The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Bruce S Mcewen - One of the best experts on this subject based on the ideXlab platform.

  • sleep deprivation and circadian disruption stress Allostasis and allostatic load
    Sleep Medicine Clinics, 2015
    Co-Authors: Bruce S Mcewen, Ilia N Karatsoreos
    Abstract:

    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 disruption and deprivation are from anxiety, depression, shift work, long-distance air travel, or a hectic lifestyle, there are consequences that impair brain functions and contribute to the cumulative wear and tear on body systems caused by too much stress and/or inefficient management of the systems that promote adaptation.

  • Nursing research in stress, psychoneuroimmunology, and Allostasis.
    Biological research for nursing, 2012
    Co-Authors: Maureen Groer, Bruce S Mcewen
    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

  • adverse childhood experiences Allostasis allostatic load and age related disease
    Physiology & Behavior, 2012
    Co-Authors: Andrea Danese, Bruce S Mcewen
    Abstract:

    Abstract How do adverse childhood experiences get ‘under the skin’ and influence health outcomes through the life-course? Research reviewed here suggests that adverse childhood experiences are associated with changes in biological systems responsible for maintaining physiological stability through environmental changes, or Allostasis. Children exposed to maltreatment showed smaller volume of the prefrontal cortex, greater activation of the HPA axis, and elevation in inflammation levels compared to non-maltreated children. Adults with a history of childhood maltreatment showed smaller volume of the prefrontal cortex and hippocampus, greater activation of the HPA axis, and elevation in inflammation levels compared to non-maltreated individuals. Despite the clear limitations in making longitudinal claims from cross-sectional studies, work so far suggests that adverse childhood experiences are associated with enduring changes in the nervous, endocrine, and immune systems. These changes are already observable in childhood years and remain apparent in adult life. Adverse childhood experiences induce significant biological changes in children (biological embedding), modifying the maturation and the operating balance of allostatic systems. Their chronic activation can lead to progressive wear and tear, or allostatic load and overload, and, thus, can exert long-term effects on biological aging and health.

  • psychobiological Allostasis resistance resilience and vulnerability
    Trends in Cognitive Sciences, 2011
    Co-Authors: Ilia N Karatsoreos, Bruce S Mcewen
    Abstract:

    The brain and body need to adapt constantly to changing social and physical environments. A key mechanism for this adaptation is the ‘stress response’, which is necessary and not negative in and of itself. The term ‘stress’, however, is ambiguous and has acquired negative connotations. We argue that the concept of Allostasis can be used instead to describe the mechanisms employed to achieve stability of homeostatic systems through active intervention (adaptive plasticity). In the context of Allostasis, resilience denotes the ability of an organism to respond to stressors in the environment by means of the appropriate engagement and efficient termination of allostatic responses. In this review, we discuss the neurobiological and organismal factors that modulate resilience, such as growth factors, chaperone molecules and circadian rhythms, and highlight its consequences for cognition and behavior. Brain adaptation, resilience and vulnerability The brain and body constantly adapt. Indeed, the brain may be considered the primary organ allowing for adaptation to changing environments. The brain constantly sorts relevant from irrelevant environmental inputs and engages body systems to respond to these changes. However, it is only in the past few decades that the brain has been recognized as an adaptable and resilient organ not

  • Stress- and Allostasis-Induced Brain Plasticity
    Annual review of medicine, 2011
    Co-Authors: Bruce S Mcewen, Pj J Gianaros
    Abstract:

    The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (Allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, Allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prev...

David S Goldstein - One of the best experts on this subject based on the ideXlab platform.

  • stress allostatic load catecholamines and other neurotransmitters in neurodegenerative diseases
    Cellular and Molecular Neurobiology, 2012
    Co-Authors: David S Goldstein
    Abstract:

    As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of Allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators—“homeostats.” Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of Allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholaminergic neurons leak vesicular contents into the cytoplasm continuously during life and that catecholamines in the neuronal cytoplasm are autotoxic. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time.

  • stress allostatic load catecholamines and other neurotransmitters in neurodegenerative diseases
    Endocrine Regulations, 2011
    Co-Authors: David S Goldstein
    Abstract:

    : As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of Allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple interacting effectors regulated by homeostatic comparators-"homeostats." Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of Allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholamines in the neuronal cytoplasm are autotoxic and that catecholamines from storage visicles leak into the cytoplasm continuously during life. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time.

