisting of walking an hour a day, 5 out of 7 days a week, increases hippocampal volume in previously sedentary adults.⁹⁵ This finding complements work showing that fit individuals have larger hippocampal volumes than sedentary adults of the same age range.⁸⁰ It is also well known that regular physical activity is an effective antidepressant and protects against cardiovascular disease, diabetes, and dementia.^96-100 Moreover, intensive learning has also been shown to increase the volume of the human hippocampus.¹⁰¹

Social integration and support and finding meaning and purpose in life are known to be protective against AL and overload¹⁰² and dementia,¹⁰³ and programs such as the Experience Corps that promote these along with increased physical activity have been shown to slow the decline of physical and mental health and to improve prefrontal cortical blood flow in a similar manner to regular physical activity.^104,105

Depression and anxiety disorders are examples of a loss of resilience, in the sense that changes in brain circuitry and function—caused by the stressors that precipitate the disorder—become "locked" in a particular state and thus need external intervention. Indeed, prolonged depression is associated with shrinkage of the hippocampus^75,106 and prefrontal cortex.¹⁰⁷ While there appears to be no neuronal loss, there is evidence for glial cell loss and smaller neuronal cell nuclei,^82,108 which is consistent with a shrinking of the dendritic tree described above after chronic stress. Indeed, a few studies indicate that pharmacological treatment may reverse the decreased hippocampal volume in unipolar¹⁰⁹ and bipolar¹¹⁰ depression, but the possible influence of concurrent cognitive-behavioral therapy in these studies is unclear. And, yet, from the discussion of reversal of amblyopia (above), it is possible that a combination of a pharmaceutical or behavioral (e.g., exercise) intervention that opens up a "window of plasticity" might improve the efficacy of behavioral therapies.

In this connection, it is important to reiterate that successful behavioral therapy, which is tailored to individual needs, can produce volumetric changes in both prefrontal cortex in the case of chronic fatigue,¹¹¹ and in amygdala, in the case of chronic anxiety¹¹² as measured in the same subjects longitudinally. This reinforces the notion that plasticity-facilitating treatments should be given within the framework of a positive behavioral or physical therapy intervention. On the other hand, negative experiences during the window of enhanced plasticity may have undesirable consequences, such as a person going back into a bad family environment that may have precipitated anxiety or depression in the first place.⁸⁷ In that connection, it should be noted that BDNF, a plasticity enhancing class of molecules, also has the ability to promote pathophysiology, as in seizures.^113–115

At the societal level, the most important top-down interventions are the policies of government and the private sector that not only improve education but also allow people to make choices that improve their chances for a healthy life.¹² This point was made by the Acheson report of the British Government in 1998,¹¹⁶ which recognized that no public policy of virtually any kind should be enacted without considering the implications for the health of all citizens. Thus, basic education, housing, taxation, setting of a minimum wage, and addressing occupational health and safety and environmental pollution regulations are all likely to affect health via a myriad of mechanisms. At the same time, providing higher quality food and making it affordable and accessible in poor, as well as in affluent neighborhoods will be necessary for people to eat better, providing they also learn what types of food to eat.¹¹⁷ Likewise, making neighborhoods safer and more congenial and supportive can improve opportunities for positive social interactions and increased recreational physical activity.^118,119 However, government policies are not the only way to reduce allostatic load. for example, businesses that encourage healthy lifestyle practices among their employees are likely to gain reduced health insurance costs and possibly a more loyal workforce.^120-122

Conclusion

Biomedical science has progressed from the concept of identifying and treating single causes of disease, as in the germ theory, to the recognition of multiple risk factors, as in the biopsychosocial model, and now to "lifecourse health development" that recognizes multiple contributing factors from genes and experiences over the life course that epigenetically alter trajectories of health and disease.³ At the same time, the behavioral and social sciences are recognizing that "biology is not destiny," and that social and behavioral influences continually affect the body through the brain. Together with recognition of the central role of the brain and behavior (Figure 1), the emerging science of "epigenetics" recognizes the continuing role of the physical and social environments, and of behavior, in getting "under the skin" to shape expression of inherited characteristics in a continuous and evolving manner over an individual's lifespan. The complexities and degrees of freedom made possible by the many ways that "epigenetics" affects expression of the genetic blueprint make it essential that the social and behavioral sciences work closely with the biological sciences to achieve better understanding of brain and body function for the good of our own species and all living creatures on this earth.

