Showing papers by "Bruce S. McEwen published in 2012"

The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission

Abstract: Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.

Brain on stress: How the social environment gets under the skin

Abstract: Stress is a state of the mind, involving both brain and body as well as their interactions; it differs among individuals and reflects not only major life events but also the conflicts and pressures of daily life that alter physiological systems to produce a chronic stress burden that, in turn, is a factor in the expression of disease. This burden reflects the impact of not only life experiences but also genetic variations and individual health behaviors such as diet, physical activity, sleep, and substance abuse; it also reflects stable epigenetic modifications in development that set lifelong patterns of physiological reactivity and behavior through biological embedding of early environments interacting with cumulative change from experiences over the lifespan. Hormones associated with the chronic stress burden protect the body in the short run and promote adaptation (allostasis), but in the long run, the burden of chronic stress causes changes in the brain and body that can lead to disease (allostatic load and overload). Brain circuits are plastic and remodeled by stress to change the balance between anxiety, mood control, memory, and decision making. Such changes may have adaptive value in particular contexts, but their persistence and lack of reversibility can be maladaptive. However, the capacity of brain plasticity to effects of stressful experiences in adult life has only begun to be explored along with the efficacy of top-down strategies for helping the brain change itself, sometimes aided by pharmaceutical agents and other treatments.

Social influences on neuroplasticity: stress and interventions to promote well-being

Abstract: Experiential factors shape the neural circuits underlying social and emotional behavior from the prenatal period to the end of life. These factors include both incidental influences, such as early adversity, and intentional influences that can be produced in humans through specific interventions designed to promote prosocial behavior and well-being. Here we review important extant evidence in animal models and humans. Although the precise mechanisms of plasticity are still not fully understood, moderate to severe stress appears to increase the growth of several sectors of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. Structural and functional changes in the brain have been observed with cognitive therapy and certain forms of meditation and lead to the suggestion that well-being and other prosocial characteristics might be enhanced through training.

Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms.

Abstract: From its origins in how the brain controls the endocrine system via the hypothalamus and pituitary gland, neuroendocrinology has evolved into a science that now includes hormone action on many aspects of brain function. These actions involve the whole central nervous system and not just the hypothalamus. Advances in our understanding of cellular and molecular actions of steroid hormones have gone beyond the important cell nuclear actions of steroid hormone receptors to include signaling pathways that intersect with other mediators such as neurotransmitters and neuromodulators. This has, in turn, broadened the search for and identification of steroid receptors to include non-nuclear sites in synapses, dendrites, mitochondria and glial cells, as well as cell nuclei. The study of estrogen receptors and estrogen actions on processes related to cognition, mood, autonomic regulation, pain and neuroprotection, among other functions, has led the way in this new view of hormone actions on the brain. In this review we summarize past and current work in our laboratory on this topic. This exciting and growing field involving many laboratories continues to reshape our ideas and approaches to neuroendocrinology both at the bench and the bedside.

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Abstract: The hippocampus is a highly plastic brain region particularly susceptible to the effects of environmental stress; it also shows dynamic changes in epigenetic marks in response to stress and learning. We have previously shown that, in the rat, acute (30 min) restraint stress induces a substantial, regionally specific, increase in hippocampal levels of the repressive histone H3 lysine 9 trimethylation (H3K9me3). Because of the large magnitude of this effect and the fact that stress can induce the expression of endogenous retroviruses and transposable elements in many systems, we hypothesized that the H3K9me3 response was targeted to these elements as a means of containing potential genomic instability. We used ChIP coupled with next generation sequencing (ChIP-Seq) to determine the genomic localization of the H3K9me3 response. Although there was a general increase in this response across the genome, our results validated this hypothesis by demonstrating that stress increases H3K9me3 enrichment at transposable element loci and, using RT-PCR, we demonstrate that this effect represses expression of intracisternal-A particle endogenous retrovirus elements and B2 short interspersed elements, but it does not appear to have a repressive effect on long interspersed element RNA. In addition, we present data showing that the histone H3K9-specific methyltransferases Suv39h2 is up-regulated by acute stress in the hippocampus, and that this may explain the hippocampal specificity we observe. These results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic terra incognita represented by transposable elements.

