Trained in chemistry and cell biology, and following post-doctoral work in the new field of “neuroscience,” I became a junior faculty member in the laboratory of Neal Miller at The Rockefeller University in 1966 and was inspired by his integrative view of brain–body interactions and his pioneering work in defining the field of behavioral medicine. Together with my interest in hormone action on gene expression and the fact that very little was known about how and where hormones act in the brain, this led to a serendipitous discovery. In 1968, I discovered that the stress hormone, cortisol, secreted by our adrenal glands, is taken up from the blood and binds to receptors in the brain region known as the hippocampus. We now know that cortisol regulates gene expression and other cellular processes related to cognitive function and mood, acting in the hippocampus as well as elsewhere in the brain by epigenetic mechanisms. Epigenetics is the emerging science of how genes are seamlessly regulated by the environment, and it plays an important role in the emerging collaborations between the social and biological sciences. Here is the story of how this all happened.

What Is This Discovery?

The discovery: that stress hormones affect a brain region that we now know is involved in episodic, spatial, and contextual memory and mood regulation, rather than just affecting the hypothalamus and vegetative functions such as hunger, thirst, and sex. This discovery has triggered many studies on rats and mice, with increasing translation to human stress-related disorders, such as depression and anxiety, accelerated aging, and Alzheimer's disease. We discovered that the effects of acute and chronic stress involve not brain damage, but, rather, a remodeling of neural architecture – turnover of synaptic connections, shrinkage and growth of dendrites, and the suppression of neurogenesis (i.e., the generation of new neurons in the dentate gyrus of the hippocampus). This discovery has also engendered a broader view of brain–body interactions that has led me and colleagues to develop the concepts of allostasis and allostatic load and overload (i.e., how the body as well as the brain can be altered by too much stress so as to cause disease, as explained further below).

INTRODUCTION

The discovery that there are gradients of health across the full range of income and education, known as socioeconomic status (SES; Adler et al., 1994, 1999; Brunner et al., 1997; Marmot et al., 1991), has emphasized the need to have a biological framework in which to conceptualize and measure the cumulative impact of social factors (i.e., social status, income, education, working and living environments, lifestyle, health-related behaviors, and stressful life experiences on physical and mental health). Biologists are very good at studying mechanisms and not so successful in providing concepts and methods that are usable by social scientists, including epidemiologists, economists, sociologists and health psychologists, for collecting data on groups of individuals in relation to psychosocial variables. In an attempt to make some progress in this direction within the framework of the MacArthur Foundation Research Network on Socioeconomic Status and Health, a number of us have developed a set of concepts and terminology that are intended to help organize the design and measurement of long-term effects of psychosocial factors on disease processes (McEwen, 1998, 2000; McEwen and Stellar, 1993; Schulkin et al., 1994; Seeman et al., 1997; McEwen and Seeman, 1999).

One of the main challenges has been to expand beyond the limitations and ambiguities imposed by the terms “stress” and “homeostasis.” One purpose of this essay is to discuss the physiology of the response to “stress” in terms of a new formulation involving two concepts: “allostasis” and “allostatic load.” We believe that these two terms allow for a more restricted and precise definition of “stress” that refers to an event or series of events that evoke a set of behavioral and physiological responses. These terms also clarify inherent ambiguities in the concept of homeostasis, and we also note the ways in which they replace and clarify aspects of the “general adaptation syndrome” as formulated by the late Hans Selye.

Introduction

Circulating gonadal and adrenal steroid hormones readily cross the blood–brain barrier and affect neural circuits that subserve various aspects of brain function and behavior. When investigating the interactions between hormones and neurotransmitter systems, it is particularly important to study a model system where there is a behavioral endpoint for which the neural control sites are discrete and accessible. Mating behavior in the female rat provides such a system (Pfaff 1980). The ovarian steroid hormones estradiol (E) and progesterone (P) synchronize the occurrence of mating and ovulation, and thereby increase the likelihood of reproductive success. Our goal is to take advantage of this useful model system in order to elucidate the mechanisms of steroid hormone action on neuronal activity and connectivity. In addition to enhancing our knowledge of the specific events that control this biologically important behavior, such studies may have broader implications for the analysis of hormone–neurotransmitter interactions.

It is well known that ovariectomized (OVX) female rats display very little sexual behavior. Estradiol replacement reverses this condition, however, by sensitizing specific neural circuits to stimuli that elicit sexual behavior. Approximately 48 hours after E is administered, OVX female rats display sexual behavior when they encounter a male. Progesterone treatment, given after E and about 4 hours before behavioral testing, further enhances female sexual behavior (Boling and Blandau 1939). Treatment with P is ineffective unless the animals have been primed with E, in part because E induces expression of a subset of P receptors (MacLusky and McEwen 1978).