  • computer models of stress Allostasis and acute and chronic diseases
    Annals of the New York Academy of Sciences, 2008
    Co-Authors: David S Goldstein
    Abstract:

    The past century has seen a profound shift in diseases of humankind. Acute, unifactorial diseases are being replaced increasingly by multifactorial disorders that arise from complex interactions among genes, environment, concurrent morbidities and treatments, and time. According to the concept of Allostasis, there is no single, ideal set of steady-state conditions in life. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators--"homeostats." Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a set point for response leads to activation of effectors, reducing the discrepancy. "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of Allostasis. From the analogy of a home temperature control system, the temperature can be maintained at any of a variety of levels (allostatic states) by multiple means (effectors), regulated by a comparator thermostat (homeostat). Stress might exert adverse health consequences via allostatic load. This presentation describes models of homeostatic systems that incorporate negative feedback regulation, multiple effectors, effector sharing, environmental influences, intrinsic obsolescence, and destabilizing positive feedback loops. These models can be used to predict effects of environmental and genetic alterations on allostatic load and therefore on the development of multisystem disorders and failures.

  • Allostasis homeostats and the nature of stress
    Stress, 2002
    Co-Authors: David S Goldstein, Bruce S Mcewen
    Abstract:

    This essay continues discussion of a new formulation of homeostasis that uses the concepts of Allostasis and homeostats. The new formulation moves beyond Cannon's concept of "homeostasis," which posits an ideal set of conditions for maintenance of the internal environment. The notion of Allostasis recognizes that there is no single ideal set of steady-state conditions in life, and different stressors elicit different patterns of activation of the sympathetic nervous and adrenomedullary hormonal systems. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators--"homeostats." "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of Allostasis. From the analogy of a home temperature control system, the temperature can be maintained at any of a variety of levels (allostatic states) by multiple means (effectors), regulated by the thermostat (homeostat). Allostatic load and risks of system breakdown increase when, for example, the front door is left open in the winter. Applying these notions can aid in understanding how acute and chronic stress can exert adverse health consequences via allostatic load.

John C. Wingfield - One of the best experts on this subject based on the ideXlab platform.

  • what is in a name integrating homeostasis Allostasis and stress
    Hormones and Behavior, 2010
    Co-Authors: Bruce S Mcewen, John C. Wingfield
    Abstract:

    All organisms must adjust morphology, physiology and behavior as they go about their life cycles. For vertebrates, including humans, these adjustments occur as daily routines and in many cases, as seasonal routines as well. Superimposed on this predictable life cycle are unpredictable events, including many potential stressors, requiring immediate physiological and behavioral adjustments to cope. Additionally, infection, disease, age, old injuries, social status etc. may influence how an individual goes about its life cycle routines and responds to unpredictable perturbations. The classic concept of homeostasis (sensu Cannon, 1932) is fundamental to these adjustments. However, unless we have misinterpreted or overlooked something, homeostasis in its pure form does not incorporate adequately all of the processes involved and we believe that it is very useful to have supplemental terminology such as the Allostasis concept in view of the many ambiguities of the uses of the words “homeostasis” as well as “stress”. For example, a cow that begins lactation undergoes morphological, physiological and behavioral changes so it can raise a calf. None of this is essential for the maintenance of homeostasis of the cow, although homeostatic set points will have changed from pre-lactation levels (Baumann, 2000). Another example is the migration of a songbird from Mexico to Alaska in spring and back again in autumn. Here again there are major changes in morphology, physiology and behavior that allow this animal to complete a journey of almost 5000 Km in less than a month. But none of this is essential for maintenance of homeostasis. In both examples, the process of preparing for lactation or migration involves regulation of gene expression. Furthermore, termination of lactation and migration involves turning off of many genes involved. Of course both the cow lactating and the songbird migrating must do so to reproduce successfully. But the adjustments in homeostasis that occur during these life cycle events are to accommodate changed physiology as part of the predictable life cycle, not simply responses to deviations from some set point that maintains life processes. It is also important to bear in mind that changes in morphology, physiology and behavior associated with life cycle events such as lactation and migration also alter the responsiveness of the individual to unpredictable, and potentially stressful, events. Usually, a process such as lactation or migration results in the individual becoming more susceptible to perturbations of the environment, and adjustments in the stress response are made in anticipation of this. As far as we know, the classic concept of homeostasis does not incorporate all of these processes – homeostasis of daily routines, responses to perturbations, changed susceptibility to those perturbations and anticipatory adjustments to cope with them for at least part of the life cycle. Furthermore, there is growing evidence that many organisms change their sensitivity to stresses temporarily (e.g. when breeding, Wingfield and Sapolsky, 2003) by adjusting secretions of mediators of Allostasis that help maintain homeostasis (such as glucocorticoids). At first this seems counter intuitive, but temporary suspension of the classic stress response (and homeostatic adjustments in response to a perturbation) allows an individual to breed successfully, but the trade-off is potential permanent damage owing to the failure to show immediate responses that would normally promote adaptation. How do we model this apparently frequent strategy? It is in this context that we offer some ideas and responses to the article by Romero and colleagues (2009) who present a different terminology and a new model for conceptualizing and describing the impact of stress on the body, combining traditional notions of stress and homeostasis with the more recent terminology of Allostasis and allostatic load. It is our specific goal to point out where the concept of Allostasis adds to the concept of homeostasis but also presents a framework by which to incorporate major events of the predictable life cycle (such as reproduction, migration etc.) with perturbations and the potential for stress. In our opinion, certain aspects of this formulation, summarized below, will be a useful addition to the ongoing discussion of this topic, but first some conceptual issues must be addressed that also involve semantics.

