The General Adaptation Syndrome Psychology Essay

The General Adaptation Syndrome Psychology Essay Stress is inescapably present in the lives of every living organism. While some stress can be beneficial, too much of it is almost always disadvantageous. Frequently the word stress is used to describe the imposition of an undesirable psychological or physical state through uncontrollable or overwhelming circumstances. We tend to think of stress as a burden that we carry around with us. One individual might perceive that they are under an enormous amount of stress because of multiple impending deadlines, while another might feel stressed out because their house is not clean and unexpected guests are on their way. Despite the predominantly negative description above, stress itself is not necessarily bad. In fact, stress is an adaptive process without which our survival would be seriously compromised. Moderate stress can even have beneficial effects, such as improving cognitive function to facilitate meeting multiple deadlines and increasing energy supply to muscles to quickly clean th e entire house in a matter of minutes. However, too much or prolonged stress can result in a variety of detrimental effects on both physiological function and cognitive processes. Definition In order to properly understand the effects of stress on cognition, as measured by performance in a variety of mazes, we must first come to an understanding of what stress is. At its core, stress is can be defined as the response to a threat (or perceived threat) against homeostasis, the tendency of a system to maintain a stable internal environment. Living organisms, including humans and rodents, are open systems which work to maintain homeostasis despite being constantly bombarded by numerous external environmental insults. Homeostasis The concept of homeostasis was initially conceived by the French physiologist Claude Bernard in1854. He used the term milieu intà ©rierur to describe the ability of the internal environment (primarily the blood in Bernards time) of the body to compensate for and re-equilibrate in response to the external environment [1,2]. However, it was Walter Cannon who developed the concept of homeostasis. He proposed that the body maintained steady state conditions through multiple cooperative self-regulating mechanisms. One phenomenon observed by Cannon was that organisms respond to a threat by releasing epinephrine (aka adrenaline) from the adrenal medulla thereby increasing the bodys heart rate, respiration, and blood pressure while mobilizing glucose stores and inhibiting non-essential functions such as digestion and reproduction. This phenomenon is the prototypical sympathetic nervous system (a branch of the autonomic nervous system) response, for which Cannon coined the term fight-or-flig ht response [3]. Simply put, when confronted with a threat, an organism, through the narrowing of bodily functions and mobilization of available energy, is primed to respond actively, whether through fleeing or fighting. Thus, the primary contribution of Walter Cannon to the definition of stress was that in response to an environmental insult threatening the internal steady stated, the body initiates the sympathetic response to maintain homeostasis and ultimately increase survival. General Adaptation Syndrome The second major contributor to stress research was endocrinologist Hans Selye. Selye was working to discover a new hormone by injecting ovarian extracts in to rats and observing the physiological effects. He noted several changes after injection of this extract, including the 1) enlargement of the adrenal gland, 2) the atrophy of the thymus and lymph nodes and 3) the presence of gastric ulcers [4]. While he initially thought these effects were direct effects of a novel hormone, through additional control experiments he discovered that the injection of numerous agents, physical injury or even excessive exercise produced the same reliable effects [5]. Emphasizing the non-specificity of this response, Selye called these effects the General Adaptation Syndrome initially and later used the term stress to describe it. He further defined stressors as the factors or agents that triggered the stress response. In addition, Selye established the role of glucocorticoids, steroid hormones excret ed from the adrenal cortex, in the stress response. Furthermore, Selye described that prolonged exposure to stressors (and the stress response) can lead to illness or disease. Summary The combined work of Walter Cannon and Hans Selye formed the basis of stress research. Both agreed that when confronted with disruptive environmental factors, the body generated an adaptive response aimed at re-establishing homeostasis within the internal environment. Cannon focused on the sympathetic branch of this response, while Selye focused on the hormonal (i.e., endocrine) branch of this response. Modern thinking has modified the conceptualization of stress, as it turned out to be not quite as simple as originally thought. Importantly it is no longer thought that stress is non-specific as the magnitude and more subtle characteristics of the stress response are varied based on the type of stressor, the individuals perception of the stress and ability to cope. The following basic features of stress can be gleaned from this historical work: Stressors are any event, experience or environmental insult that threatens or is perceived to threaten homeostasis Stress is an adaptive response to re-establish and maintain homeostasis Stress is ultimately mediated by two branches: The sympathetic nervous system via release of epinephrine from the adrenal medulla The endocrine system via release of glucocorticoids from the adrenal cortex These definitions and characteristics are more conducive to scientific study than the layman use of the term stress which does not distinguish between the trigger and the response, as described in the opening of this section. Thus, the definitions above will be utilized in the following sections. This chapter will further develop these basic concepts and present 1) an overview of the stress response, 2) descriptions of the different types of stressors, 3) the effects of both acute and chronic stress on learning and memory and 4) practical details on how to deal with the nuances of stress in behavioral testing. THE PHYSIOLOGY OF THE ACUTE STRESS RESPONSE When a stressor is encountered, the brain triggers a physiological response, aimed at coping with the stressor and restoring homeostasis [6]. This response is governed by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Both of these systems are always actively engaged in maintaining homeostasis, but when posed with a disruption to an organisms internal