Author's Affiliation

Bruce S. McEwen, PhD, is the Alfred E. Mirsky Professor of Neuroscience and runs the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University.

Address correspondence to: Bruce S. McEwen, PhD, Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065; email: mcewen@rockefeller.edu

References

1. Mehler MF. Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog Neurobiol 2008; 86:305-41.
2. McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm & Behav 2003;43:2-15.
3. Halfon N, Larson K, Lu M, et al. Lifecourse health development: past, present and future. Matern Child Health J 2014; 18:344-65.
4. McEwen BS. Protective and damaging effects of stress mediators. N Engl J.Med 1998; 338:171-9.
5. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999; 354:1435-9.
6. Adler NE, Boyce TW, Chesney MA, et al. Socioeconomic inequalities in health. JAMA 1993; 269:3140-5.
7. Goodman E, Huang B, Schafer-Kalkhoff T, et al. Perceived socioeconomic status: a new type of identity that influences adolescents' self-rated health. J Adolesc Health 2007; 41:479-87.
8. Marmot MG, Wilkinson RG. Social determinants of health. Oxford, New York: Oxford University Press; 2006.
9. Wilkinson RG, Pickett K. The spirit level: Why greater equality makes societies stronger. New York: Bloomsbury Press; 2010.
10. McEwen BS. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci 2006; 8(4):367-81.
11. McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med 1993; 153:2093-101.
12. Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev 2010; 35:2-16.
13. Seeman T, Epel E, Gruenewald T, et al. Socio- economic differentials in peripheral biology: cumulative allostatic load. Ann NY Acad Sci 2010; 1186:223-39.
14. Seeman T, Gruenewald T, Karlamangla A, et al. Modeling multisystem biological risk in young adults: the Coronary Artery Risk Development in Young Adults Study. Am J Hum Biol 2010; 22:463-72.
15. Blackburn EH, Epel ES. Telomeres and adversity: too toxic to ignore. Nature 2012; 490:169-71.
16. Epel ES, Blackburn EH, Lin J, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci 2004; 101:17312-15.
17. McEwen BS, Seeman T. Protective and damaging effects of mediators of stress: elaborating and testing the concepts of allostasis and allostatic load. Ann NY Acad Sci 1999; 896:30-47.
18. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007; 164:1476-88.
19. McGrath CL, Kelley ME, Holtzheimer PE, et al. toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry 2013; 70(8):821-9.
20. Seeman TE, Singer BH, Rowe JW, et al. Price of adaptation—allostatic load and its health consequences: MacArthur studies of successful aging. Arch Intern Med 1997; 157:2259-68.
21. Seeman TE, McEwen BS, Singer BH, et al. Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging. J Clin Endocrinol Metab 1997; 82:2458-65.
22. Schulz AJ, Mentz G, Lachance L, et al. Associations between socioeconomic status and allostatic load: effects of neighborhood poverty and tests of mediating pathways. Am J Public Health 2012; 102:1706-14.
23. Seeman TE, Singer BH, Ryff CD, et al. Social relationships, gender, and allostatic load across two age cohorts. Psychosom Med 2002; 64:395-406.
24. Bizik G, Picard M, Nijjar R. Allostatic load as a tool for monitoring physiological dysregulations and comorbidities in patients with severe mental illnesses. Harvard Rev Psychiatry 2013; 21:296-313.
25. Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 2008; 32:675-92.
26. Beckie TM. A systematic review of allostatic load, health, and health disparities. Biol Res Nurs 2012; 14:311-46.
27. McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22:105-22.
28. Vyas A, Mitra R, Rao BSS, et al. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 2002; 22:6810-8.
29. McEwen BS, Gianaros PJ. Stress- and allostasis-induced brain plasticity. Annu Rev Med 2011; 62:431-45.
30. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007; 87:873-904.
31. McEwen BS, Morrison JH. The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course. Neuron 2013; 79:16-29.
32. Drevets WC, Videen TO, Price JL, et al. A functional anatomical study of unipolar depression. J Neurosci 1992; 3628-41.
33. McEwen BS. Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. Ann N Y Acad Sci 2010; 1204(Suppl):E38-59.
34. Juster RP, Bizik G, Picard M, et al. A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development. Dev Psychopathol 2011; 23:725-76.
