Showing papers by "Bruce S. McEwen published in 2016"
TL;DR: Findings in animal models have resulted in translation to the human brain and have helped change thinking about the nature of brain malfunction in psychiatric disorders and during aging, as well as the mechanisms of the effects of early-life adversity on the brain and the body.
912 citations
TL;DR: There are no magic bullets and drugs cannot substitute for targeted interventions that help an individual become resilient, of which mindfulness‐based stress reduction and meditation are emerging as useful tools.
Abstract: 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 by chronic stress can have direct and indirect effects on cumulative allostatic overload, which refers to the cost of adaptation. There is much new knowledge on the neural control of systemic physiology and the feedback actions of physiologic mediators on brain regions regulating higher cognitive function, emotional regulation, and self-regulation. The healthy brain has a considerable capacity for resilience, based upon its ability to respond to interventions designed to open "windows of plasticity" and redirect its function toward better health. As a result, plasticity-facilitating treatments should be given within the framework of a positive behavioral intervention; negative experiences during this window may even make matters worse. Indeed, there are no magic bullets and drugs cannot substitute for targeted interventions that help an individual become resilient, of which mindfulness-based stress reduction and meditation are emerging as useful tools.
212 citations
TL;DR: Sex differences, and responses to sex hormones in brain regions and upon functions not previously regarded as subject to such differences, indicate that the authors are entering a new era in their ability to understand and appreciate the diversity of gender-related behaviors and brain functions.
Abstract: 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 for many of these functions that are developmentally programmed by hormones and by not yet precisely defined genetic factors, including the mitochondrial genome. These sex differences, and responses to sex hormones in brain regions and upon functions not previously regarded as subject to such differences, indicate that we are entering a new era in our ability to understand and appreciate the diversity of gender-related behaviors and brain functions.
145 citations
TL;DR: It is shown that glucocorticoid stress hormones, acting through their receptors, regulate the expression of mitochondrial genes in the brain and demonstrate a direct molecular linkage between stress and mitochondrial function.
Abstract: 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 (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.
108 citations
TL;DR: The discovery of steroid hormone receptors in brain regions that mediate virtually 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.
74 citations
TL;DR: The hypothesis that insulin resistance (IR) is a missing link between mood disorders and dementia has exploded with the data supporting all components of the model, especially the connection between depressive disorders and IR.
Abstract: 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.3, 4 Increasing number of studies also confirm a role of depressive disorders in accelerating onset of dementia.5, 6, 7 IR is a modifiable metabolic proinflammatory state underlying type 2 diabetes mellitus (T2DM), cardiovascular disease, vascular dementia and Alzheimer’s disease. Today both, mass media and specialty literature are replete with information on the topic and ‘stress’ is often cited as the cause. Yet, while ‘stress’ is invoked, the profound epigenetic effects of stressful and other daily experiences and the resulting health-related behaviors resulting from them need to be more clearly recognized and defined.
63 citations
TL;DR: The data indicate that chronic elevations in CRH signaling, as is seen following exposure to chronic Elevations in corticosterone or stress, drive persistent changes in eCB function.
44 citations
TL;DR: The risk factor composite was higher in individuals with chronic pain, greater with increasing pain severity, and influenced by health behaviors, which would have significant clinical and research utility.
Abstract: Funding was supported by a collaborative grant from the International Association for the Study of Pain (IASP) and the Scan Design Foundation by Inger & Jens Bruun, the Norwegian Research Council (Project no. 177725), and the Norwegian Health Association and through the National Institutes of Health: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIAMS K23AR062099 (KS) and CTSI RR029890, and National Institute of Aging, AG0333906 (RBF).
40 citations
TL;DR: In this paper, the authors focus on allostatic load indices of multisystemic physiological dysregulations among marginalized populations, including early adversity, socioeconomic health gradients, race/ethnicity and discrimination, Brazil's shifting economy, the struggles of North American and Australian Indigenous peoples, and finally sex/gender diversity and sexual orientation as key determinants of allosteric load.
Abstract: 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 adversity, socioeconomic health gradients, race/ethnicity and discrimination, Brazil's shifting economy, the struggles of North American and Australian Indigenous peoples, and finally sex/gender diversity and sexual orientation as key determinants of allostatic load. We then present innovative biochemical, neurological, and cognitive approaches for future empirical consideration, with conclusions centered on clinical and social policy implications. In espousing a developmental psychopathology approach that emphasizes causal processes, developmental mechanisms, and diverse conceptualizations of health, we highlight allostatic load studies that focus on resilient pathways and how these trajectories can be promoted to protect populations otherwise considered vulnerable.