Early life stress followed by subsequent adult chronic stress potentiates anxiety and blunts hippocampal structural remodeling.

Abstract: Early life stress produces long-term alterations in cognition, emotionality, and stress responsiveness. The stress-sensitive hippocampal formation plays a role in producing many of these alterations. We report that adult male rats exposed to early life stress, in the form of maternal separation (MS), exhibit baseline impairment of hippocampal dependent memory and following three weeks of chronic restraint stress (CRS) exhibit heightened anxiety-like behavior and alterations in the morphology of hippocampal CA3 pyramidal neurons. Specifically, as measured by the object placement task, MS offspring demonstrated impaired spatial memory compared with nonmaternally separated rats (NMS). Moreover, compared with NMS rats, subsequent CRS exposure of MS rats increased novelty-induced corticosterone secretion and potentiated anxiety-like behavior as measured by the elevated plus maze. Further, CRS exposed MS rats did not exhibit shortening of apical dendritic length compared with nonstressed MS rats, whereas CRS exposed NMS rats did show significant dendritic shrinkage compared with nonstressed NMS rats. The blunted CRS-induced remodeling of apical dendritic length in MS rats is likely due to a baseline deficiency in dendritic length; MS rats exhibit a trend towards shorter apical dendrites in comparison to NMS rats. CRS exposure in both MS and NMS rats, however, induced a reduction in apical dendritic branching. Finally, there was a significant correlation between apical dendritic length and novelty-induced corticosterone level, while there was not a significant correlation with anxiety-like behavior. Overall, our results suggest preserved but blunted hippocampal structural plasticity in MS rats that is not sufficient to compensate for hippocampal dysfunction and hypersensitivity to CRS.

The Ever-Changing Brain: Cellular and Molecular Mechanisms for the Effects of Stressful Experiences

Abstract: The adult brain is capable of considerable structural and functional plasticity and the study of hormone actions in brain has contributed to our understanding of this important phenomenon. In particular, stress and stress-related hormones such as glucocorticoids and mineralocorticoids play a key role in the ability of acute and chronic stress to cause reversible remodeling of neuronal connections in the hippocampus, prefrontal cortex, and amygdala. To produce this plasticity, these hormones act by both genomic and non-genomic mechanisms together with ongoing, experience-driven neural activity mediated by excitatory amino acid neurotransmitters, neurotrophic factors such as brain derived neurotrophic factor, extracellular molecules such as neural cell adhesion molecule, neuropeptides such as corticotrophin releasing factor, and endocannabinoids. The result is a dynamic brain architecture that can be modified by experience. Under this view, the role of pharmaceutical agents, such as antidepressants, is to facilitate such plasticity that must also be guided by experiences.

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

Abstract: Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5′-bromo-2′deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5′-bromo-2′deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.

Glucocorticoids Modulate the mTOR Pathway in the Hippocampus: Differential Effects Depending on Stress History

Abstract: Glucocorticoid (GC) hormones, released by the adrenals in response to stress, are key regulators of neuronal plasticity. In the brain, the hippocampus is a major target of GC, with abundant expression of the GC receptor. GC differentially affect the hippocampal transcriptome and consequently neuronal plasticity in a subregion-specific manner, with consequences for hippocampal information flow and memory formation. Here, we show that GC directly affect the mammalian target of rapamycin (mTOR) signaling pathway, which plays a central role in translational control and has long-lasting effects on the plasticity of specific brain circuits. We demonstrate that regulators of the mTOR pathway, DNA damage-induced transcript (DDIT)4 and FK506-binding protein 51 are transcriptionally up-regulated by an acute GC challenge in the dentate gyrus (DG) subregion of the rat hippocampus, most likely via a GC-response element-driven mechanism. Furthermore, two other mTOR pathway members, the mTOR regulator DDIT4-like and the mTOR target DDIT3, are down-regulated by GC in the rat DG. Interestingly, the GC responsiveness of DDIT4 and DDIT3 was lost in animals with a recent history of chronic stress. Basal hippocampal mTOR protein levels were higher in animals exposed to chronic stress than in controls. Moreover, an acute GC challenge significantly reduced mTOR protein levels in the hippocampus of animals with a chronic stress history but not in unstressed controls. Based on these findings, we propose that direct regulation of the mTOR pathway by GC represents an important mechanism regulating neuronal plasticity in the rat DG, which changes after exposure to chronic stress.