35. Lupien SJ, McEwen BS, Gunnar MR, et al. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Rev Neurosci 2009; 10:434-45.
36. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The adverse childhood experiences (ACE) study. Am J Prev Med 1998; 14:245-58.
37. Levine S, Haltmeyer G, Kara G, et al. Physiological and behavioral effects of infantile stimulation. Physiol Behav 1967; 2:55-59.
38. Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 2005; 7:103-23
39. Akers KG, Yang Z, DelVecchio DP, et al. Social competitiveness and plasticity of neuroendocrine function in old age: influence of neonatal novelty exposure and maternal care reliability. PLoS ONE 2008; 3(7):e2840.
40. Tang AC, Akers KG, Reeb BC, et al. Programming social, cognitive, and neuroendocrine development by early exposure to novelty. Proc Natl Acad Sci USA 2006; 103:15716-21.
41. Parker KJ, Buckmaster CL, Sundlass K, et al. Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primates. Proc Natl Acad Sci USA 2006; 103:3000-5.
42. Isgor C, Kabbaj M, Akil H, et al. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 2004; 14:636-48.
43. Moriceau S, Sullivan R. Maternal presence serves as a switch between learning fear and attraction in infancy. Nature Neurosci 2006; 8:1004-6.
44. Coplan JD, Smith ELP, Altemus M, et al. Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates. Biol Psychiat 2001; 50:200-4.
45. Kaufman D, Smith ELP, Gohil BC, et al. Early appearance of the metabolic syndrome in socially reared bonnet macaques. J Clin Endocrin Metab 2005; 90:404- 8.
46. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav 2012; 106:29-39.
47. Danese A, Moffitt TE, Harrington H, et al. Adverse childhood experiences and adult risk factors for age- related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med 2009; 163:1135-43.
48. Miller GE, Chen E. Harsh family climate in early life presages the emergence of a proinflammatory phenotype in adolescence. Psychol Sci 2010; 21:848-56.
49. Evans GW, Gonnella C, Marcynyszyn LA, et al. The role of chaos in poverty and children's socioemotional adjustment. Psychol Sci 2005; 16:560-5.
50. Anda RF, Butchart A, Felitti VJ, et al. Building a framework for global surveillance of the public health implications of adverse childhood experiences. Am J Prev Med 2010; 39:93-8.
51. McEwen BS, Tucker P. Critical biological pathways for chronic psychosocial stress and research opportunities to advance the consideration of stress in chemical risk assessment. Am J Public Health 2011; 101(Suppl 1):S131-9.
52. Farah MJ, Shera DM, Savage JH, et al. Childhood poverty: specific associations with neurocognitive development. Brain Res 2006; 1110: 66-74.
53. Hart B, Risley, TR. 1995. Meaningful differences in the everyday experience of young American children. Baltimore, MD: Brookes Publishing Company; 1995. 304 p.
54. Hanson JL, Chandra A, Wolfe BL, et al. Association between income and the hippocampus. PLoS One 2011; 6:e18712.
55. Hanson JL, Hair N, Shen DG, et al. Family poverty affects the rate of human infant brain growth. PLoS One 2013; 8:e80954.
56. Kim P, Evans GW, Angstadt M, et al. Effects of childhood poverty and chronic stress on emotion regulatory brain function in adulthood. Proc Natl Acad Sci USA 2013; 110:18442-7.
57. Hanson JL, Adluru N, Chung MK, et al. Early neglect is associated with alterations in white matter integrity and cognitive functioning. Child Dev 2013; 84:1566- 78.
58. Gianaros PJ, Horenstein JA, Cohen S, et al. Perigenual anterior cingulate morphology covaries with perceived social standing. Soc Cogn Affect Neurosci 2007; 2:161-73.
59. Gianaros PJ, Horenstein JA, Hariri AR, et al. Potential neural embedding of parental social standing. Soc Cogn Affect Neurosci 2008; 3:91-6.
60. Adler NE, Boyce TW, Chesney MA, et al. Socioeconomic inequalities in health. JAMA 1993; 269:3140-5.
61. Lupien SJ, Parent S, Evans AC, et al. Larger amygdala but no change in hippocampal volume in 10-year-old children exposed to maternal depressive symptomatology since birth. Proc Natl Acad Sci USA 2011; 108:14324-9.
62. Obradovic J, Bush NR, Stamperdahl J, et al. Biological sensitivity to context: the interactive effects of stress reactivity and family adversity on socioemotional behavior and school readiness. Child Dev 2010; 81:270-89.