Keywords:
developmental trajectories;
vulnerability;
resilience;
social inequalities;
cortisol;
allostatic load;
transdisciplinary;
health gradients
35 citations
TL;DR: This work developed a multisystem, 7-factor (20 biomarker) model of AL's network of allostatic systems, and used it to create a catalog of nine different clinical AL profiles (causal pathways), which linked each clinical profile to a typology of 23 health outcomes.
Abstract: 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 bioallostatic systems, represented by an even larger set of dynamic biomarkers; and, it is situated within a web of antecedent socioecological systems, linking AL to differences in health outcomes and disparities. To address these challenges, we employed case-based computational modeling (CBM), which allowed us to make four advances: (1) we developed a multisystem, 7-factor (20 biomarker) model of AL's network of allostatic systems; (2) used it to create a catalog of nine different clinical AL profiles (causal pathways); (3) linked each clinical profile to a typology of 23 health outcomes; and (4) explored our results (post hoc) as a function of gender, a key socioecological factor. In terms of highlights, (a) the Healthy clinical profile had few health risks; (b) the pro-inflammatory profile linked to high blood pressure and diabetes; (c) Low Stress Hormones linked to heart disease, TIA/Stroke, diabetes, and circulation problems; and (d) high stress hormones linked to heart disease and high blood pressure. Post hoc analyses also found that males were overrepresented on the High Blood Pressure (61.2%), Metabolic Syndrome (63.2%), High Stress Hormones (66.4%), and High Blood Sugar (57.1%); while females were overrepresented on the Healthy (81.9%), Low Stress Hormones (66.3%), and Low Stress Antagonists (stress buffers) (95.4%) profiles.
30 citations
TL;DR: NgR1 robustly inhibits elimination of fear expression in the adult brain and could serve as a therapeutic target for anxiety disorders, such as PTSD.
Abstract: Critical periods are temporary windows of heightened neural plasticity early in development. For example, fear memories in juvenile rodents are subject to erasure following extinction training, while after closure of this critical period, extinction training only temporarily and weakly suppresses fear memories. Persistence of fear memories is important for survival, but the inability to effectively adapt to the trauma is a characteristic of post-traumatic stress disorder (PTSD). We examined whether Nogo Receptor 1 (NgR1) regulates the plasticity associated with fear extinction. The loss of NgR1 function in adulthood eliminates spontaneous fear recovery and fear renewal, with a restoration of fear reacquisition rate equal to that of naive mice; thus, mimicking the phenotype observed in juvenile rodents. Regional gene disruption demonstrates that NgR1 expression is required in both the basolateral amygdala (BLA) and infralimbic (IL) cortex to prevent fear erasure. NgR1 expression by parvalbumin expressing interneurons is essential for limiting extinction-dependent plasticity. NgR1 gene deletion enhances anatomical changes of inhibitory synapse markers after extinction training. Thus, NgR1 robustly inhibits elimination of fear expression in the adult brain and could serve as a therapeutic target for anxiety disorders, such as PTSD.
TL;DR: A role for NMDARs during acute stress is identified in both the physiological and morphological strengthening of synaptic connectivity in the BLA in a delayed fashion, raising the possibility that activation of NMDA receptors during stress may serve as a common molecular mechanism despite the divergent patterns of plasticity that eventually emerge after stress in the amygdala and hippocampus.
Abstract: 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 amygdala (BLA) of rodents However, the physiological correlates of this delayed spinogenesis in the BLA remain unexplored Furthermore, NMDA receptors (NMDARs) have been known to underlie chronic stress-induced structural plasticity in the hippocampus, but nothing is known about the role of these receptors in the delayed spinogenesis, and its physiological consequences, in the BLA following acute stress Here, using whole-cell recordings in rat brain slices, we find that a single exposure to 2-h immobilization stress enhances the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) recorded from principal neurons in the BLA 10 days later This was also accompanied by faster use-dependent block of NMDA receptor currents during repeated stimulation of thalamic inputs to the BLA, which is indicative of higher presynaptic release probability at these inputs 10 days later Furthermore, targeted in vivo infusion of the NMDAR-antagonist APV into the BLA during the acute stress prevents the increase in mEPSC frequency and spine density 10 days later Together, these results identify a role for NMDARs during acute stress in both the physiological and morphological strengthening of synaptic connectivity in the BLA in a delayed fashion These findings also raise the possibility that activation of NMDA receptors during stress may serve as a common molecular mechanism despite the divergent patterns of plasticity that eventually emerge after stress in the amygdala and hippocampus
01 Jan 2016
TL;DR: It is shown that specific effects on the brain, behavior, and cognition emerge as a function of the timing and the duration of exposure to stress.
