Bruce S Mcewen

Bruce S Mcewen
The Rockefeller University | Rockefeller ·  Laboratory of Neuroendocrinology

Ph.D.

About

1,268
Publications
227,411
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206,600
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Publications

Publications (1,268)
Article
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Objective: Mitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses. This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function. Methods: A systematic review of the litera...
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Background: The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress response biomarkers. Mitochondria, a subcellular organelle with its own genome, produce the energy required for life and generate signals that enable stress adaptation. An emerging concept proposes that mitochondr...
Article
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Energy is required to sustain life and enable stress adaptation. At the cellular level, energy is largely derived from mitochondria - unique multifunctional organelles with their own genome. Four main elements connect mitochondria to stress: 1) Energy is required at the molecular, (epi)genetic, cellular, organ, and systemic levels to sustain compon...
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Epitranscriptomics refers to posttranscriptional alterations on an mRNA sequence that are dynamic and reproducible, and affect gene expression in a similar way to epigenetic modifications. However, the functional relevance of those modifications for the transcript, the cell, and the organism remain poorly understood. Here, we focus on RNA editing a...
Article
Microglia (MG), a heterogeneous population of phagocytic cells, play important roles in central nervous system (CNS) homeostasis and neural plasticity. Under steady-state conditions, MG maintain homeostasis by producing antiinflammatory cytokines and neurotrophic factors, support myelin production, and remove synapses and cellular debris, as well a...
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Males and females use distinct brain circuits to cope with similar challenges. Using RNA sequencing of ribosome-bound mRNA from hippocampal CA3 neurons, we found remarkable sex differences and discovered that female mice displayed greater gene expression activation after acute stress than males. Stress-sensitive BDNF Val66Met mice of both sexes sho...
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Numerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female m...
Article
We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupa...
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Sleep-disordered breathing (SDB) is a common disorder in aging that is associated with cognitive decline, including significant executive dysfunction, for which the neurobiological underpinnings remain poorly understood. Using proton magnetic resonance spectroscopy (1H MRS), this study assessed whether dysregulation of the homeostatic balance of th...
Article
Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic lo...
Article
Why are children of poor parents more likely to be poor as adults than other children? Early-childhood adversities resulting from social structures and relationships impact children’s bodily systems and brain development through recurrent stress. These socially patterned biological processes influence social reproduction. Social support and interve...
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An estimated 50% of depressed patients are inadequately treated by available interventions. Even with an eventual recovery, many patients require a trial and error approach, as there are no reliable guidelines to match patients to optimal treatments and many patients develop treatment resistance over time. This situation derives from the heterogene...
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Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remain...
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The term ‘stress’ − coined in 1936 − has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach − based on the ‘free energy principle’ − defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources t...
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Insulin resistance and markers of Allostatic load in depression Introduction Among patients with major depression, increased inflammatory markers at baseline may predict an anti-depressant response. Reducing inflammation may augment response to psychotropic medications. Few studies have investigated an association between Leukocyte Telomere Length...
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Aims/hypothesisType 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by...
Article
Background: Valuable insights on the health and behavior of transit workers can be obtained from qualitative research that considers the social environment, which affects job performance and determines levels of perceived stress. Methods: Using a grounded theory approach, semi-structured interviews were conducted with American transit workers (n...
Article
Sex hormones act throughout the entire brain of both males and females via both genomic and nongenomic receptors. Sex hormones can act through many cellular and molecular processes that alter structure and function of neural systems and influence behavior as well as providing neuroprotection. Within neurons, sex hormone receptors are found in nucle...
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The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor, which promote adaptation (“allostasis”) but also contribute to pathophysiology (“allostatic load/overload”) when overused and dysregulated. The adult as wel...
Article
Elevated body mass index (BMI) is associated with increased multi-morbidity and mortality. The investigation of the relationship between BMI and brain organization has the potential to provide new insights relevant to clinical and policy strategies for weight control. Here, we quantified the association between increasing BMI and the functional org...