  • Allostasis and Allostatic Load
    Encyclopedia of Stress, 2007
    Co-Authors: Bruce S Mcewen, John C. Wingfield
    Abstract:

    Allostasis and allostatic load are terms which supplement the classic terms homeostasis and stress. Allostasis is the active process that leads to adaptation to a stressor, and mediators of Allostasis include stress hormones as well as the autonomic nervous systems and pro-inflammatory cytokines and metabolic hormones. Allostatic load and its more severe form, allostatic overload, represent the cumulative effects of chronic physiologic stress, which may be generated by internal processes (e.g., anxiety) and by external factors such as chronic stressors or by life styles (e.g., overeating, insufficient sleep) that also dysregulate the mediators of Allostasis. Consequences of allostatic overload include many of the common diseases of modern life. In nature, however, allostatic load is used to achieve beneficial effects such as putting on fat for hibernation.

  • actions of glucocorticoids at a seasonal baseline as compared to stress related levels in the regulation of periodic life processes
    General and Comparative Endocrinology, 2006
    Co-Authors: Mėta M Landys, Marilyn Ramenofsky, John C. Wingfield
    Abstract:

    For decades, demands associated with the predictable life-history cycle have been considered stressful and have not been distinguished from stress that occurs in association with unpredictable and life-threatening perturbations in the environment. The recent emergence of the concept of Allostasis distinguishes behavioral and physiological responses to predictable routines as opposed to unpredictable perturbations, and allows for their comparison within one theoretical framework. Glucocorticosteroids (GCs) have been proposed as important mediators of Allostasis, as they allow for rapid readjustment and support of behavior and physiology in response to predictable and unpredictable demands (allostatic load). Much work has already been done in defining GC action at the high concentrations that accompany life-threatening perturbations. However, less is known about the role of GCs in relation to daily and seasonal life processes. In this review, we summarize the known behavioral and physiological effects of GCs relating to the predictable life-history cycle, paying particular attention to feeding behavior, locomotor activity and energy metabolism. Although we utilize a comparative approach, emphasis is placed on birds. In addition, we briefly review effects of GCs at stress-related concentrations to test the hypothesis that different levels of GCs play specific and distinct roles in the regulation of life processes and, thus, participate in the promotion of different physiological states. We also examine the receptor types through which GC action may be mediated and suggest mechanisms whereby different GC concentrations may exert their actions. In conclusion, we argue that biological actions of GCs at "non-stress" seasonal concentrations play a critical role in the adjustment of responses that accompany predictable variability in the environment and demand more careful consideration in future studies.

  • the concept of Allostasis coping with a capricious environment
    Journal of Mammalogy, 2005
    Co-Authors: John C. Wingfield
    Abstract:

    Vertebrates have regular patterns and routines that involve obtaining food and carrying out life-history stages such as breeding, migrating, molting, and hibernating. These are generally regulated by predictable changes in the environment, for example, seasons. Superimposed on these are unpredictable challenges, for example, storms and natural disasters, which have great potential for stress. The concept of Allostasis, maintaining stability through change, has been introduced as a fundamental process through which organisms actively adjust to both predictable and unpredictable events. This process considers the predictable and unpredictable components of the environment as a continuum and includes the effects of body condition (parasites and injuries), experience, and habitat configuration. It combines classical homeostasis with anticipatory responses, stress, and social status. By using the balance between energy input and expenditure as the basis for applying the concept of Allostasis, 2 types of allostatic overload have been proposed. Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in activation of the emergency life-history stage. This serves to direct the animal away from normal life-history stages into a survival mode that decreases allostatic load and regains positive energy balance. The normal life cycle can be resumed when the perturbation passes. Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. The latter is the case in human society, and in some situations affecting animals in captivity and possibly in natural conditions as well. In all cases, secretion of glucocorticoids increases with allostatic load, but if it is chronically high, then pathologies develop. Curiously, type 2 allostatic overload does not trigger an escape response, and can only be counteracted through learning or changes in social structure.

