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The basis of the stress reaction
Abstract
The ubiquitous presence of stressful stimuli makes stress one of the most important causes of physiological or pathophysiological changes in an organism during its entire lifespan. The stressors can be divided (according to their nature) into physical, chemical, psychological, social and disturbing cardiovascular/metabolic homeostasis effects, which can affect multiple systems. Here we emphasize that although stress is classified according to its nature, multiple mechanisms are affected. We will focus on mechanisms of stress reaction with the aim of maximal brevity. The pathways that are activated in response to stressful stimuli with respect to specific types of stressors are described. The central processing of a stress response comprises central aminergic neurons, non-catecholaminergic brainstem neurons, hypothalamic nuclei and structures of the limbic system. As a response, specific efferent pathways are activated. Special attention is given to stress effects in the central nervous system and vital functions (heart function and respiration).
... [17] As Table 3, sanction stressors are from the psychological category (emotional and depressional type), which strongly affects social reflexes and social category (isolational and risk of alive type), which strongly affects psychological reflexes and properly affected physical reflexes. [18] If the stressful stimuli comprise brain circuits that are activated specifically by precise stressors, it may lead to change of decision or behavior in person and society. However, in central processing, stressful stimuli activate structures involved in memory processing, like the hippocampus, [19] and reward structures, such as the ventral striatum [20] and the cerebellum. ...
Background: Economic sanction is a United Nations' pressure tool on a target government and civilians for changing strategic decisions about violating international norms of behavior, but many authors argue that in several cases, sanctions do not work. A nonpolitical and noneconomic study about economic sanction outcomes is scarce. In this study, we reviewed the related official documents, translated the sanction process by neuroscience language, and tried to recognize the type of stress process related to different outcomes in the target countries. Methods: We do this job in three phases: phase one is related to the literal review, phase two focuses on definition analysis according to neuroscience approaches, and phase three comes on neuroscientific target analysis. Defining stress process related to different outcomes by neuroscience is mentioned in the discussion based on using of other papers' data. Results: Stress act of sanctions As: Act of aggression, Threat, Keeping enemy, Restriction, Pursuing, Blocking, Compression to force, and Loss of some things are means that how could sanctions affect civilians and run the process of social pressure in the target entities. Conclusion: We concluded that sanctions are always threatening political tools and their effectiveness completely depends on the politicians view to threat proximity and the type of response to stresses of sanctions.
... Social isolation is a stressor (Myslivecek and Kvetnansky, 2006), and the increased activity of the catecholaminergic system and further release of glucocorticoids (Myslivecek, 2015) are tightly connected with the separation of social animals from the natural group. Social isolation increases the responses to beta-adrenergic stimulation in mice (Francès et al., 1980). ...
Social species form organizations that support individuals because the consequent social behaviors help these organisms survive. The isolation of these individuals may be a stressor. We reviewed the potential mechanisms of the effects of social isolation on cholinergic signaling and vice versa how changes in cholinergic signaling affect changes due to social isolation.There are two important problems regarding this topic. First, isolation schemes differ in their duration (1–165 days) and initiation (immediately after birth to adulthood). Second, there is an important problem that is generally not considered when studying the role of the cholinergic system in neurobehavioral correlates: muscarinic and nicotinic receptor subtypes do not differ sufficiently in their affinity for orthosteric site agonists and antagonists. Some potential cholinesterase inhibitors also affect other targets, such as receptors or other neurotransmitter systems. Therefore, the role of the cholinergic system in social isolation should be carefully considered, and multiple receptor systems may be involved in the central nervous system response, although some subtypes are involved in specific functions. To determine the role of a specific receptor subtype, the presence of a specific subtype in the central nervous system should be determined using search in knockout studies with the careful application of specific agonists/antagonists.
... However, these responses are often complex, thus systematic approaches are required to establish when the actions of hormones associated with stress responses result (Abbas et al., 2017;Tilbrook and Ralph, 2018). These responses are modulated by different factors that consequently could have a positive impact (known as eustress) or negative impact (known as distress) in any organism (Myslivecek, 2015). Yet prolonged exposure to stressors or even short exposure to high intensity stress factors can lead to distress with accumulation of a biological costs and effects on the welfare of animals and compromising future productivity (Popescu and Diugan, 2017). ...