environment, the HPA axis and SNS go into overdrive. When stressors are encountered several central nervous system (CNS) structures are activated to initiate the stress response, including the preganglionic sympathetic neurons of the spinal cord in addition to several brainstem and limbic forebrain structures [7]. These structures then recruit neural and neuroendocrine systems to initiate a stress response, culminating with the secretion of adrenal glucocorticoids (GCs) and epinephrine, the principle mediators of this adaptive response. The Sympathetic Nervous System Two primary pathways are activated by stressors within the SNS, the brain norepinephrine neurons in the locus coeruleus (LC) and the sympathetic adrenomedullary circuitry. Many, but not all stressors result in norepinephrine release from the LC, which ultimately contributes to the majority of circulating NE levels as well as numerous adaptive behaviors [8,9]. Activation of the sympathetic adrenomedullary circuitry via preganglionic neurons results in the release of the excitatory neurotransmitter acetylcholine (ACh) onto postganglionic neurons and the adrenal medulla. Sympathetic postganglionic neurons primarily release of norepinephrine directly onto various target organs. On the other hand, activation of the adrenal medulla results in the synthesis and release of epinephrine into the circulation and indirectly onto target organs. Target organs activated by these catecholamines neurotransmitters correspond directly to the symptoms of the fight-or-flight response, including increased heart rate, blood pressure and respiration, pupil dilation, and inhibition of digestion, liver, kidney and gall bladder function. The Hypothalamic-Pituitary-Adrenal Axis (Figure 1: HPA axis from Lupien 2009 Review) The present chapter will focus on the endocrine branch of the stress response. While the activation of the sympathetic nervous system is a key part of stress, many of the effects of stress on learning and memory have been shown to be dependent on GCs. The secretion of adrenal GC hormones is under the stimulatory drive of the medial parvocellular neurons in the paraventricular nucleus (PVN) of the hypothalamus. In response to stressors, brainstem and limbic forebrain regions activate these neurons to secrete corticotropin releasing hormone (CRH) and vasopressin into the hypophysial circulation to stimulate the anterior pituitary to release adrenocorticotrophic hormone (ACTH) into the peripheral circulation which ultimately results in the release of GCs from the adrenal gland [10]. GCs are carried to every organ via the circulation to allow for a coordinated adaptive response between the brain and bodily functions. GCs mobilize energy, suppress immune and inflammatory responses, inhibi t bone and muscle growth and reproductive function as well as increase attention and impact learning and memory processes [11]. GCs also regulate further CRH and ACTH release via negative feedback loops by binding receptors in the pituitary, PVN, hippocampus (HPC) and prefrontal cortex (PFC) to inhibit further GC release and to return the homeostatic balance of the HPA axis [10] (Fig. 1). While these are the primary targets of GCs, virtually every neuron in the brain has receptors for these hormones. Thus, GCs are an important enabler of normal brain function in addition to their role in HPA axis function. Corticosterone (CORT), the primary GC in the rat, is the ligand for the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), steroid hormone receptors that function as transcription factors and regulate neuronal gene transcription. GR and MR have different affinities for CORT in the brain. GRs are expressed ubiquitously in the brain, and are most concentrated in the CRH neurons of the PVN and ACTH releasing neurons in the anterior pituitary and also in the HPC [10]. The highest expression of MRs in the brain is in the HPC, though they are expressed in other forebrain regions [10]. MRs are saturated by modest levels of CORT, such as those generated during circadian oscillations, and thus mediate daily changes in HPA axis activity. On the other hand, GRs are saturated by more extreme levels of CORT, such as those seen following a stressful experience, and mediate negative feedback to restore homeostasis [12,10]. Time Course of the Acute Stress Response (Figure 2: rise and fall of CORT) The typical stress response begins within a very short period of time. The SNS response occurs more rapidly than the HPA axis response, due to direct neurotransmitter release on target tissues vs. indirect hormonal release into the circulation, respectively. Within seconds, the post-ganglionic neurons of the SNS release norepinephrine and the adrenal medulla releases epinephrine into circulation. Also within seconds, CRH is released from the PVN of the hypothalamus, followed quickly by the release of ACTH into peripheral circulation from the anterior pituitary [13]. Within 3-5 minutes, the adrenal cortex releases CORT into the circulation, by which time peak plasma ACTH levels are reached. While peak levels of GCs vary according to stressor type and duration, circulating CORT levels typically reach peak levels15-30 minutes after stressor initiation [14]. At this time ACTH levels have also returned to baseline [14]. However, the effects of GCs on target tissues do not occur until abou t an hour after stressor initiation [13]. After peak CORT levels are reached, negative feedback mechanisms shut down further CORT secretion so that circulating CORT levels recover to near baseline levels within 60-120 minutes after stressor initiation [15,14]. The time required to reach baseline levels also varies depending on stressor type and duration. Circulating levels of norepinephrine and epinephrine follow a similar trajectory, but with more rapid increases and decreases [16]. Biological Rhythms Plasma levels of CORT are not static, but follow a circadian rhythm that is closely aligned with the sleep-wake cycles. In both humans and rodents, plasma GCs rise as the sleep cycle (inactive phase) ends and peaks upon waking up. From this peak, GC levels fall during the active phase and eventually reach the circadian trough or nadir (the lowest point in the cycle) [17,18]. However, as nocturnal animals, the active phase for rodents is during the dark period and the inactive phase occurs during the light period. Thus, in laboratory animals, peak CORT levels are found just after the lights are turned off and nadir CORT levels are measured when the lights are turned on. In addition, within this circadian rhythm GCs are released in an ultradian (cycles repeated within the 24 hour period) pulsatile pattern which rises and falls according to the circadian rhythm [19]. Basal levels of CORT measured