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The future of medicine is discussed in the context of epigenetic influences during the entire life course and the lived experiences of each person, avoiding as much as possible the “medicalization” of the individual and taking a more humanistic view. The reciprocal communication between brain and body via the neuroendocrine, autonomic, metabolic an...
Chapter
In this article, stress is defined as a threat, real or implied, to the psychological or physiological integrity of an individual. As a result of the perception of threat, an individual makes behavioral and physiological responses that are intended to protect and defend the body and psyche from damage.
Chapter
Why do some individuals succumb to stress and develop debilitating psychiatric deseases including depression and posttraumatic disorders, whereas others adapt well in the face of adverse events? Resilience is the ability to cope with, learn from, and thrive in the face of adversity. Resilience is built over the life course, beginning early in life,...
Article
Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hi...
Article
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Contrary to popular belief, sex hormones act throughout the entire brain of both males and females via both genomic and nongenomic receptors. Many neural and behavioral functions are affected by estrogens, including mood, cognitive function, blood pressure regulation, motor coordination, pain, and opioid sensitivity. Subtle sex differences exist fo...
Article
We aimed to determine the short-term effects of early-life stress in the form of maternal separation (MS) on anxiety-like behavior in male rat pups. In order to assess anxiety, we measured 40 kHz separation-induced ultrasonic vocalizations (USV) on postnatal day (PND) 11. We further aimed to evaluate the potential involvement of two neurochemical s...
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A recent study by Wiley, Gruenewald, Karlamangla, and Seeman modeling multisystemic allostatic load (AL) was published in Psychosomatic Medicine. The observations reported in this article are consistent with the accumulating evidence published in this journal supporting the role of ad- ditive dysregulated biological and physiological processes in a...
Article
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There is growing evidence that stress leads to contrasting patterns of structural plasticity in the hippocampus and amygdala, two brain areas implicated in the cognitive and affective symptoms of stress‐related psychiatric disorders. Acute stress has been shown to trigger a delayed increase in the density of dendritic spines in the basolateral amyg...
Article
Fifteen years ago, one of us proposed the hypothesis that insulin resistance (IR) is a missing link between mood disorders and dementia.1, 2 See Figure 1. Recently, the field has exploded with the data supporting all components of the model, especially the connection between depressive disorders and IR. Increasing number of studies also confirm a r...
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As a behavioral neuroscientist and neuroendocrinologist, Randall Sakai appreciated the extensive and complex interactions between the brain and the body as exemplified by his seminal studies on the regulation of salt appetite and the brain and body effects in the Visible Burrow System. He applied state-of-the-art methods to probe underlying mechani...
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Arduini et al. raise interesting issues related to mechanisms involving carnitine (1). The authors ask whether there is a free-carnitine deficiency in Flinders Sensitive Line rats (FSL) (2) and, more broadly, raise the question of whether the deficiency of acetyl-l-carnitine (LAC) occurs systemically or in the brain in FSL (1). We found that carnit...
Article
Chronic diseases (i.e., Noncommunicable Diseases), mainly cardiovascular disease, cancer, respiratory diseases and type-2-diabetes, are now the leading cause of death, disability and diminished quality of life on the planet. Moreover, these diseases are also a major financial burden worldwide, significantly impacting the economy of many countries....
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Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA...
Article
To be useful, the concept of stress needs to be defined in biological terms linked to a broader framework of allostasis and its role in the adaptation of brain and body to positive and negative life experiences. A clear biological framework helps connect and organize animal and human research on stress. In particular, the concepts of “toxic stress”...
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Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less known. We found that an epigenetic and energetic agent, acetyl-l-carnitine (LAC, oral administration), rapidly rescued the depressive- and central and systemic metabolic-like phenotype of LAC-deficie...
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The adult brain is capable of adapting to internal and external stressors by undergoing structural plasticity, and failure to be resilient and preserve normal structure and function is likely to contribute to depression and anxiety disorders. Although the hippocampus has provided the gateway for understanding stress effects on the brain, less is kn...
Chapter
Many studies published over the last two decades show that chronic exposure to stress hormones, from the prenatal to aging period, can have deleterious effects on brain structures involved in cognition and mental health. In this selective review of the literature, we show that specific effects on the brain, behavior, and cognition emerge as a funct...
Article
Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequen...
Article