The objective of this paper is to review the existing literature regarding the advantages and disadvantages that different weaning practices have on the stress responses and productivity of water buffalo in different breeding systems. On farms where water buffalo are bred for milk production, early weaning favors the amount of milk produced, reduces breeding costs and improves the reproductive rate. However, this early separation may be associated with the restriction of colostrum and essential nutrients for water buffalo calves, which cannot be replaced by the use of milk replacers made for cattle. Consequently, colostrum restriction can lead to an increase in disease susceptibility, high mortality rates and compromises future performance. In addition, mothers show a more temperamental behavior, making milk ejection difficult due to the anatomical characteristics of the udder in this species. On the other hand, a continuous suckling system may be more beneficial to weight, immune status, and welfare of calves but may cause economic losses due to delayed postpartum estrus. The results in terms of susceptibility to stress are contradictory; some authors conclude that separation between mother and calves does not generate stress, as long as weaning is carried out within the first hours or days after birth (3-6 days old) after colostrum intake, compared to weaning at 45 and 90 days. However, these calves have greater difficulty in learning to eat on their own and show an increase in abnormal behaviors. The most commonly utilized form of weaning is abrupt. Behavioral and physiological indicators suggest that abrupt weaning is stressful for both the mother and the offspring. The protocols for performing gradual weaning seem to offer advantages in reducing stress in buffalo compared to abrupt weaning. On buffalo farms, calf management is one of the critical points of breeding, therefore, more studies are required to improve current breeding systems and promote the welfare of water buffalo calves.
... co (Hemsworth et al., 2011), que desencadena una serie de cambios fisiológicos que incluyen la activación del sistema nervioso autónomo, activación del eje H-H-A, activación del sistema inmune, secreción de citocinas pro-inflamatorias y comportamientos redirigidos (Shepherdson et al., 2013). La actividad del eje H-H-A está mediada por la amenaza percibida y la modulación de la corteza prefrontal (Roelofs et al., 2005) y que además, juega un rol indispensable en la formación de la memoria emocional a nivel de la amígdala en el sistema límbico (Myslivecek, 2015). Por otro lado, se sabe que también existen cambios plasmáticos secundarios en respuesta hormonal (cambios en los electrolitos, metabolitos y enzimas), los cuales pueden ser considerados "biomarcadores secundarios de estrés" (Fazio et al., 2015). ...
Uno de los principales factores que afectan el bienestar y la productividad de los animales es la calidad de la relación existente con los humanos (Napolitano et al., 2011). En la producción animal generalmente existen problemas de bienestar independientemente de que los sistemas sean extensivos o intensivos (Petherick, 2005), ya que los animales son sometidos a diversas prácticas invasivas que a su vez se refuerzan negativamente, tales como; marcaje en orejas, administración de hierro, corte de colmillos, corte de cola, descorne, castración, tratamientos médicos, etc. (Raussi, 2003; Probst et al., 2012). Aunque algunas otras, no necesariamente lo sean, por ejemplo, el ingreso de los animales a las mangas de trabajo durante las prácticas de rutina puede ser percibido como neutral y no amenazante para algunos individuos, mientras que para otros, lo novedoso de esta práctica puede desencadenar diversos desajustes fisiológicos y conductuales que podrían disminuir su bienestar (Grandin, 1997), lo cual, dificultar su manipulación y como consecuencia una actitud negativa y enérgica de las personas hacia los animales (Rehn et al., 2014), volviéndolos más propensos a contraer lesiones u ocasionarlas a las personas encargadas de su manipulación (Petherick, 2005; Napolitano et al., 2011). Cuanto más aversiva es la manipulación, los animales se resistirán más a regresar a ese lugar y por lo tanto se requerirá de más fuerza y tiempo para moverlos (Pajor et al., 2000).
La reacción de los animales a los seres humanos no sólo es negativa, sino que también es posible una interacción positiva (Waiblinger et al., 2006). Misma que puede conseguirse mediante la habituación de los animales o el incremento del contacto positivo con los humanos, aumentando la docilidad, disminuyendo el miedo y nerviosismo hacia los seres humanos (Boivin et al., 2001; Probst et al., 2012). Algunas actitudes de los trabajadores, como, acariciar, tocar y hablar con voz baja se refleja en estados positivos en los animales y en menor evitación a los humanos (Ellingsen et al., 2014). Es por ello, que el objetivo del presente artículo es explicar la importancia de mantener una relación entre humanos y animales positiva, además, revisar algunas de las técnicas utilizadas para medir la interacción hombre animal en las unidades de producción.