Viral-induced encephalitis initiates distinct and functional CD103+ CD11b+ brain dendritic cell populations within the olfactory bulb

Abstract: Dendritic cells (DC) are antigen-presenting cells found in both lymphoid and nonlymphoid organs, including the brain (bDC) of Cd11c/eyfp transgenic C57BL/6 mice. Using an intranasal vesicular stomatitis virus infection, we demonstrated that EYFP+ cells amass in areas associated with viral antigens, take on an activated morphology, and project their processes into infected neuronal tissue within the olfactory bulb. These bDC separated into three EYFP+ CD45+ CD11b+ populations, all but one being able to functionally promote both T lymphocyte proliferation and TH1 cytokine production. One population was shown to emanate from the brain and a second population was peripherally derived. The third population was of indeterminate origin, being both radiosensitive and not replenished by donor bone marrow. Finally, each EYFP+ population contained CD11b+ CD103+ subpopulations and could be distinguished in terms of CD115, Gr-1, and Ly-6C expression, highlighting mucosal and monocyte-derived DC lineages.

Maternal modulation of novelty effects on physical development

Abstract: Familiarity to the mother and the novelty afforded by the postnatal environment are two contrasting sources of neonatal influence. One hypothesis regarding their relationship is the maternal modulation hypothesis, which predicts that the same neonatal stimulation may have different effects depending on the maternal context. Here we tested this hypothesis using physical development, indexed by body weight, as an endpoint and found that, among offspring of mothers with a high initial swim-stress–induced corticosterone (CORT) response, neonatal novelty exposure induced an enhancement in early growth, and among offspring with mothers of a low initial CORT response, the same neonatal stimulation induced an impairment. At an older age, a novelty-induced increase in body weight was also found among offspring of mothers with high postnatal care reliability and a novelty-induced reduction found among offspring of mothers with low care reliability. These results support a maternal modulation of early stimulation effects on physical development and demonstrate that the maternal influence originates from multiple instead of any singular sources. These results (i) significantly extend the findings of maternal modulation from the domain of cognitive development to the domain of physical development; (ii) offer a unifying explanation for a previously inconsistent literature regarding early stimulation effects on body weight; and (iii) highlight the notion that the early experience effect involves no causal primacy but higher order interactions among the initial triggering events and subsequent events involving a multitude of maternal and nonmaternal influences.

What Is Stress

Abstract: Stress is a word that is used throughout the world, and it has many meanings. There is “good stress” and “bad stress.” Some would prefer to use “stress” to refer only to the experience and consequences of a situation when one is unable to cope physically or psychologically with the challenge (Cohen et al. 2007; Lazarus and Folkman 1984).

Nursing research in stress, psychoneuroimmunology, and allostasis.