in rats can typically range from 0-200 ng/mL in adult male rats or 100-500 ng/mL in adult f emale rats [18]. In response to acute stressors, peak stress levels of CORT generally range from 200-600 ng/mL in adult male rats and 500-1000 ng/mL in adult female rats. Both basal and peak stress levels of CORT can vary depending on the sampling time within the circadian rhythm. Sex, Age and Strain Differences As noted above, sex differences in HPA axis activity and responses to acute stressors are well documented. Female rodents exhibit higher basal and stress induced levels of both ACTH and CORT [20,21]. Sex differences in CORT secretion are primarily mediated by estrogen, with higher levels of ACTH and CORT found during proestrus, when circulating levels of estrogen are high [20,18]. Much of the research on gonadal steroid regulation of the HPA axis suggests that estrogen has excitatory effects while androgens have inhibitory effects [22-26]. In addition, females have higher levels of corticosteroid binding globulin (CBG), which partially buffers the higher levels of CORT [27,24]. CBG binds circulating CORT and renders it biologically inactive [28,29]. However, CBG levels take several hours to increase after exposure to a stressor, resulting in higher levels of biologically active CORT in females in response to stressors [30]. Acute stress responses can also vary across the lifespan. After birth, from day 2 to 14, rats experience a stress hyporesponsive period (SHRP) wherein circulating basal CORT remain very low and neonatal pups fail to show an elevation in CORT in response to stress or ACTH administration[31-33]. Adolescence is the next developmental epoch, which includes three stages: pre-pubescence/early adolescence (21-34 days), mid-adolescence (34-46 days) and late adolescence (46-59 days) [34,35]. During early adolescence, rats exhibit an exaggerated HPA axis response to both acute and chronic stress compared to adults [36,37]. In addition, sex differences in HPA axis function mature over the adolescent period [38,39]. The acute stress response has also been investigated in aging animals, though a great deal of heterogeneity, particularly with respect to the aging model has been found [40]. However, the general consensus, based on earlier studies, is that aged animals exhibit elevated baseline (or basal) CORT and a prolonged stress-induced elevation in CORT release, possibly due to decreased GR-mediated negative feedback [41,42]. It should also be noted that aging is associated with increased variability in the acute stress response [40]. Sex differences in acute HPA axis responses are not frequently examined in aged rats. However, since estrogen decreases with age, and males demonstrate increased basal CORT, it would be expected that sex differences would become less robust [43,44] Robust strain differences in both basal and peak stress levels of CORT also exist. In general, the in bred Fischer 344 (F344) strain of rats secrete higher levels of both basal and stress induced CORT levels compared to both the inbred Lewis (LEW) strain and the outbred Sprague Dawley (SD) strain (Dhabar 1993). Interestingly, both F344 and SD rats show increased basal CORT levels at the end of the inactive period, while LEW rats did not show a robust circadian rhythm (Dhabar 1993). As mentioned above, strain differences can also interact with age differences to further complicate the picture of a normal HPA axis stress response across the lifespan. CHRONIC STRESS Exposure to chronic stress can result in long term elevations in GCs and has been shown to alter the structure and function of the brain regions involved in regulating the HPA axis as well as learning and memory and numerous other behaviors [7]. Two general responses in HPA axis function occur as a result of chronic stress, namely habituation and sensitization. Habituation typically occurs following repeated exposure to the same (homotypic) mild stressor, with the magnitude of the HPA axis response (i.e. CORT secretion) diminishing with each subsequent exposure to the stressor [45,46]. On the other hand, repeated exposure to different (heterotypic) and unpredictable stressors can diminish the habituation of the HPA axis response [47-49]. Interestingly, both chronic homotypic and heterotypic unpredictable stressors cause sensitization of the HPA axis response to a novel stressor, resulting in increased ACTH and CORT secretion [45,48]. The most frequently studied brain regions that are vulnerable to chronic stress are the HPC, amygdala (AMG) and PFC [50]. In both the HPC and PFC, chronic restraint stress results in dendritic atrophy and decreased GR expression, which facilitates decreased HPA axis feedback and impaired memory [51-54,7]. In addition, chronic stress can also lead to altered hippocampal excitability, neurochemistry and neurogenesis (refs from Conrad 2010 review if needed?). On the other hand, chronic stress causes dendritic hypertrophy and increased CRH expression in the AMG as well as dendritic hypertrophy in the dorsolateral striatum (DLS), which facilitate HPA axis excitability and anxiety and habitual behavior, respectively [7,55-58]. Sex, Age and Strain Differences Sex differences in response to chronic stress exposure are less frequently examined. The above-mentioned effects are well documented in males. However, chronic stress does not appear to have the same effects in females. For example, females appear to be resilient against chronic stress induced dendritic atrophy in the HPC and spatial memory impairments [59-63]. In the PFC, females exhibit dendritic hypertrophy, whereas males demonstrate dendritic atrophy in response to repeated stress exposure [64]. In addition, chronic stress is associated with sex-specific PFC-mediated behavioral effects. Chronically stressed males show impairments in recall of fear extinction, possibly reflecting decreased behavioral flexibility [65-67]. However, chronically stressed females demonstrate impaired memory for the acquisition of fear conditioning, which is more dependent on the AMG [68-70]. Interestingly, males show dendritic hypertrophy and increased activation of the AMG and an associated increase i n the acquisition of fear conditioning following chronic stress [67]. Thus, in females, chronic stress causes more moderate morphological and behavioral outcomes that may be related to sex-specific changes in AMG function. Chronic stress also has differential effects across the lifespan. In general, earlier exposure to chronic stress (i.e. prenatal and neonatal) have protracted and irreversible effects compared to adult chronic stress. Exposing pregnant rat dams to chronic stress increases circulating CORT which crosses through the placenta and reaches the developing fetus to