Monitoring the driver’s behavior in the cabin of a vehicle is an urgent task for modern automated driver support systems (Advanced Driver Assistance Systems), which belong to the class of active safety systems. Existing research and solutions in the field of modern driver assistance systems are more focused on the use of electronic devices in the form of video cameras, lasers, and radars that provide measurement information about the driver in the cabin. However, the use of wearable electronic devices that measure the heart rate, electrocardiogram, user movements, and other indicators,
allows one to obtain results about the driver’s dangerous behavior more accurately and reliably. The paper proposes an
approach to detecting dangerous states in the driver’s behavior in the cabin of a vehicle based on the use of information from wearable electronic devices. The study shows that it is sufficient to use heart rate measurements passed from wearable electronic devices to detect dangerous states, such as aggression and stress. The developed mobile application on the Android platform allows detecting signs of aggression and stress in the driver’s behavior using data obtained from sensors of wearable electronic devices. When the driver shows dangerous behavior in the cabin, the mobile application warns the driver by vibrating the wearable electronic device and an audio signal played by the smartphone.
The developed approach is tested on a data set collected in real driving conditions on public roads in the city and on country roads in various driving conditions. Detection of signs of aggression and stress in the driver’s behavior allows one to supplement information about the driver, and thereby improve the effectiveness of driver monitoring systems in the cabin of the vehicle, aimed at preventing and reducing the risk of road accidents and improving the skills of road users. The proposed approach can be used in combination with other technologies for monitoring driver behavior when
building an intelligent driver support system.
With the rapid development of ultra high voltage alternating current (UHV AC) transmission, the intensity of environmental power frequency electric field (PFEF) near UHV AC transmission lines increased continuously, which has attracted considerable public attention on the potential health effects of PFEF. In this study, the effect of PFEF exposure on the kidney was explored. Institute of Cancer Research (ICR) mice were exposed to 35 kV/m PFEF (50 Hz). Two indicators relating to renal function (urea nitrogen and creatinine) were tested after the exposure of 7d, 14d, 21d, 35d and 49d. The pathological morphology and cellular ultrastructure of kidney were observed respectively by light microscopy and electron microscopy after the exposure of 25d and 52d. Results showed that compared with that of the control group, the concentration of urea nitrogen of 35 kV/m PFEF exposure group significantly increased on the 21st and 35th days, and the concentration of creatinine significantly increased on the 14th, 21st and 35th days. However, the concentrations of creatinine and urea nitrogen both returned to normal levels on the 49th day. Furthermore, an enlarged Bowman's space, the vacuolation of renal tubular epithelial cells and the foot process effacement of podocyte were found after 25d exposure, but no abnormality was observed after 52d exposure. Obviously, a short-term (35d) exposure of 35 kV/m PFEF could cause kidney injury, which could be recovered after a longer-term (52d) exposure. Based on this study and relevant literatures, one explanation for this two-way effect is as follows. Kidney injury was caused by the disequilibrium of mitochondrial dynamics under 35 kV/m PFEF exposure. PFEF could also activate Wnt/β-catenin signal to promote the recovery of renal tubular epithelial cells and glomerular podocytes, so kidney injury could be repaired.
Oxygen sensing is critical for cell survival and for a living organism's ability to adapt to changing environments or physiological conditions. Cellular responses to oxygen are complex, involving multiple genes and signaling pathways. Clinical consequences of impaired oxygen sensing presumably
The literature of organizational change is dominated by the idea that stress and resistance are two independent phenomena, and that they are immediate and natural reactions to organizational change. This paper suggests a model of organizational change that views the stress as a mediator between organizational change and resistance to change. According to this model, stress and resistance are not inevitable reactions to organizational change. Rather, what makes organizational change stressful or susceptible to resistance of employees is the way people are treated during implementation of the change. The model introduces strategies for reducing negative stress and resistance, and for increasing positive stress and positive health outcomes among employees adapting to change.
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).
Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.