  • the darwinian concept of stress benefits of Allostasis and costs of allostatic load and the trade offs in health and disease
    Neuroscience & Biobehavioral Reviews, 2005
    Co-Authors: Mechiel S Korte, John C. Wingfield, J M Koolhaas, Bruce S Mcewen
    Abstract:

    Why do we get the stress-related diseases we do? Why do some people have flare ups of autoimmune disease, whereas others suffer from melancholic depression during a stressful period in their life? In the present review possible explanations will be given by using different levels of analysis. First, we explain in evolutionary terms why different organisms adopt different behavioral strategies to cope with stress. It has become clear that natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population. The existence of these personality types (Hawks-Doves) is widespread in the animal kingdom, not only between males and females but also within the same gender across species. Second, proximate (causal) explanations are given for the different stress responses and how they work. Hawks and Doves differ in underlying physiology and these differences are associated with their respective behavioral strategies; for example, bold Hawks preferentially adopt the fight-flight response when establishing a new territory or defending an existing territory, while cautious Doves show the freeze-hide response to adapt to threats in their environment. Thus, adaptive processes that actively maintain stability through change (Allostasis) depend on the personality type and the associated stress responses. Third, we describe how the expression of the various stress responses can result in specific benefits to the organism. Fourth, we discuss how the benefits of Allostasis and the costs of adaptation (allostatic load) lead to different trade-offs in health and disease, thereby reinforcing a Darwinian concept of stress. Collectively, this provides some explanation of why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and non-aggressive Doves in a population. A conceptual framework is presented showing that Hawks, due to inefficient management of mediators of Allostasis, are more likely to be violent, to develop impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, chronic fatigue states and inflammation. In contrast, Doves, due to the greater release of mediators of Allostasis (surplus), are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states and infection.

George F Koob - One of the best experts on this subject based on the ideXlab platform.

  • Allostasis and addiction role of the dopamine and corticotropin releasing factor systems
    Physiology & Behavior, 2012
    Co-Authors: Olivier George, Michel Le Moal, George F Koob
    Abstract:

    Allostasis, originally conceptualized to explain persistent morbidity of arousal and autonomic function, is defined as the process of achieving stability through physiological or behavioral change. Two types of biological processes have been proposed to describe the mechanisms underlying Allostasis in drug addiction, a within-system adaptation and a between-system adaptation. In the within-system process, the drug elicits an opposing, neutralizing reaction within the same system in which the drug elicits its primary and unconditioned reinforcing actions, while in the between-system process, different neurobiological systems that the one initially activated by the drug are recruited. In this review, we will focus our interest on alterations in the dopaminergic and corticotropin releasing factor systems as within-system and between-system neuroadaptations respectively, that underlie the opponent process to drugs of abuse. We hypothesize that repeated compromised activity in the dopaminergic system and sustained activation of the CRF-CRF1R system with withdrawal episodes may lead to an allostatic load contributing significantly to the transition to drug addiction.

  • alcoholism corticotropin releasing factor and molecular genetic Allostasis
    Biological Psychiatry, 2008
    Co-Authors: George F Koob
    Abstract:

    Alcoholism, or Substance Dependence on alcohol, is a chronic relapsing disorder characterized by loss of control over intake (compulsive use) and the emergence of a negative emotional state during abstinence. Stress long has been considered a key element in the etiology of alcohol dependence, yet the exact mechanisms by which stress exacerbates and interacts with alcohol dependence have remained elusive. Recent work on the brain neurotransmitter corticotropin-releasing factor (CRF) [see footnote on nomenclature] has provided new insights into the stress-alcohol dependence interaction. Two papers in this issue of Biological Psychiatry (1, 2) provide an exciting molecular mechanism for this interaction that may have heuristic value for future translational advances. CRF is a 41 amino acid polypeptide with a wide distribution throughout the brain but high concentrations of cell bodies in the paraventricular nucleus of the hypothalamus, the basal forebrain (notably the amygdala and bed nucleus of the stria terminalis) and the brainstem. Central administration of CRF mimics the behavioral response to activation and stress in rodents, and administration of competitive CRF receptor antagonists generally have anti-stress effects (3). Two major CRF receptors have been identified, with CRF1 receptor activation associated with increased stress responsiveness and CRF2 receptor activation associated with decreases in feeding and decreased stress responsiveness, although there is some controversy in this area depending on the location of the CRF2 receptors in question. In the current issue of Biological Psychiatry, Sommer et al. (1) studied rats using an animal model of alcohol dependence and showed that CRF and expression of the crh1 transcript within the amygdala are upregulated in postdependent animals. Animals trained to self-administer alcohol in a two-bottle, free-choice procedure and exposed to intermittent ethanol vapors to induce dependence showed a doubling of ethanol intake and increased sensitivity to stress which was reversed by a CRF receptor antagonist. CRF mRNA was increased in the central nucleus of the amygdala, and crh1 transcript expression was increased in the basolateral amygdala, with a concomitant decrease in crh2 transcript expression in the basolateral amygdala. These new results fit well with a burgeoning dataset implicating an increase in extrahypothalamic CRF function with the excessive drinking associated with alcohol dependence in animal models. Rats with either a genetic predisposition for anxiety-like behavior and excessive drinking, or with a history of dependence, show decreases in drinking with administration of CRF1 antagonists administered systemically (4, 5). CRF antagonists also block stress-induced reinstatement to alcohol and other drugs of abuse (6). These effects have been localized to the region of the central nucleus of the amygdala; local injection of a CRF1/CRF2 antagonist produced similar effects (7). A CRF2 agonist microinjected into the central nucleus of the amygdala also had a similar effect, consistent with the opposing actions on crh1 and crh2 gene transcripts in the present Sommer results. Thus, it appears that not only is there increased expression of CRF neuropeptide activity in the amygdala in dependent rats, but also an increase in CRF1 receptor activity and a concomitant decrease in CRF2 receptor activity. Another innovative aspect of the Sommer results is that these molecular and behavioral effects persist into protracted abstinence, supporting the data from earlier pharmacological studies (8). Altogether, these results demonstrate numerous targets for treatment of alcohol dependence and open a new vista for addiction treatment in general. In Blomeyer et al. (2) in the current issue, an ongoing cohort from the Mannheim Study of Children at Risk were genotyped for two alleles of the CRF1 receptor. Results showed that individuals homozygous for the C allele of one single nucleotide polymorphism of the CRF1 receptor (rs1876831) drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking but only in relation to negative life events. No similar gene × environment interactions were observed for the other crh1 allele (rs242938). These results are consistent with the observation that the genetically selected Marchigian-Sardinian alcohol preferring (msP) rat line has high alcohol preference with increased behavioral responsivity to stress and an innate upregulation of the crh1 transcript in several brain regions. Both the single nucleotide polymorphism observed in Marchigian rats and the one in the human study were in non-coding regions of the gene that can potentially influence transcription, with the former in a promoter region and the latter in an intron. Together these results suggest the exciting possibility that certain single nucleotide polymorphisms in the human population may predict vulnerability to certain subtypes of excessive drinking syndromes and, perhaps somewhat more mundane but equally provocative, may predict responsiveness to the use of CRF receptor antagonists for the treatment of alcoholism. Of course, as the authors noted, some caution must be considered given the relatively small sample size for a genetic association study. Replication of this association with attention to defined phenotypes will be an important future pursuit. Finally, the two present studies have provided molecular insight into a hypothesized conceptual framework for addiction that, in a sense, is reorienting neurobiology of addiction field. Addiction, and alcoholism in particular, has been hypothesized to reflect a break with homeostasis that represents a chronic change in reward set point that results in the emergence of a negative emotional state during abstinence. Continued drug taking to “self-medicate” the elevation in reward set point produces short-term relief but drives the set point further from homeostasis. Such a physiological change represents a classic allostatic mechanism (9) and has been hypothesized to be driven by not only decreases in reward neurotransmission (e.g., the action of opioid peptides or dopamine), but also by recruitment of brain stress systems such as CRF, neuropeptide Y, and norepinephrine (10). Most remarkable about the two studies in this issue of Biological Psychiatry is that a molecular target has been identified supporting the dark (stress) side of this conceptual framework that can be influenced by both the genetic makeup of the organism (“being born that way”) and by excessive drug taking (environmental insult) resulting in a possible gene × environment interaction. The implications of the CRF story for the treatment, diagnosis, and prevention of alcoholism are profound.