alter brain development and HPA axis activity [71]. The long-term effects of prenatal stress include increased basal and stress induced CORT secretion as well as learning impairments, increased anxiety- and depression-like behaviors and sensitivity to drugs of abuse [72,73]. Postnatal stress is typically induced by disrupting the maternal-pup interactions (i.e., maternal separation or daily handling of pups). The long-term effects of early postnatal stress include altered anxiety-like behavior and stress-induced HPA axis activity in adulthood though the direction of these effects are varied and highly dependent on the age of the p up, as well as the type and duration of the manipulations [72,74,75]. Chronic adolescent stress can result in enduring effects in adulthood, including decreased hippocampal volume, impaired spatial learning, and increased anxiety-like behavior adulthood [76-79]. However, there is less evidence for adolescent stress exposure to result in depressive behaviors in adulthood [80,81]. Studies of long lasting effects of adolescent stress exposure on HPA axis function are mixed, while most report no effect on basal or stress-induced CORT or ACTH secretion, some studies find increased basal and stress induced CORT secretion in adulthood [82,78,76,83,84]. Chronic stress exposure during adolescence can lead to long term behavioral and neuroendocrine effects, depending on the timing of exposure, the sex of the animal and the type of stressors used [82,84,85]. In aged animals, chronic stress has differential effects compared to young or middle-aged adult rats. For example, following 3 weeks of c hronic restraint stress in aged males and females, stress-induced sex differences were no longer evident on spatial and non-spatial memory tasks and chronic stress either facilitated or did not impair performance in aged male rats [86,87]. In addition, in aged animals sex-specific effects of chronic stress are reversed [86,87]. Furthermore, chronic stress in aged rats may potentiate stress-induced neurotoxicity, particularly in the HPC [72,88]. Strain differences are also noted in the effects of chronic stress. Interestingly, and in line with acute stress strain differences, the inbred F344 strain do not demonstrate habituation of the plasma CORT response to chronic stress with a repeated homotypic stressor, while SD and LEW rat strains do [46]. F344, but not SD and LEW, rats also exhibit adrenal gland hypertrophy after 3 sessions of restraint over 10 days [46]. F344 rats also exhibit a lack of HPA axis habituation following 14 days of restraint compared to SD rats [89]. Consistent with these findings, robust differences between SD and LEW rats were not found in either male or female rats in HPA axis response to an acute stressor after chronic exposure to unpredictable heteroptyic stressors [90]. TYPES OF STRESSORS Acute Stressors (Figure 3: Equipment/Stressors) In addition to being a threat against homeostasis, stressors can be described as any event or environment that is novel, unpredictable, poses a threat to well-being or ego, or creates a sense of loss of control (Lupien 2007). Acute stressors are stressors which occur on a single occasion with varying durations. Typically acute stressors last anywhere from 5 minutes to upwards of 6 hours, but in general for a period of time less than 24 hours. Acute stressors of longer durations are sometimes referred to as single prolonged stressors. Essentially the purpose of an acute stressor is for the experimental subject to mount a single stress response, or activation of the HPA axis. There are many different types of stressors and categorization of these stressors is attempted by many, though not all stress researchers agree. Stressors can vary in the type of perceived stress such as physical or psychological (or some combination of the two) as well as intensity and duration. Depending on the type of stressor used, differential effects on the HPA axis and SNS responses will occur. Physical stressors are stressors that are predominantly identified or perceived through the senses or involuntary (autonomic) mechanisms. Examples of physical stressors include extreme temperatures, loud noise, chemical exposure, extreme activity, metabolic or immune system disruptions, hemorrhage and pain. The most extreme physical stressors are necessarily limited to short durations due to discomfort. Many physical stressors can be administered in multiple ways or in combination with other stressors. To manipulate temperature, rodent subjects can be place in a standard cold room (~4-6 °C) or a hot room (~30-40 °C) or in cold (~18-20 °C) or hot water (~25-35 °C) as part of a forced swim stressor (forced exercise) [91-93]. Loud noises stressors are most effective at a range of ~90-110 dB [94]. Chemical stressors include exposure to ether vapors, hypoxic conditions, and injection of formalin or other noxious substances [93,95]. Stressors involving extreme activity include forc ed swim and on the opposite end of the spectrum, immobilization, wherein the subject is splayed out on a board with all its limbs and head secured to prevent movement. Metabolic disruptions can include fasting or food restriction, injections of insulin to induce hypoglycemia or lipopolysaccharide to induce an immune reaction. Hemorrhage or hypovolemia is induced by removing a percentage of blood volume with a moderate hemorrhage consisting of removal of ~20% estimated blood volume [96]. Finally, pain can be induced via numerous methods. Frequently used stressors include tail pinch with clothespins or hemostats. Another common stressor associated with pain is mild ( Psychological stressors are perceived threats against homeostasis or well-being. Important qualities of psychological stressors include loss of control, unpredictability and novelty. Identification of psychological stressors can also be experience or species dependent, in that the anticipation of the event itself can be a stressor, even in the absence of the actual event. Psychological stressors may also induce fear, anxiety or other behavioral changes. The effectiveness of psychological stressors is primarily under the control of limbic brain regions such as the HPC, AMG and PFC [7]. Several types of psychological stressors are used, including those that activate innate and species-specific behaviors and fear, inescapable/uncontrollable stressors, and social stressors. Activation of innate fear (based on a threat to safety/survival) in rodents can be accomplished with exposure to a predator (i.e. a cat or snake) or to a novel or unfamiliar environments particularly those with are op en and brightly lit (i.e. open field or elevated plus maze). Inescapable and uncontrollable stressors include inescapable foot or tail