Activation of the dynorphin/κ-opioid receptor (KOR) system by repeated stress exposure or agonist treatment produces place aversion, social avoidance, and reinstatement of extinguished cocaine place preference behaviors by stimulation of p38α MAPK, which subsequently causes the translocation of the serotonin transporter (SERT, SLC6A4) to the synaptic terminals of serotonergic neurons. In the present study we extend those findings by showing that stress-induced potentiation of cocaine conditioned place preference occurred by a similar mechanism. In addition, SERT knock-out mice did not show KOR-mediated aversion, and selective reexpression of SERT by lentiviral injection into the dorsal raphe restored the prodepressive effects of KOR activation. Kinetic analysis of several neurotransporters demonstrated that repeated swim stress exposure selectively increased the V(max) but not K(m) of SERT without affecting dopamine transport or the high-capacity, low-affinity transporters. Although the serotonergic neurons in the dorsal raphe project throughout the forebrain, a significant stress-induced increase in cell-surface SERT expression was only evident in the ventral striatum, and not in the dorsal striatum, hippocampus, prefrontal cortex, amygdala, or dorsal raphe. Stereotaxic microinjections of the long-lasting KOR antagonist norbinaltorphimine demonstrated that local KOR activation in the nucleus accumbens, but not dorsal raphe, mediated this stress-induced increase in ventral striatal surface SERT expression. Together, these results support the hypothesis that stress-induced activation of the dynorphin/KOR system produces a transient increase in serotonin transport locally in the ventral striatum that may underlie some of the adverse consequences of stress exposure, including the potentiation of the rewarding effects of cocaine.
Mood, motivation, attention, and arousal are behavioral states having a profound impact on cognition. Behavioral states are mediated though the peripheral nervous system and neuromodulatory systems in the brainstem. The noradrenergic nucleus locus coeruleus is activated in parallel with the autonomic system in response to biological imperatives. These responses can be spontaneous, to unexpected salient or threatening stimuli, or they can be conditioned responses to awaited behaviorally relevant stimuli. Noradrenaline, released in forebrain structures, will facilitate sensory processing, enhance cognitive flexibility and executive function in the frontal cortex, and promote offline memory consolidation in limbic structures. Central activation of neuromodulatory neurons and peripheral arousal, together, prepare the organism for a reorientation or reset of cortical networks and an adaptive behavioral response.
Ferredoxins are electron shuttles harboring iron-sulfur clusters which participate in oxido-reductive pathways in organisms displaying very different lifestyles. Ferredoxin levels decline in plants and cyanobacteria exposed to environmental stress and iron starvation. Flavodoxin is an isofunctional flavoprotein present in cyanobacteria and algae (not plants) which is induced and replaces ferredoxin under stress. Expression of a chloroplast-targeted flavodoxin in plants confers tolerance to multiple stresses and iron deficit. We discuss herein the bases for functional equivalence between the two proteins, the reasons for ferredoxin conservation despite its susceptibility to aerobic stress and for the loss of flavodoxin as an adaptive trait in higher eukaryotes. We also propose a mechanism to explain the tolerance conferred by flavodoxin when expressed in plants.
Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT) from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN) and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease.
Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also functions for host defense from invading pathogens by elevating body core temperature, a response known as fever. Thermoregulation and fever involve a variety of involuntary effector responses, and this review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenesis in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release. To defend thermal homeostasis from environmental thermal challenges, feedforward thermosensory information on environmental temperature sensed by skin thermoreceptors ascends through the spinal cord and lateral parabrachial nucleus to the preoptic area (POA). The POA also receives feedback signals from local thermosensitive neurons, as well as pyrogenic signals of prostaglandin E(2) produced in response to infection. These afferent signals are integrated and affect the activity of GABAergic inhibitory projection neurons descending from the POA to the dorsomedial hypothalamus (DMH) or to the rostral medullary raphe region (rMR). Attenuation of the descending inhibition by cooling or pyrogenic signals leads to disinhibition of thermogenic neurons in the DMH and sympathetic and somatic premotor neurons in the rMR, which then drive spinal motor output mechanisms to elicit thermogenesis, tachycardia, and cutaneous vasoconstriction. Warming signals enhance the descending inhibition from the POA to inhibit the motor outputs, resulting in cutaneous vasodilation and inhibited thermogenesis. This central thermoregulatory mechanism also functions for metabolic regulation and stress-induced hyperthermia.
Social regulation of the internal milieu is a fundamental behavioral adaptation. Cephalic capability is reflected by anticipatory behaviors to serve systemic physiological regulation. Homeostatic regulation, a dominant perspective, reflects reactive responses; allostatic regulation, the physiology of change, emphasizes longer-term anticipatory, and feedforward systems. Steroids, such as cortisol, and peptides such as corticotrophin releasing hormone are but one example of such anticipatory regulatory systems. The concept of "allostasis" is in part to take account of anticipatory control amidst diverse forms of adaptation underlying this regulatory adaptation that supports social contact and the internal milieu.