63. Boyce WT, Ellis BJ. Biological sensitivity to context: An evolutionary-developmental theory of the origins and functions of stress reactivity. Dev Psychopathol 2005; 17:271-301.
64. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301:386-9.
65. Suomi SJ. Risk, resilience, and gene x environment interactions in rhesus monkeys. Ann NY Acad Sci 2006; 1094:52-62.
66. Del Giudice M, Ellis BJ, Shirtcliff EA. The Adaptive Calibration Model of stress responsivity. Neurosci Biobehav Rev 2011; 35:1562-92.
67. Jackson JS, Knight KM, Rafferty JA. Race and unhealthy behaviors: chronic stress, the HPA axis, and physical and mental health disparities over the life course. Am J Public Health 2010; 100:933-9.
68. Cameron HA, Gould E. The control of neuronal birth and survival. In Shaw C (ed), Receptor Dynamics in Neural Development, pp. 141-57. Boca Raton, FL: CRC Press.
69. Popoli M, Yan Z, McEwen BS, et al. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2012; 13:22-37.
70. Du J, McEwen BS, Manji HK. Glucocorticoid receptors modulate mitochondrial function. Commun Integr Biol 2009; 2:1-3.
71. Hill MN, McEwen BS. Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocorticoids. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:791-7.
72. Tasker JG, Di S, Malcher-Lopes R. Minireview: rapid glucocorticoid signaling via membrane-associated receptors. Endocrinology 2006; 147:5549-56.
73. de Leon MJ, George AE, Golomb J, et al. Frequency of hippocampus atrophy in normal elderly and Alzheimer's disease patients. Neurobiol Aging 1997; 18:1-11.
74. Gold SM, Dziobek I, Sweat V, et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 2007; 50:711-9.
75. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiat 2003; 54:338-52.
76. Starkman MN, Giordani B, Gebrski SS, et al. decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Biol Psychiat 1999; 46:1595-602.
77. Gurvits TV, Shenton ME, Hokama H, et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996; 40:1091-9.
78. Gianaros PJ, Jennings JR, Sheu LK, et al. Prospective reports of chronic life stress predict decreased grey matter volume in the hippocampus. NeuroImage 2007; 35:795-803.
79. Marsland AL, Gianaros PJ, Abramowitch SM, et al. interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiat 2008; 64:484-90.
80. Erickson KI, Prakash RS, Voss MW, et al. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 2009; 19:1030-9.
81. Cho K. Chronic 'jet lag' produces temporal lobe atrophy and spatial cognitive deficits. Nature Neurosci 2001; 4:567-8. The Brain on Stress: How Behavior and the Social Environment "Get Under the Skin"
82. Stockmeier CA, Mahajan GJ, Konick LC, et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiat 2004; 56:640-50.
83. Liston C, Gan WB. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci USA 2011; 108:16074-9.
84. Liston C, Cichon JM, Jeanneteau F, et al. Circadian glucocorticoid oscillations promote learning- dependent synapse formation and maintenance. Nat Neurosci 2013; 16:698-705.
85. Vetencourt JFM, Sale A, Viegi A, et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 2008; 320:385-8.
86. Spolidoro M, Baroncelli L, Putignano E, et al. Food restriction enhances visual cortex plasticity in adulthood. Nat Commun 2011; 2:320.
87. Castren E, Rantamaki T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 2010; 70:289-97.
88. Bavelier D, Levi DM, Li RW, et al. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J Neurosci 2010; 30:14964-71.
89. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiat 2006; 59:1116-27.
90. Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 2011; 10:123-30.
91. Fredrickson BL, Grewen KM, Coffey KA, et al. A functional genomic perspective on human well-being. Proc Natl Acad Sci USA 2013; 110:13684-9.
92. Ryff CD, Singer B. The contours of positive human health. Psychol Inq 1998; 9:1-28.
93. Singer B, Friedman E, Seeman T, et al. Protective environments and health status: cross-talk between human and animal studies. Neurobiol Aging 2005; 26(Suppl):S113-8.
94. Colcombe SJ, Kramer AF, Erickson KI, et al. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci USA 2004; 101:3316-21.
95. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 2011; 108:3017-22.
96. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633-8.
97. Bonen A. Benefits of exercise for Type II diabetics: convergence of epidemiologic, physiologic, and molecular evidence. Can J Appl Physiol 1997; 20: 261-79.