shock, forced swim and restraint. Rodent restraint is the most frequently used and well-documented stressor. It can also be combined with other physical stressors such as being placed in a rotating platform or in combination with tail pinch. Interestingly, even animal handling can be categorized as this type a stressor. Social stressors make up their own entire subcategory. Many researchers believe that social stressors are the most translationally relevant because the primary source of stress in humans comes from social interactions, expectations and even trauma. Rats are by nature social animals, but too much or too little can elicit a stress response. Two of the least effortful social stressors are isolation housing and high density housing (i.e. crowding). Interestingly males show a greater stress response to crowding while females show a greater stress response to single (i.e. isolation) housing [98]. A popular social stressor is social defeat, utilizing the resident intruder paradigm. This paradigm consists of using aggressive male rats (i.e. retired breeders or reared in isolation without handling) as the resident rat. The experimental rat (i.e. the one which will mount a stress response) is the intruder and is placed in the home cage of the resident rat. Typically the rats are allowed contac t with each other until the intruder demonstrates defeat behaviors (i.e. submissive supine posturing). In one modification of this paradigm, the intruder remains in the home cage of the resident rat but is separated, and therefore protected from physical harm, by a wire mesh enclosure [99,100]. A novel socially based stressor that is less labor intensive is to place a male rat in the dirty cage of another male rat. Thus the male rat is in an inescapable territory of another male rat, without physical contact [101]. Chronic Stress Paradigms Chronic stress is prolonged stress that typically occurs for at least 5 days, typically 1-3 weeks and sometimes up to 6 weeks or more. Many different types of chronic stress paradigms can be used, depending on the desired outcome measures. An additional variable to consider with chronic stress paradigms is the likelihood of habituation of the stress response over time, as mentioned above. Examples of chronic stress paradigms include chronic restraint, chronic mild stress, chronic unpredictable stress, chronic variable stress, chronic social stress, and chronic intermittent stress. Chronic restraint stress and chronic mild stress have historically been the most frequently used chronic stress paradigms. Interestingly, these paradigms have different phenotypic outcomes. Chronic restraint stress is frequently carried out with daily 6 hour restraint sessions for 3 weeks (Conrad XXXX). However, because chronic restraint stress is repeated exposure to a single homotypic stressor, habituation of the stress response after the first few days likely occurs as evidenced by blunted CORT and ACTH release in response to restraint following completion of the chronic restraint paradigm [102,103]. This paradigm is well characterized with regard to spatial learning and memory deficits as well as altered dendritic morphology, particularly dendritic retraction in the hippocampus [104]. Interestingly, spontaneous recovery of both altered dendritic morphology and spatial learning and memory deficits has been observed [105]. Chronic restraint stress also alters anxiety- and depressiv e-like behaviors, impairs response inhibition, facilitates fear learning and reduces motivation for food reward [106-108,53] Chronic mild stress (CMS) is typically used to induce an anhedonic (i.e. depressive-like) phenotype [109]. This paradigm typically involves exposure of the subjects to one mild stressor a day, typically for 6-8 weeks [109,110]. Stressors are administered on a set weekly schedule and include wet bedding, cage tilt, mild footshock, alterations in the light-dark cycle, food/water deprivation and cage changes [109,110]. Anhedonic effects of CMS, which can last up to 3 months, include decreased sucrose consumption, increased threshold for intracranial self-stimulation and decreased locomotor activity in the absence an anxiety-like phenotype [109]. Chronic unpredictable stress (CUS) is essentially an iteration of CMS, which lasts for a shorter period of time (~2 weeks) and presents mild to moderate stressors once a day in a more randomized order and time of day [111,112]. Depressive-like phenotypes are seen after CUS exposure in addition to anxiety-like phenotypes and cognitive deficits [1 12,91]. Chronic variable stress (CVS) is yet another more severe iteration of a repeated administration of heterotypic stressors. More recently, CVS paradigms have differentiated themselves from CMS paradig

International Relations: Important Theories

Realism makes four basic assumptions about international relations: * The state is the most important actor in international relations. This means that national governments are the most important player in the game of international politics–interest groups like Amnesty International or individual figures like the pope have no effect on how nations relate to one another. * The state is a unitary and rational actor. Unitary means that â€Å"the state speaks with one voice;† although members of a nation may have many different views on the best approach to a situation, only one approach will be enacted. Rational means that the state is capable of â€Å"identifying goals and preferences and determining their relative importance. † * International relations are essential conflictual because of anarchy. In this case, anarchy does not mean chaos–instead it refers to the absence of a higher authority to prevent aggression or arbitrate disputes. Just as men might run amok and attack one another without the government to punish them, nations will attack one another so long as they believe it in their best interest. Anarchy also compels states to arm themseves in order to feel secure. The stockpiling of arms and the building of a military, however, are provocative actions which prompt neighbouring states to feel insecure and build up their own weapons. * Security and strategic issues, known as high politics, dominate the international agenda. This means that states' paramount goal is to maximize their power in the international community, and that they are primarily concerned with military power. An example of a nation operating according to this maxim is North Korea in the early 90s–the downfall of the Soviet Union left them without Communist allies, so they began a nuclear weapons development program and threw out UN observers. They believed that if their government gained nuclear power, it would survive in the international community because other