Stress responses play a key role in allowing animals to cope with change and challenge in the face of both environmental certainty and uncertainty. Measurement of glucocorticoid levels, key elements in the neuroendocrine stress axis, can give insight into an animal's well-being and can aid understanding ecological and evolutionary processes as well as conservation and management issues. We give an overview of the four main biological samples that have been utilized [blood, saliva, excreta (feces and urine), and integumentary structures (hair and feathers)], their advantages and disadvantages for use with wildlife, and some of the background and pitfalls that users must consider in interpreting their results. The matrix of choice will depend on the nature of the study and of the species, on whether one is examining the impact of acute versus chronic stressors, and on the degree of invasiveness that is possible or desirable. In some cases, more than one matrix can be measured to achieve the same ends. All require a significant degree of expertise, sometimes in obtaining the sample and always in extracting and analyzing the glucocorticoid or its metabolites. Glucocorticoid measurement is proving to be a powerful integrator of environmental stressors and of an animal's condition.
Based on concepts proposed by Langley, Cannon, and Selye, adrenal responses to stress occur in a syndrome that reflects activation of the sympathoadrenal system and hypothalamic–pituitary–adrenocortical (HPA) axis; and a "stress syndrome" maintains homeostasis in emergencies such as "fight or flight" situations, but if the stress response is excessive or prolonged then any of a variety of clinical disorders can arise. The idea of a unitary sympathoadrenal system does not account for evidence that different stressors elicit different patterns of autonomic responses, with exposure to some stressors differentially affecting sympathetic noradrenergic and adrenomedullary hormonal activities. Instead, adrenomedullary responses to stressors are more closely tied to adrenocortical than to sympathetic noradrenergic responses. Distress involves concurrent activation of the HPA and adrenomedullary neuroendocrine systems.
To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus.
We tested the hypothesis that single and repeated immobilization stress affect densities of alpha(1)-adrenoceptor (alpha(1)-AR) and beta-AR subtypes, muscarinic receptors (MR), adenylyl cyclase activity (AC) and phospholipase C activity (PLC) in lungs of male and female wild type (WT) and corticotropin-releasing hormone gene (CRH-knockout (KO)) disrupted mice. We found sex differences in the basal levels of alpha(1)-AR subtypes (females had 2-3 times higher density of receptors than males) and MR (males had twice the density found in females). In marked contrast, beta-AR subtype densities did not differ between sexes. CRH gene disruption decreased all three studied receptors in intact mice (to 20-50% of WT) in both sexes (except beta(1)-AR in females). Stress induced sexually dimorphic responses, while all alpha(1)-AR subtypes decreased in females (to 30% of control approximately), only alpha(1A)-AR level diminished (about 50%) in males. beta(1)-AR decreased in males (to about 40%) but remained stable in females. beta(2)-AR diminished in females (to about 20-60%) and also in males (to about 30-60%). MR decreased in both sexes (approximately to 50%). AC activity diminished in males (to < 50%) while PLC activity was not changed. In CRH-KO mice, the stress response was severely diminished. Paradoxically, the receptor response to stress was less affected by CRH-KO in males than in females. AC activity did not change in CRH-KO mice. In conclusion, in mice the stress reaction is sexually dimorphic and an intact hypothalamo-pituitary-adrenocortical system is required for the normal reaction of pulmonary adrenergic and MR to stress.
Corticotropin releasing factor (CRF) is a neuropeptide that is a major regulator of the hypothalamic-pituitary-adrenal system. Recent findings have shown that CRF exists in extrahypothalamic areas in the brain as well as in the hypothalamus, and extrahypothalamic CRF is also deeply involved in stress responses. Therefore, CRF has been a major target of drug development for treatment of stress-related disorders. However, whether CRF is a cause or a result of fear/anxiety has not been investigated extensively, even though this issue is extremely important to the development of treatments for stress-related disorders. This article aims to 1) introduce readers to several functional aspects of CRF, focusing on aspects that have been missed or ignored when determining the roles of CRF in responses to emotional stress; 2) critically review previous studies regarding the roles of CRF in responses to emotional stress, considering functional aspects of CRF described in 1); and 3) put forward a hypothesis about the roles of CRF in stress responses. Considering different functional aspects of CRF, it was suggested that CRF is a result of fear/anxiety, rather than a cause. In other words, CRF could be responsible for stress responses to cope with dangerous situations but not for fear/anxiety itself. CRF as a potential target of drug development for treatment of stress-related disorders is also discussed.