  • drug addiction and Allostasis
    2004
    Co-Authors: George F Koob, Michel Le Moal
    Abstract:

    INTRODUCTION Allostasis is a concept developed originally by neurobiologist Peter Sterling and epidemiologist James Eyer to explain the physiological basis for changes in patterns of human morbidity and mortality. They observed that the baby boom generation of individuals born after World War II had reached an age when major causes of death were renal, cerebral, and cardiovascular disease and that the single largest contributor to these diseases was hypertension. These researchers could find no explanation for these findings and no explanation for why hypertension was most prevalent where social disruption was greatest (Sterling and Eyer, 1988). They argued that the only possible link between the sociopsychological and physiological phenomena is in the brain. Using this backdrop, they argued for a form of brain-body regulation different from homeostasis , that of Allostasis . Homeostasis can be defined as “preserving constancy in the internal environment.” Allostasis can be defined as stability through change. Claude Bernard is credited with being the first to suggest that the internal milieu of the body is critically important for establishing and maintaining stable states within the body (this concept was later termed homeostasis by Walter Cannon in 1926). Bernard argued as early as 1859–60 that two environments affect an organism: a general milieu that is the outside world of inanimate and animate objects, and an internal milieu , where the elements of a living body find an optimal climate for operation. Originally described largely for the circulatory system, Bernard later argued for involvement of the lymphatic systems as well (Cannon, 1929, 1932, 1935). Bernard further argued that not only was an organism required to respond to outside stimuli to regulate energy by bodily adjustments, but that the body also maintained the internal milieu remarkably constant in the face of such challenges making the organism at some level independent of the exterior challenges. Finally, he argued that all the vital mechanisms of the body have but one goal of maintaining the conditions of the life of the internal milieu constant (Cannon, 1929, 1932, 1935).

  • vertical shifts in dose injection curves reflect reward Allostasis not sensitization
    Psychopharmacology, 2004
    Co-Authors: Serge H Ahmed, George F Koob
    Abstract:

    In 1998, we reported that increasing access time to cocaine (from 1 h to 6 h per day) precipitates a rapid escalation of intake that is associated with a vertical upward shift in the dose–injection curve, without detectable parallel shifts to the right or to the left (Ahmed and Koob 1998, 1999). Zernig et al. (2003) have suggested that this post-escalation vertical shift may result from tolerance to the rate-suppressing effects of the drug (e.g. “sedation, induction of stereotypy, aversion, etc”) and not—as suggested by other researchers—from tolerance to its rewarding effects or sensitization to its incentive effects (references in Zernig et al.). Unfortunately, Zernig et al. misinterpret our own hypothesis of drug intake escalation and misrepresent it as another version of the sensitization hypothesis of drug addiction. Briefly, according to our reward Allostasis hypothesis, prolonged drug exposure induces a chronic decrease in baseline reward sensitivity, a process called reward Allostasis (Koob and Le Moal 1997, 2001). As a result, the user becomes both increasingly motivated to seek the reward-facilitating effects of the drug (to avoid anhedonia and recover initial sensitivity) and increasingly tolerant to these effects (due to the shift in baseline sensitivity). In the following comments, we explain why the model offered by Zernig et al. fails to provide a more parsimonious explanation of our data than our reward Allostasis hypothesis. According to the model by Zernig et al., dose–response rate functions for drug self-administration represent the net effect of two antagonistic, S-shaped dose-dependent processes (with same efficacy but different potency), one increasing, the other suppressing responding for the drug. The resulting dose–response rate curve is an inverted U. For Zernig et al., the ascending limb of the dose–response curve “is easy to interpret”: the reinforcing effects of the drug increase with the unit dose and “thus leads to an increase in the rate of responding.” In the model by Zernig et al., simulating tolerance to the rate-suppressing effects of the drug results in both an upward and a rightward shift of the theoretical inverted U (Fig. 2C of Zernig et al.). They consider this complex shift as a theoretical approximation of our experimental data, although we did not observe any shift of the dose– injection curve to the right after escalation of cocaine selfadministration (compare Fig. 1C with Fig. 2C of Zernig et al.). Despite its apparent simplicity, the model by Zernig et al. misses the target. Escalation of cocaine intake and associated vertical shifts in dose–injection curves were observed under a schedule of continuous reinforcement (Ahmed and Koob 1998, 1999). Under this type of schedule, the dependent variable is the rate of injections, not the (inter-reinforcement) rate of responses, as wrongly assumed by Zernig et al. The rate of injections decreases with the duration of the rewarding effects of the drug which increases with the unit dose. Resulting dose– injection curves are predominantly characterized by a descending limb that covers the largest and most meaningful range of doses (Fig. 1C, D of Zernig et al.). Ascending limbs are rarely observed and difficult to interpret. In contrast, the descending limb of the dose– injection curve “is easy to interpret”: it reflects the behavioral regulation which allows the individual user to maintain the cumulative effect of the drug above some set level, at least down to a certain threshold dose, below which the rate of injections breaks down (Fig. 1C of Zernig et al.). At this threshold dose, the required rate of injections is probably higher than the maximum rate This reply refers to the letter http://dx.doi.org/10.1007/s00213-0031601-0

  • alcoholism Allostasis and beyond
    Alcoholism: Clinical and Experimental Research, 2003
    Co-Authors: George F Koob
    Abstract:

    Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.