countries would fear them. Liberalism * Liberal international relations theories are based on the idea that humans are PERFECTABLE. In contrast to the greedy man of realism or even he survival man of realism, liberal theories tend to see man as rational as well as learning, striving, and improving over time. Liberals believe in PROGRESS. * Liberals believe that humans can learn to COOPERATE to improve their lives PEACE is seen as a preferred condition and therefore ways should be found to foster peace among states. This allows man to focus on the substantive things that make up the good life: food, art, culture, literature, farming, families. Everything but weapons and the fighting of war. Liberals believe that war stems from INADEQUATE INSTITUTIONS OR MISUNDERSTANDINGS, so we prevent war by crafting better institutions and eliminating the possibility of misunderstanding through education and discussion. * War stems from misery, POVERTY, INEQUALITY. * Liberal approaches often also see man as tied to fellow man by a COMMON HUMANITY. Therefore, the limits imposed by state boundaries are artificial. This leads to ideas such as the pursuit of human rights violators across state boundaries, seeking to engage in development assistance. League of Nations and UN Charters have strains of this type of liberal idealism: making peaceful settlement of disputes a new norm. Overcome past international conflict through institutionalized collective security mechanisms. * Some influential liberal ideas today: INTERDEPENDENCE and the rise of NON-STATE ACTORS. * Interdependence: Economic linkages, communication technologies finally making possible one world with one common humanity. All linked together, can’t go to war without causing hardship to all. This has been developed further in the 1990s to a school of thought which sees globalization as rendering war among major powers as impossible, would impoverish everyone, no one has an incentive to rock the globalization boat. * Rise of non-state actors: new non-state actors becoming more influential than the old states of realist international relations discourse: multinational companies many of which have greater annual turnover than developing countries’ GDPs, new cross-national issue groups: the Greens, Greenpeace, Amnesty International. These corporations and organizations are breaking down the state, establishing common interests across borders. Generally, foster peace. * Also, recently re-in vogue in the liberal camp is the DEMOCRATIC PEACE THESIS, the idea that democracies do not fight one another. * Liberal approaches have fostered much of the growth of INTERNATIONAL ORGANIZATIONS (neo-liberalism with emphasis on institutions). International organizations are seen as ways of mediating conflict among states, establishing bases of cooperation, establishing rational-legalistic codes of conduct under which all will be better off. Some liberal internationalists see the evolution of international organizations, the development of international law, the growth of cross-national civil society groups as evidence that the state is being transgressed, or at least having its capacity for war-generating action reduced. * ANALOGY TO DOMESTIC STATE at international level. As in the domestic state where the government provides some order to relations among citizens, so international organizations (while not a world government) can provide some stability, security, and predictability to inter-state interactions. Can prevent states from being trapped in the SECURITY DILEMMA (need force to protect self, arms build up scares others into thinking you are going to attack, they build up their forces, they scare you, endless cycle of build-up ultimately leading to violence. By making self more secure through arms, make self less secure by compelling arms acquisition on neighbour/rival), can foster and build on areas where cooperation helpful to solve mutual interests, cooperation reinforcing. States can learn through international organizations/cooperation and change their preferences and behaviors. * IRAQ WAR: Liberals would certainly see Saddam Hussein as a problem: authoritarian, had shown proclivity to invade others. Marxism Marxism is one of the basic theories of international relations. According to Marxists, both realism and liberalism/idealism are simply self-serving ideologies introduced by the economic elites to defend and justify global inequality. Instead, Marxists argue, class is the fundamental unit of analysis of international relations, and the international system has been constructed by the upper classes and the wealthiest nations in order to protect and defend their interests. The various Marxist theories of international relations agree that the international state system was constructed by capitalists and therefore serves the interests of wealthy states and corporations, which seek to protect and expand their wealth. According to Marxist theory the â€Å"First World† and â€Å"Third World† are merely components of a larger world system which originated in 16th-century European colonialism. Instead, these states actually make up the â€Å"core† and â€Å"periphery† of the world system — respectively, the central wealthy states which own and chiefly benefit from the mechanisms of production, and the impoverished â€Å"developing† countries which supply most of the human labour and natural resources exploited by the rich. States which do not fit either class, but lie somewhere in the middle of the model, are referred to as â€Å"semi-peripheral. † The core-periphery thesis of world-systems theory is based upon another body of work, dependency theory, which argues that the basis of international politics is the transfer of natural resources from peripheral developing countries to core wealthy states, mostly the Western industrialized democracies. The poor countries of the world, like the poor classes of the world, are said to provide inexpensive human and natural capital, while the wealthy countries' foreign policies are devoted to creating and maintaining this system of inequality. International economic law (such as the World Trade Organization) and other such systems are seen as means by which this is done. To combat these systems of inequality, traditional Marxists and dependency theorists have argued that poor countries should adopt economic control policies that can break them out of the prison of international economic controls, such as import substitution (government assistance to domestic producers and barriers to wealthy international corporations attempting to flood the market with mass-produced imports) rather than the export-based models usually favoured by international economic organizations such as the World Bank and International Monetary Fund.