Stressful stimuli evoke complex endocrine, autonomic, and behavioral responses that are extremely variable and specific depending on the type and nature of the stressors. We first provide a short overview of physiology, biochemistry, and molecular genetics of sympatho-adrenomedullary, sympatho-neural, and brain catecholaminergic systems. Important processes of catecholamine biosynthesis, storage, release, secretion, uptake, reuptake, degradation, and transporters in acutely or chronically stressed organisms are described. We emphasize the structural variability of catecholamine systems and the molecular genetics of enzymes involved in biosynthesis and degradation of catecholamines and transporters. Characterization of enzyme gene promoters, transcriptional and posttranscriptional mechanisms, transcription factors, gene expression and protein translation, as well as different phases of stress-activated transcription and quantitative determination of mRNA levels in stressed organisms are discussed. Data from catecholamine enzyme gene knockout mice are shown. Interaction of catecholaminergic systems with other neurotransmitter and hormonal systems are discussed. We describe the effects of homotypic and heterotypic stressors, adaptation and maladaptation of the organism, and the specificity of stressors (physical, emotional, metabolic, etc.) on activation of catecholaminergic systems at all levels from plasma catecholamines to gene expression of catecholamine enzymes. We also discuss cross-adaptation and the effect of novel heterotypic stressors on organisms adapted to long-term monotypic stressors. The extra-adrenal nonneuronal adrenergic system is described. Stress-related central neuronal regulatory circuits and central organization of responses to various stressors are presented with selected examples of regulatory molecular mechanisms. Data summarized here indicate that catecholaminergic systems are activated in different ways following exposure to distinct stressful stimuli.
Adrenergic regulation of the heart function is well documented by many studies. Catecholamines act through alpha(1)-, beta(1)-, beta(2)-, and beta(3)-adrenoceptors (ARs) in the heart. There are many findings about the changes of beta(1)- and beta(2)-AR in heart failure (HF). On the other hand, the role of other AR subtypes is not clear yet. We focused on determining how HF could affect gene expression and specific ligand binding to alpha(1A)-, alpha(1B)-, alpha(1D)-, beta(1)-, beta(2)-, and beta(3)-AR. Hearts from 11 patients with HF subjected to transplantation were investigated. As a control, corresponding parts from hearts not suitable for transplantation were used. We have found significantly higher mRNA levels of alpha(1A)-, alpha(1B)-,beta(1)-, and beta(2)-AR in the left ventricle of failing hearts compared to the levels in controls. beta(3)-AR mRNA levels in the left ventricle of failing hearts were not changed. No changes in mRNA levels of all receptors studied in other cardiac areas were found. On the other hand, binding studies showed a substantial decrease in left ventricles of failing hearts in all alpha(1)-AR subtypes and in beta(1)- and beta(2)-AR. However, the binding to beta(3)-AR was not changed. Our results suggest that alpha(1)-AR changes might be part of a compensatory mechanism, by which the heart suffering from the HF tries to secure its function, and it could be hypothesized that ineffective beta(3)-AR regulation might be involved in development of HF. According to our knowledge, this is the first report about the beta(3)-AR binding in HF.
The limbic system is the border zone where psychiatry meets neurology. The authors provide a model of limbic function that combines phylogenetic, anatomic, functional, and clinical data to interpret diseases relevant to neuropsychiatry. They provide evidence supporting two major divisions in the limbic system: a paleocortical division with the amygdala and orbitofrontal cortex at its center, and an archicortical division with the hippocampus and cingulate cortex at its center. The implicit integration of affect, drives, and object associations is the function of the paleocortical limbic division; explicit sensory processing, encoding, and attentional control is the function of the archicortical limbic division. The two work in concert to integrate thought, feeling, and action. Understanding their development and organization informs us about how best to care for our patients.
Stress promotes adaptation, but prolonged stress leads over time to wear-and-tear on the body (allostatic load). Neural changes mirror the pattern seen in other body systems, that is, short-term adaptation vs. long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in the brain. Many of these processes are seen in major depressive illness and may be expressed also in other chronic anxiety disorders. The brain controls the physiological and behavioral coping responses to daily events and stressors. The hippocampal formation expresses high levels of adrenal steroid receptors and is a malleable brain structure that is important for certain types of learning and memory. It is also vulnerable to the effects of stress and trauma. The amygdala mediates physiological and behavioral responses associated with fear. The prefrontal cortex plays an important role in working memory and executive function and is also involved in extinction of learning. All three regions are targets of stress hormones. In animal models, neurons in the hippocampus and prefrontal cortex respond to repeated stress by showing atrophy, whereas neurons in amygdala show a growth response. Yet, these are not necessarily "damaged" and may be treatable with the right medications.