The brain is the central organ of perceiving, responding, and adapting to life experiences, and it communicates in a reciprocal manner with the rest of the body via autonomic, neuroendocrine, metabolic, and immune mediators that are essential for adaptation to stressful experiences by a process referred to as “allostasis.” Singletary reminds us tha...
Article
The brain is the central organ for adaptation to experiences, including stressors, which are capable of changing brain architecture as well as altering systemic function through neuroendocrine, autonomic, immune, and metabolic systems. Because the brain is the master regulator of these systems, as well as of behavior, alterations in brain function...
Chapter
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Vulnerability and resilience are intertwined yet unraveling constructs in the allostatic load literature centered on stress-disease pathways. In examining this paradigm shift, this chapter focuses on allostatic load indices of multisystemic physiological dysregulations among marginalized populations. Social inequalities reviewed include early adver...
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Background. Chronic pain is associated with increased morbidity and mortality, predominated by cardiovascular disease and cancer. Investigating related risk factor measures may elucidate the biological burden of chronic pain. Objectives. We hypothesized that chronic pain severity would be positively associated with the risk factor composite. Method...
Article
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Allostatic load (AL) is a complex clinical construct, providing a unique window into the cumulative impact of stress. However, due to its inherent complexity, AL presents two major measurement challenges to conventional statistical modeling (the field’s dominant methodology): it is comprised of a complex causal network of bio-allostatic systems, re...
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Exercise enhances adult hippocampal neurogenesis (AHN), although the exact nature of how this happens remains controversial. The beneficial effects of exercise vary depending upon the exercise condition, especially intensity. Most animal studies, however, have used wheel running, which only evaluates running distance (exercise volume) and does not...
Article
This study reveals the presence of dendritic cells (DCs) in the pituitary gland, which play a role in communicating immune activation to the hypothalamic pituitary adrenal (HPA) axis. Using enhanced yellow fluorescent protein (eyfp) expression as a reporter for CD11c+, a marker of DCs, we demonstrate anatomically the presence of CD11c/eyfp+ cells t...
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Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediat...
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Background: Multimorbidity receives increasing scientific attention. So does the detrimental health impact of adverse childhood experiences (ACE). Aetiological pathways from ACE to complex disease burdens are under investigation. In this context, the concept of allostatic overload is relevant, denoting the link between chronic detrimental stress,...
Article
The hippocampus provided the gateway into much of what we have learned about stress and brain structural and functional plasticity, and this initial focus has expanded to other interconnected brain regions, such as the amygdala and prefrontal cortex. Starting with the discovery of adrenal steroid, and later, estrogen receptors in the hippocampal fo...
Chapter
Emerging research examines biological processes not as primary causes of social outcomes but rather as mechanisms that themselves depend on social environments. In particular, environments that produce toxic stress help shape brain development and brain and body function throughout the lifespan. Early life stress, in particular, has serious consequ...
Article
The discovery of steroid hormone receptors in brain regions that mediate every aspect of brain function has broadened the definition of "neuroendocrinology" to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives a...
Article
Sleep has important homeostatic functions, and circadian rhythms organize physiology and behavior on a daily basis to insure optimal function. Sleep deprivation and circadian disruption can be stressors, enhancers of other stressors that have consequences for the brain and many body systems. Whether the origins of circadian disruption and sleep dis...
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Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampu...
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As the central organ of stress and adaptation to stressors, the brain plays a pivotal role in behavioral and physiological responses that may lead to successful adaptation or to pathophysiology and mental and physical disease. In this context, resilience can be defined as "achieving a positive outcome in the face of adversity". Underlying this dece...
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Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate...
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The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age...
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Why do some people get sick, and others do not? This basic question, of vulnerability and resilience, is of crucial importance in physical and mental health research. Determining factors that impart resilience, or contribute to vulnerability, could be a turning point in our fundamental understanding of disease. This collection explores current data...
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Stress plays a substantial role in shaping behavior and brain function, often with lasting effects. How these lasting effects occur in the context of a fixed postmitotic neuronal genome has been an enduring question for the field. Synaptic plasticity and neurogenesis have provided some of the answers to this question, and more recently epigenetic m...
Article
Biomarkers are important in stress biology in relation to assessing individual and population health.