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  • what is health Allostasis and the evolution of human design
    2020
    Co-Authors: Peter Sterling
    Abstract:

    An argument that health is optimal responsiveness and is often best treated at the system level.Medical education centers on the venerable ?no-fault? concept of homeostasis, whereby local mechanisms impose constancy by correcting errors, and the brain serves mainly for emergencies. Yet, it turns out that most parameters are not constant; moreover, despite the importance of local mechanisms, the brain is definitely in charge. In this book, the eminent neuroscientist Peter Sterling describes a broader concept: Allostasis (coined by Sterling and Joseph Eyer in the 1980s), whereby the brain anticipates needs and efficiently mobilizes supplies to prevent errors.Allostasis evolved early, Sterling explains, to optimize energy efficiency, relying heavily on brain circuits that deliver a brief reward for each positive surprise. Modern life so reduces the opportunities for surprise that we are driven to seek it in consumption: bigger burgers, more opioids, and innumerable activities that involve higher carbon emissions. The consequences include addiction, obesity, type 2 diabetes, and climate change. Sterling concludes that solutions must go beyond the merely technical to restore possibilities for daily small rewards and revivify the capacities for egalitarianism that were hard-wired into our nature.Sterling explains that Allostasis offers what is not found in any medical textbook: principled definitions of health and disease: health as the capacity for adaptive variation and disease as shrinkage of that capacity. Sterling argues that since health is optimal responsiveness, many significant conditions are best treated at the system level.

  • Allostasis a brain centered predictive mode of physiological regulation
    Trends in Neurosciences, 2019
    Co-Authors: Jay Schulkin, Peter Sterling
    Abstract:

    Although the concept of Allostasis was proposed some 30 years ago, doubts persist about its precise meaning and whether it is useful. Here we review the concept in the context of recent studies as a strategy to efficiently regulate physiology and behavior. The brain, sensing the internal and external milieu, and consulting its database, predicts what is likely to be needed; then, it computes the best response. The brain rewards a better-than-predicted result with a pulse of dopamine, thereby encouraging the organism to learn effective regulatory behaviors. The brain, by prioritizing behaviors and dynamically adjusting the flows of energy and nutrients, reduces costly errors and exploits more opportunities. Despite significant costs of computation, Allostasis pays off and can now be recognized as a core principle of organismal design.

  • homeostasis vs Allostasis implications for brain function and mental disorders
    JAMA Psychiatry, 2014
    Co-Authors: Peter Sterling
    Abstract:

    Most drugs that alter mental function, whether for recreational purposes or to treat mental disorders, affect synaptic transmission. Some drugs reshape the action potential, altering release of neurotransmitter; others antagonize or enhance the effect of a neurotransmitter on its synaptic receptor protein. Still other drugs inhibit reuptake of the neurotransmitter from the extracellular space, thus prolonging its action at the synapse. This leads naturally to the idea that disorders of thought, attention, and mood are fundamentally disorders of the synapse. Moreover, it presents a rationale for treating mental disorders by pharmacotherapy of the synapse. The rationale follows the venerable model of physiological regulation, homeostasis, where each parameter is supposed to maintain a certain value. A higher or lower value is considered “inappropriate” and thus potentially both a cause of disorder and a logical target for therapeutic readjustment. Normal mental functioning supposedly requires various synaptic parameters to hold their set values, whereas mental disorders supposedly result from “inappropriate” values. Certain neurons might release too much transmitter; others might release too little. A transmitter’s action might be too weak or too strong; or it might be too brief or too prolonged. Such are the hypothetical “inappropriate” values that drugs are sup

  • Allostasis a model of predictive regulation
    Physiology & Behavior, 2012
    Co-Authors: Peter Sterling
    Abstract:

    Abstract The premise of the standard regulatory model, “homeostasis”, is flawed: the goal of regulation is not to preserve constancy of the internal milieu. Rather, it is to continually adjust the milieu to promote survival and reproduction. Regulatory mechanisms need to be efficient, but homeostasis (error-correction by feedback) is inherently inefficient. Thus, although feedbacks are certainly ubiquitous, they could not possibly serve as the primary regulatory mechanism. A newer model, “Allostasis”, proposes that efficient regulation requires anticipating needs and preparing to satisfy them before they arise. The advantages: (i) errors are reduced in magnitude and frequency; (ii) response capacities of different components are matched -- to prevent bottlenecks and reduce safety factors; (iii) resources are shared between systems to minimize reserve capacities; (iv) errors are remembered and used to reduce future errors. This regulatory strategy requires a dedicated organ, the brain. The brain tracks multitudinous variables and integrates their values with prior knowledge to predict needs and set priorities. The brain coordinates effectors to mobilize resources from modest bodily stores and enforces a system of flexible trade-offs: from each organ according to its ability, to each organ according to its need. The brain also helps regulate the internal milieu by governing anticipatory behavior. Thus, an animal conserves energy by moving to a warmer place – before it cools, and it conserves salt and water by moving to a cooler one before it sweats. The behavioral strategy requires continuously updating a set of specific “shopping lists” that document the growing need for each key component (warmth, food, salt, water). These appetites funnel into a common pathway that employs a “stick” to drive the organism toward filling the need, plus a “carrot” to relax the organism when the need is satisfied. The stick corresponds broadly to the sense of anxiety, and the carrot broadly to the sense of pleasure. This design constrains anxieties to be non-adapting and pleasures to be brief -- fast-adapting -- to make way for the next anxiety. The stick/carrot mechanisms evolved early and expanded so that in humans they govern higher level learning and social organization. Correspondingly, the “funnel” widened to allow innumerable activities and experiences to each provide non-adapting anxieties and brief pleasures, their reward values depending partly on the effort expended. But modern life narrows the variety of small pleasures and reduces effort, thereby reducing their reward value and requiring larger portions for equivalent satisfaction – a cycle that generates addictive behaviors. Homeostasis and Allostasis locate pathology at different levels. Homeostasis identifies proximate causes; for example, it attributes essential hypertension to excess salt water in too small a vascular reservoir. Thus it directs pharmacotherapy toward reducing salt and water, expanding the reservoir, and blocking feedbacks that would counteract these measures. Allostasis attributes essential hypertension to the brain. Chronically anticipating a need for higher pressure, the brain mobilizes all the low level mechanisms in concert: kidney to retain salt and water, vascular system to tighten, and salt appetite to rise. Correspondingly, Allostasis would direct therapy toward higher levels – to reduce demand and increase sense of control -- so that the brain can down-shift its prediction and relax all the low-level mechanisms in concert. For disorders of addiction homeostasis pursues pharmacological treatments: drugs to treat drug addiction, obesity, and other compulsive behaviors. Allostasis suggests broader approaches – such as re-expanding the range of possible pleasures and providing opportunities to expend effort in their pursuit.

  • principles of Allostasis optimal design predictive regulation pathophysiology and rational therapeutics
    2004
    Co-Authors: Peter Sterling
    Abstract:

    INTRODUCTION This chapter compares two alternative models of physiological regulation. The first model, homeostasis (“stability through constancy”), has dominated physiology and medicine since Claude Bernard declared, “All the vital mechanisms … have only one object – to preserve constant the conditions of … the internal environment.” His dictum has been interpreted literally to mean that the purpose of physiological regulation is to clamp each internal parameter at a “setpoint” by sensing errors and correcting them with negative feedback (Fig. 1.1; Cannon, 1935). Based on this model, physicians reason that when a parameter deviates from its setpoint value, some internal mechanism must be broken. Consequently, they design therapies to restore the “inappropriate” value to “normal.” The homeostasis model has contributed immeasurably to the theory and practice of scientific medicine, so to criticize it might almost seem absurd. Yet all scientific models eventually encounter new facts that do not fit, and this is now the case for homeostasis. In physiology, evidence accumulates that parameters are not constant. Their variations, rather than signifying error, are apparently designed to reduce error. In medicine, major diseases now rise in prevalence, such as essential hyper-tension and type 2 diabetes, whose causes the homeostasis model cannot explain. For in contrast to the hypertension caused by a constricted renal artery and the diabetes caused by immune destruction of insulin-secreting cells, these newer disorders present no obviously defective mechanism. Treating them with drugs to fix low-level mechanisms that are not broken turns out not to work particularly well. The chapter expands on each of these points. The second model, Allostasis (“stability through change”), takes virtually the opposite view. It suggests that the goal of regulation is not constancy, but rather fitness under natural selection. Fitness constrains regulation to be efficient, which implies preventing errors and minimizing costs. Both needs are best accomplished by using prior information to predict demand and then adjusting all parameters to meet it (Fig. 1.1).