Daily rhythms are evident across our physiology, ranging from overt behavioural patterns like sleep to intricate molecular rhythms in epigenetic coding. Driving these rhythms at an anatomical and cellular level are circadian clock networks comprising core clock genes and an ever-expanding list of clock-controlled genes. Research over the past decade has revealed an intimate relationship between the clockwork and metabolic processes. In line with this, feeding behaviour in many species exhibits a strong circadian rhythm and, when restricted, food becomes the most potent entraining stimulus for clocks of the body. Critically, there are several indications that disturbance of our daily rhythms contributes to the development of obesity and diabetes. Given our 24-h society, it is important that we understand how the circadian clock influences what and when we eat.
Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors.
This selective review discusses the psychobiological mediation of nociception and pain. Summarizing literature from physiology and neuroscience, first an overview of the neuroanatomic and neurochemical systems underpinning pain perception and modulation is provided. Second, findings from psychological science are used to elucidate cognitive, emotional, and behavioral factors central to the pain experience. This review has implications for clinical practice with patients suffering from chronic pain, and provides strong rationale for assessing and treating pain from a biopsychosocial perspective.
The maximal contraction of the small intestine by acetylcholine greatly decreased during repeated cold stress. This change was mainly due to decrease in muscarinic receptors in small intestine, whose amounts were measured by the binding of 3-quinuclidinyl benzilate. Injection of norepinephrine or a tricyclic antidepressant, carpipramine during the exposure to the stress prevented this decrease in muscarinic receptors. The physiological significance of this phenomenon is discussed in relation to vagal hyperactivity under the stress.
The carotid body is a sensory organ that detects acute changes in arterial blood oxygen (O2) levels and reflexly mediates systemic cardiac, vascular, and respiratory responses to hypoxia. This article provides a brief update of the roles of gas messengers as well as redox homeostasis by hypoxia-inducible factors (HIFs) in hypoxic sensing by the carotid body. Carbon monoxide (CO) and nitric oxide (NO), generated by heme oxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, inhibit carotid body activity. Molecular O2 is a required substrate for the enzymatic activities of HO-2 and nNOS. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO and NO. Glomus cells, the site of O2 sensing in the carotid body, express cystathionine γ-lyase (CSE), an H2S generating enzyme. Cth
−/−
mice, which lack CSE, exhibit severely impaired hypoxia-induced H2S generation, sensory excitation, and stimulation of breathing in response to low O2. Hypoxia-evoked H2S generation in the carotid body requires the interaction of CSE with HO-2, which generates CO. Carotid bodies from Hif1a
+/−
mice with partial HIF-1α deficiency do not respond to hypoxia, whereas carotid bodies from mice with partial HIF-2α deficiency are hyper-responsive to hypoxia. The opposing roles of HIF-1α and HIF-2α in the carotid body have provided novel insight into molecular mechanisms of redox homeostasis and its role in hypoxia sensing. Heightened carotid body activity has been implicated in the pathogenesis of autonomic morbidities associated with sleep-disordered breathing, congestive heart failure, and essential hypertension. The enzymes that generate gas messengers and redox regulation by HIFs represent potential therapeutic targets for normalizing carotid body function and downstream autonomic output in these disease states.
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.
The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease. During sensorimotor learning, the arrival of a conditioned stimulus reporting a reward evokes a pause response in the firing of the tonically active cholinergic interneurons in targeted areas of the striatum, whereas the same stimulus triggers an increase in the firing frequency of the dopaminergic neurons in the substantia nigra pars compacta. The pause response of the cholinergic interneurons begins with an initial depolarizing phase followed by a pause in spike firing and ensuing rebound excitation. The timing of the pause phase coincides well with the surge in dopaminergic firing, indicating that a dramatic rise in dopamine (DA) release occurs while nicotinic receptors remain unbound by acetylcholine. The pause response begins with dopamine D5 receptor-dependent synaptic plasticity in the cholinergic neurons and an increased GABAergic IPSP, which is followed by a long pause in firing through D2 and D5 receptor-dependent modulation of ion channels. Inactivation of muscarinic receptors on the projection neurons eventually yields endocannabinoid-mediated, dopamine-dependent long-term depression in the medium spiny projection neurons. Breakdown of acetylcholine-dopamine balance hampers proper functioning of the cortico-basal ganglia-thalamocortical loop circuits. In Parkinson's disease, dopamine depletion blocks autoinhibition of acetylcholine release through muscarinic autoreceptors, leading to excessive acetylcholine release which eventually prunes spines of the indirect-pathway projection neurons of the striatum and thus interrupts information transfer from motor command centers in the cerebral cortex.