Bald Soprano Research Paper

A Cycle, A Cycle, A Cycle No one is bald, nor is there a singing soprano. So what is going on in Ionesco’s The Bald Soprano? Ionesco slowly strips his characters of all things that define them: religion, roots, the way in which they communicate and at times, even the functioning of their brains. Thus creating blank humans with no individual character who are useless and absurd. Now these people with no concrete definition to their being are to live in this gigantic world to the best of their ability. Their lives aren’t normal ones.Ionesco brings out the absurdity in his characters by excluding any solid foundation or motivation for living on earth. One very important form of guidance on life’s journey is Time. If there was no concept of time then all chaos would ensue and no one would know when anything is to be done. It is also a key factor to know how to live and work alongside time: to work with it, not against it. Will they be able to live in some sense of no rmality or will they be off on their own supernova to be absurd for evermore.Through the use of symbolism, irony and dialogue, Eugene Ionesco’s, The Bald Soprano conveys the idea that life is a never-ending cycle to express the absurdity of the human condition. The cycle of life is symbolized through the clock to reveal that the characters are stuck in an endless loop of time. The clock seems to take on a life all its own. It seems to decide when it wants to ring and how many times. The clock rings in a way that is quite shocking to the audience. This is because in the real world a clock does not normally ring 17 times. Nor is it normal for it to shoot out random times that don’t even go in order.In only one moment â€Å" The clock strikes seven times. Silence. The clock strikes three times. Silence† (The Bald Soprano 2). There seems to be no set regimen for time to follow. Time in the play is unorganized and almost absent in its common purpose. In no possible w ay could these characters even have the smallest possible chance of some normal routine when they have no constant to guide them through. Yes, Time is present but it is not the way in which we calculate it. There is no repeating pattern in this aspect and yet it still proceeds on which causes an endless loop of lunacy from which they cannot escape.The peculiar thing about it is the characters are not even finding it odd, as this is their notion of normalcy. In the play â€Å"the abnormal is treated as if it were thoroughly normal† (knowlson). And its funny because they don’t even realize that it never rings the same way or goes in a repeating pattern. The clock is random. It intrudes illogically. There is no logic in the Smith’s lives. The concept of reality is being distorted and no ounce of sense remains. The characters are flat, broad and general, which clearly emphasizes the absurdity of the human condition: trying to find a meaning and purpose to life.Even the primary characters last name, which is Smith, is so plain and typical. The plays cyclical structure accentuates repetition of the illogical happenings in the incompatible world in which the Smiths, Martins, the Maid and the Fire Chief live in. The play includes a â€Å"circular trajectory that ends where it began† (Kraus), thus causing the whole disordered cycle to start over and where the characters are involuntarily perplexed for all eternity. The characters live in a world of irony. They are lost in a continuum of memory loss without even realizing that they are losing their minds.Considering they don’t realize, they have no recollection of what has been going on around them and therefore not knowing what their purpose is in being where they are. This constant back and forth concept is for one, ironic because they have no memory of no longer having memory, but it is also mind-boggling. Mrs. Smith says, â€Å"We were expecting them. And we were hungry. Since the y didn't put in an appearance, we were going to start dinner without them. We've had nothing to eat all day† (The Bald Soprano 4). Mrs. Smith said she and Mr. Smith were going to eat but they didn’t.The characters can’t even remember what decisions they made and can’t remember to follow them. There is no stable element to guide them along a steady path. In the real world our memories our like our personal book of stories that hold the events that have happened in our lives. It defines us as a person of who we are in the past as well as who we are now. We as humans also interpret things we experience differently and remember things in different ways. Though we rely on our memory and mind quite heavily, who says it is a reliable resource to begin with?Ionesco is pointing towards the idea that our minds can’t possibly do everything for us as well as remember anything and everything we want it to. Unreliability of the memory is a concept that Ionesco wa nts us to take a look at, and that is a natural human failure that is part of our absurdity. As seen in The Bald Soprano the mind isn’t always a dependable tool that is conducive to everyday living. Our experiences make up our life’s journey and define our being. Ionesco’s characters do not know who they are and their purpose for living. At the end of the play the two couples switch places.The Smiths become the Martins and the Martins the Smiths. This results â€Å"in a da capo conclusion [with] the words that had been spoken by the Smiths at the beginning of the play [are now being spoken by the Martins]† (Knowlson). It’s ironic how they repeat the story but as different people but with the same name, because what is the purpose of having a name and being somebody if anyone can be anyone? Ionesco brings out inconsistency, which is a major factor in the play and possibly a factor in our lives. Without consistency the lives in which we lead would la ck substance and meaning.Ionesco suggests the idea of a normal daily schedule in which a human being can follow and keep order is a necessity. The human condition may seem absurd at times because what really is the point in doing the same thing everyday for as long as we live? The answer is, the consistency in the constant never ending cycle is life, which is why we are living. There may be nonsense in the play but somehow it leads to sense. The ironic statements due to memory loss show the absurdity in which humans possess. Mr. Smith is one who can be categorized as so.Without his memory he puts out ironic phrases without even putting thought to it and this leads to a lack of sentence structure. The play is made up of dialogue that sometimes seems to lack a sense of logic. The language in the play decreases in substance as the play progresses. The â€Å"language flows independently from meaning† (Feal). The words are not communicating what they seem to say but rather the und erlying meaning, which is found in the way the language is used or how really how it is informally used. Language and meaning march to the beat of a different drum.The words are separate entities that work independently yet together to convey Ionesco’s view on language, which is that it is made out to be more than what it is really worth. Language is used as a communicator and the order, or lack of it, in which words are placed, conveys a message of pure insanity. The characters â€Å"actions contradict words, and [their] words contradict [their] actions. Even the title is misleading, since there is no bald soprano in the play† (Esteban). Ionesco writes where there is meaning in no meaning, so he probably intended on writing with meaning all along.The characters talk just to talk and they really have nothing of importance to say. As the play drags on while the structure becomes less and less until dialogue has lost all value and â€Å"made into mere exchange† (K nowlson). The words on the page are out of content and have become particles of matter that are floating in the air. The more they talk, the less they are actually communicating and this is causing the precious tool of language to no longer articulate. Like when Mr. Smith states â€Å"The pope elopes! The pope's got no horoscope.The horoscope's bespoke† (The Bald Soprano 17). The play starts out with sentences that make no sense at all then it breaks down to just words without meaning until finally all that is left is a bunch of frenzied sounds. The characters have gotten quite angry that they lost all ability to communicate that their chatter swells up into mushy sound. They live in a never-ending cycle of insignificant discourse. This is Ionesco pointing out the absurdity of how humans converse. The Bald Soprano is a piece under the genre of the Absurd. It is very easy to see why.In this genre a common aspect is that the characters are rapt in an endlessly repeating cycle. This cycle usually leads nowhere as it is a cycle with no beginning and no end. Ionesco uses this cycle to emulate life. Life is filled with a bunch of meaningless things that fill our everyday lives. Banana. When something is of meaning we know because we have experienced the everyday typical life of a human. Broadway. Dreams. Goals. That’s what we are. Well that’s what we should be. Life is pretty much repeating. Repeating. Repeating. Repeating. We have a set way of doing things and we follow it.We repeat these actions to fill up our lives with substance so that there is at least something there to start with and so that we have the ability to move forward and continue. Think of it as muscles. Muscles give our body substance to stand up and it is what allows us to move as well as other necessary functions. In our world we use a clock to stay in touch with time. Time. Timing. Bad timing. Time is a fundamental concept that guides humans through life, gives structure, a s well as ages and heals. We also say funny things sometimes and we do use a language to communicate. It is how we use all these things that matters.