Abstract: 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 function of the timing and the duration of exposure to stress. We present the effects of stress on the brain and behavior for different periods, e.g., prenatal and postnatal stress, stress in adolescence and adulthood, and the effects of stress on the aging brain. We first summarize the literature on the effects of stress on the brain and behavior across the lifespan in animal models, and thereafter, we present a translational view of the effects of stress on the brain and behavior in humans. In order to better understand these effects, we summarize models that have been recently proposed to explain why different disorders emerge in populations exposed to stress at different moments of their lives. In conclusion, we discuss the importance of developing early interventions to prevent the negative effects of stress on brain development.
TL;DR: Data indicate that DORs redistribute within CA3 pyramidal cells and dentate hilar GABAergic interneurons in a sexually dimorphic manner that would promote activation and drug related learning in males after AIS and in females after CIS.
TL;DR: This chapter summarizes some of the underlying mechanisms of stress effects upon the brain and the body and provides a perspective on the emerging contribution of high-throughput technologies and next-generation interventions to develop and enhance resilience.
Abstract: 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, and is based on the remarkable plasticity of the developing and adult brains to a continuously changing environment. Understanding the neural bases of individual and sex differences in responses to stress on brain development and functions is essential to the development of better pharmaceuticals to either promote coping mechanisms (preventive care) or mitigate maladaptive stress responses (curative care). After describing the new view of epigenetics that adds to the old notion that “biology is destiny,” this chapter summarizes some of the underlying mechanisms of stress effects upon the brain and the body and provides a perspective on the emerging contribution of high-throughput technologies and next-generation interventions to develop and enhance resilience.
TL;DR: 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.
Abstract: 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" and "allostatic load and overload" highlight those experiences and situations that, as Kagan says, "compromise an organism's health and capacity to cope with daily challenges" (p. 442). A deeper understanding is needed of the epigenetic influences throughout the life course that contribute both to these negative outcomes and to positive ones.
TL;DR: The findings suggest that FGF2 may exert its anxiolytic effects in male MS rats by a compensatory increase in the acetylation of the OTR promoter to overcome reduced OT levels in the BNST.
11 Mar 2016
TL;DR: The epigenetic plasticity of the brain is key to the development of successful interventions and the continuing plasticity in the brain throughout the life course gives hope for further beneficial interventions.
Abstract: 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 that the impaired ability of the ASD-prone infant to respond to the “serve and return” interaction with parents leads to a state of frustration and chronic stress resulting in the cumulative “wear and tear” of adapting to chronic stress, called “allostatic overload,” that worsens the trajectory of the disorder and helps shape brain architecture, behavior, and systemic physiology. Singletary says that successful treatment must recognize the deviation from a normal developmental course as early as possible and intervene to redirect it. He cites examples in children where this has made a huge difference. Thus, the epigenetic plasticity of the brain is key to the devel...
01 Jan 2016
TL;DR: In this paper, stress is defined as a threat, real or implied, to the psychological or physiological integrity of an individual, and an individual makes behavioral and physiological responses that are intended to protect and defend the body and psyche from damage.
Abstract: 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.
TL;DR: It was found that carnitine acetyltransferase (CrAT) mRNA levels in the ventral dentate gyrus (vDG) were not different between FSL and Flinders Resistant Line animals; thus, the source of the deficiency is likely to be systemic.
Abstract: 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 carnitine acetyltransferase (CrAT) mRNA levels in the ventral dentate gyrus (vDG) were not different between FSL and Flinders Resistant Line animals; thus, the source of the deficiency is likely to be systemic. We are measuring blood levels of LAC and carnitine in FSL as well as other animal models and in …
01 Dec 2016