Abstract: This issue of Biological Research for Nursing, ‘‘Nursing Research in Stress, Psychoneuroimmunology, and Allostasis,’’ reflects nursing science at the leading edge of a new paradigm of human health and illness—one that illuminates many issues that nurses have tried to understand for years. Why are there such great disparities in health related to socioeconomic levels, ethnicity, and environment? How can stress affect illness risk? Why does an intervention work effectively for one patient and not for another? How does one’s history impact one’s future health? What can nurses do to prevent chronic illness? This paradigm shows us that there are answers to these questions and new ways of addressing these problems. The allostasis theory seems to resonate with nursing science due to its hypothesis-generating potential and its promise of interventions that better use allostasis for promotion of health and prevention, or at least minimization, of allostatic load and overload. Allostasis emphasizes the dynamic, nonlinear nature of a host of biological mediators that are turned on by stressors in order to maintain homeostasis and promote adaptation. The social environment in which we live is an enormous source of challenges that require allostasis. Problems arise, however, if the allostatic response to a stressor is not turned on when needed or not turned off when the stressor is over. In these cases, the body and brain experience negative consequences that, over time and repetition of stressors, may accumulate and result in pathophysiology. This is allostatic load or overload in the extreme. A related approach is that of psychoneuroimmunology, a maturing science that investigates connections among stress, emotions, neurochemistry, and immunity at every level, from molecular to ecosystem. The immune system is a very sensitive index of successful or unsuccessful allostasis since acute stress will enhance immune defenses, while chronic stress can suppress those defenses. Moreover, inflammatory processes are part of all the major disorders of modern life—from diabetes to cancer to neurodegenerative brain diseases—and the regulation of inflammation involves not only glucocorticoids but also sympathetic/parasympathetic balance. Both of these theoretical approaches to health acknowledge the central role of stress in disease. Nurses have always been cognizant of the importance of stress in health and illness. Many of our most basic approaches are inculcated with ways to address stress: the stress of hospitalization, the stress of illness, the stress of living with chronic disease, family stress, and stress in communities. But now these new frameworks are providing us with tools for deepening our understanding and intervening to minimize the negative effects of stress. In this issue, you will read of theoretical approaches and ideas, intervention with multiple populations, basic and clinical research studies and critical reviews of literature in stress, psychoneuroimmunology, and allostasis. Beckie’s comprehensive review and critique of studies that have used allostasis as a framework or explanatory model introduces us to the strengths of the model but also points out the areas that need further investigation and clarification. Granger, Johnson, Szanton, Out, and Schumann provide an in-depth review of the methodology for salivary cortisol measurement, an important stress and allostasis biomarker. There are papers that examine gender (Arroyo-Morales, Rodriguez, Rubio-Ruiz, and Olea), ethnicity (D’Alonzo, Johnson, and Fanfan), and prematurity (Weber, Harrison, and Steward). Other papers in this issue describe studies that have incorporated salivary cortisol measurement in various populations: Woods and Yefimova study cortisol patterns in nursing home patients with dementia, while Saban, Mathews, Bryant, O’Brien, and Janusek examine the relationship between depression and salivary cortisol in female caregivers. Two papers consider significant biobehavioral markers of stress, psychoneuroimmunology, and allostasis: Peace, Majors, Patel, Wang, Dell Valle-Pinero, Martino, and Henderson explore genetic variations in relationship to stress in individuals with chronic abdominal pain, while Lee and Theus focus on heart rate variability in traumatized individuals. Rounding out the perspectives provided by these outstanding investigators are papers that examine caring (Zender and Olshansky) and touch (Papathanassoglou and Mpouzika). These papers remind us that, while nursing is certainly a

Stress and Brain Function

Abstract: Publisher Summary This chapter discusses how the hippocampus, prefrontal cortex and amygdale are affected by stress, and how these stress-induced changes relate to changes in behavior. Located in the medial temporal lobe, the hippocampus is one of the most plastic and sensitive regions of the brain. It is crucially important in both cognitive function and emotionality. While glucocorticoids are a key part of stress-induced changes in hippocampal structure and function, particularly during periods of repeated or chronic stress, they can have effects that are independent of an actual stressor. Excitatory amino acids (EAAs) are described in the section that focuses on how stress and stress mediators interact with this system. EAAs are released by the mossy fiber pathway, and can be regulated by adrenal steroids. For instance, one consequence of restraint stress is significantly elevated extracellular glutamate. Another important factor to consider as a stressor in the modern world that has impacts on brain function is socioeconomic status (SES). It is largely the case that individuals with lower SES are exposed to more environmental toxins in the environment.