Gestational Diabetes - 2586 Words

Gestational Diabetes Mellitus: an Overview Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with the onset or first recognition during pregnancy. Ninety percent of those diagnosed with diabetes during pregnancy will resolve after delivery (Scollan-Koliopoulos, Guadagno, Walker, 2006). Pregnancy causes estrogen, progesterone and human placental lactogen to become elevated which provokes malfunctioning insulin, which can lead to insulin resistance and decreased cellular glucose uptake. The growing placenta causes the production of even more hormones, producing higher glucose levels and increased insulin resistance. When the pancreas can’t satisfy the demands for additional insulin, GDM results†¦show more content†¦Breasts: Assymetrical- rightleft, everted nipples, no discharge, no dimpling, tender bilaterally, no masses, no axillary nodes. Abdomen: Nontender; no organomegaly, bowel sounds x 4. FHT heard-152 bpm, +FM Pelvic: Cervix closed, parous os, creamy white discharge. Gravid uterus, SD, fundus U-2, no active bleeding, no CMT, no adnexal tenderness. Vulva without erythema, lesions. Extremities: No edema. Pedal pulses 2+. No joint irregularities. Labs: CBC, RPR, Type and screen, Hep Bs Ag, Rubella, urine culture, Rh screen, genprobe, pap, obtained today. UA in office shows trace of nitrites. U/S planned for next week with Dr. Petrie. Quad screen discussed for between 16-20 weeks. GTT planned for 20 weeks. R.B. returned to the clinic on June 1, 2010, for second prenatal visit. Lab and ultrasound results were as follows: Blood type: O+ Rh: negative Rubella: non immune Pap: normal RPR: negative GC: negative Chlamydia: negative HCT: 44.3 Hgb: 15.1 Hep B: nonreactive Urine culture: contaminated; clean catch obtained this visit. U/S: Viable fetus 16 5/7 weeks, EDC November 11, 2010, limited survey, posterior placenta, not previa. MANAGEMENT OF GESTATIONAL DIABETES R.B. presented with the risk factors for GDM including obesity, previous history of macrosomia, Hispanic descent and advanced maternal age. It is for this reason that I chose the management of gestational diabetes for the topic of discussion for this paper. GDM is occurring in five to nineShow MoreRelatedEssay On Gestational Diabetes1152 Words   |  5 Pagesin women that lived in Orange County was gestational diabetes. The stated target population is women that live in Orange County, specifically in Santa Ana. The prevalence of gestational diabetes in Orange County was 7.1% affecting nearly 3,000 women in 2009 (Ramos et al., 2011, 2). This data shows the prevalence rates according to each city in Orange County Santa Ana as well as Anaheim, Garden Grove, and Irvine made up almost half of the gestational diabetes cases in 2010 (Refowitz, 2012, 8). LookingRead MoreGestational Diabetes : The Prevalence Of Gestational Obesity932 Words   |  4 PagesG estational Diabetes in Pregnancy According to the American Diabetes Association, the  prevalence  of gestational diabetes is as high as 9.2% in pregnant women due to obesity or being overweight. Not only can it be harmful to the mother, but it can also be harmful to her baby. Gestational diabetes can increase the chances of pregnant women delivering a baby that weighs more than 9 pounds. Having gestational diabetes can also increase the mother’s chance for needing a cesarean section delivery. SomeRead MoreThe Prevalence Of Gestational Diabetes1223 Words   |  5 PagesAccording to the American Diabetes Association, the  prevalence  of gestational diabetes is as high as 9.2% in pregnant women due to obesity or being overweight. Not only can it be harmful to the mother, but it can also be harmful to her baby. 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Some of these risksRead MoreDiabetes : Diabetes And Gestational Diabetes1209 Words   |  5 Pageslive with diabetes (Phillips Mehl, 2015). According to Medical News Today [MNT], diabetes is a metabolic disorder; which causes patients to be extremely thirsty and produce a lot of urine. Diabetes arises due to high blood pressure, due to the body not being able to produce enough insulin or because the body does not respond well to high insulin levels (MNT, 2016). There are four types of diabetes; there is the pre-diabetic stage, type 1 diabetes, ty pe 2 diabetes and gestational diabetes. In 2014Read MoreThe Prevalence Of Gestational Diabetes1325 Words   |  6 PagesGestational diabetes is a glucose intolerance that develops during pregnancy. Early diagnosis and effective treatment are important because gestational diabetes can cause serious maternal and fetal complications. 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No pregnant woman should eat anything she wants during pregnancy, but this is especially true for the gestational diabetic. There can be many complications if blood sugars are not managed during the pregnancy. If diagnosed with gestational diabetes, it does not mean you had diabetes before you were pregnant, though the doctor may check in a couple months after the baby is born to be sure you are not a type 2 diabetic. What is Gestational Diabetes? Gestational diabetes