98. Kahle EB, Zipf WB, Lamb DR, et al. Association between mild, routine exercise and improved insulin dynamics and glucose control in obese adolescents. Int J Sports Med 1996; 17:1-6.
99. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age or older. Ann Intern Med 2006; 144:73-81.
100. Rovio S, Kareholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 2005; 4:705-11.
101. Draganski B, Gaser C, Kempermann G, et al. Temporal and spatial dynamics of brain structure changes during extensive learning. J Neurosci 2006; 26:6314-7.
102. Seeman TE, Singer BH, Ryff CD, et al. Social relationships, gender, and allostatic load across two age cohorts. Psychosom Med 2002; 64:395-406.
103. Boyle PA, Buchman AS, Barnes LL, et al. Effect of a purpose in life on risk of incident Alzheimer disease and mild cognitive impairment in community-dwelling older persons. Arch Gen Psychiatry 2010; 67:304-10.
104. Carlson MC, Erickson KI, Kramer AF, et al. Evidence for neurocognitive plasticity in at-risk older adults: the experience corps program. J Gerontol A Biol Sci Med Sci 2009; 64:1275-82.
105. Fried LP, Carlson MC, Freedman M, et al. A social model for health promotion for an aging population: initial evidence on the experience corps model. J Urban Health Bull NY Acad Med 2004; 81:64-78.
106. Sheline YI. Hippocampal atrophy in major depression: a result of depression-induced neurotoxicity? Mol Psychiatry 1996; 1:298-9.
107. Drevets WC, Price JL, Simpson Jr JR, Todd RD, Reich T, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386:824-27.
108. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiat 2000; 48:766-77.
109. Vythilingam M, Vermetten E, Anderson GM, et al. Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment. Biol Psychiat 2004; 56:101-12.
110. Moore GJ, Bebehuk JM, Wilds IB, et al. Lithium- induced increase in human brain grey matter. Lancet 2000; 356:1241-2.
111. de Lange FP, Koers A, Kalkman JS, et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain 2008; 131:2172-80.
112. Holzel BK, Carmody J, Evans KC, et al. Stress reduction correlates with structural changes in the amygdala. Soc Cogn Affect Neurosci 2010; 5:11-7.
113. Heinrich C, Lahteinen S, Suzuki F, et al. Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol Dis 2011; 42:35-47.
114. Kokaia M, Ernfors P, Kokaia Z, et al. Suppressed epileptogenesis in BDNF mutant mice. Exp Neurol 1995; 133:215-24.
115. Scharfman HE. Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J Neurophysiol 1997; 78:1082-95.
116. Acheson SD. Independent inquiry into inequalities in health report. London: The Stationary Office; 1998.
117. Drewnowski A, Specter SE. Poverty and obesity: the role of energy density and energy costs. Am J Clin Nutr 2004; 79:6-16.
118. Kawachi I, Kennedy BP, Lochner K, et al. Social capital, income inequality, and mortality. Am J Public Health 1997; 87:1491-8.
119. Sampson RJ, Raudenbush SW, Earls F. Neighborhoods and violent crime: a multilevel study of collective effects. Science 1997; 277:918-24.
120. Aldana SG. Financial impact of health promotion programs: a comprehensive review of the literature. Am J Health Promot 2001; 15:296-320.
121. Pelletier KR. A review and analysis of the clinical- and cost-effectiveness studies of comprehensive health promotion and disease management programs at the worksite: 1998-2000 update. Am J Health Promot 2001; 16:107-15.
122. Whitmer RW, Pelletier KR, Anderson DR, et al. A wake-up call for corporate America. J Occup Environ Med 2003; 45:916-25.

^a. Refer to the University of California, San Francisco's MacArthur Research Network on Socioeconomic Status and Health. Available at http://www.macses.ucsf.edu/.

^b. Refer to Reaching for a Healthier Life; Facts on Socioeconomic Status and Health in the U.S. Available at http://www.macses.ucsf.edu/downloads/Reaching_for_a_Healthier_Life.pdf.

Bruce S. McEwen, PhD, is the Alfred E. Mirsky Professor of Neuroscience and heads the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University. As a neuroscientist and neuroendocrinologist, he studies environmentally-regulated, variable gene expression in the brain. His laboratory discovered adrenal steroid receptors in the hippocampus in 1968. He is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and the National Council on the Developing Child. Dr. McEwen served as President of the Society for Neuroscience in 1997-98.