Ghrelin is a stomach hormone, secreted into the bloodstream, that initiates food intake by activating NPY/AgRP neurons in the hypothalamic acruate nucleus. This review focuses on recent evidence that details the mechanisms through which ghrelin activate receptors on NPY neurons and downstream signaling within NPY neurons. The downstream signaling involves a novel CaMKK-AMPK-CPT1-UCP2 pathway that enhances mitochondrial efficiency and buffers reactive oxygen species in order to maintain an appropriate firing response in NPY. Recent evidence that shows metabolic status affects ghrelin signaling in NPY is also described. In particular, ghrelin does not activate NPY neurons in diet-induced obese mice and ghrelin does not increase food intake. The potential mechanisms and implications of ghrelin resistance are discussed.
In mammals, the initial bridge between the physical world of sound and perception of that sound is established by neurons of the spiral ganglion. The cell bodies of these neurons give rise to peripheral processes that contact acoustic receptors in the organ of Corti, and the central processes collect together to form the auditory nerve that projects into the brain. In order to better understand hearing at this initial stage, we need to know the following about spiral ganglion neurons: (1) their cell biology including cytoplasmic, cytoskeletal, and membrane properties, (2) their peripheral and central connections including synaptic structure; (3) the nature of their neural signaling; and (4) their capacity for plasticity and rehabilitation. In this report, we will update the progress on these topics and indicate important issues still awaiting resolution.
This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor expression varies remarkably between species and even strains. Apparently, cholinergic features can be flexibly adjusted to the needs of a species or strain. Nevertheless, it can be generalized that circadian rhythmicity in the cholinergic system is characterized by high ACh release during the active phase of an individual. During the active phase, the activity of the ACh synthesizing enzyme Choline Acetyltransferase (ChAT) is enhanced, and the activity of the ACh degrading enzyme Acetylcholinesterase (AChE) is reduced. The number of free, unbound and thus available muscarinic acetylcholine receptors (mAChRs) is highest when ACh release is lowest. The cholinergic innervation of the suprachiasmatic nucleus (SCN), the hypothalamic circadian master clock, arises from the cholinergic forebrain and brain stem nuclei. The density of cholinergic fibers and terminals is modest as compared to other hypothalamic nuclei. This is the case for rat, hamster and mouse, three chronobiological model rodent species studied by us. A new finding is that the rat SCN contains some local cholinergic neurons. Hamster SCN contains less cholinergic neurons, whereas the mouse SCN is devoid of such cells. ACh has an excitatory effect on SCN cells (at least in vivo), and functions in close interaction with other neurotransmitters. Originally it was thought that ACh transferred retinal light information to the SCN. This turned out to be wrong. Thereafter, the phase shifting effects of ACh prompted researches to view ACh as an agent for nocturnal clock resetting. It is still not clear, however, what the function consequence is of SCN cholinergic neurotransmission. Here, we postulate the hypothesis that cholinergic neurotransmission in the SCN provides the brain with a mechanism to support the formation of time memory via 'time stamping'. We define time memory as the memory of a specific time of the day, for which an animal made an association with a certain event and/or location (for example in case of time-place association). We use the term 'time stamping' to refer to the process underlying the encoding of a specific time of day (the time stamp). Only relatively brief but arousing events seem to be time stamped at SCN level. This time stamping requires the engagement of mAChRs. New data suggests that the SCN uses the neuropeptide vasopressin (AVP) as an output system to transfer the specific time of day information to other brain regions such as hippocampus and neocortex where time memory is supposed to be acquired, consolidated and stored. Since time stamping is a cholinergically mediated function of the circadian system, the early disruption of the cholinergic and circadian systems as seen in Alzheimer's disease (AD) may contribute to the cognitive disruption of temporal organization of memory and behavior in these patients.
Understanding genetic contributions to individual differences in the capacity for emotional memory has tremendous implications for understanding normal human memory as well as pathological reactions to traumatic stress. Research in the last decade has identified genetic polymorphisms thought to influence cognitive/affective processes that may contribute to emotional memory capacity. In this paper, we review key polymorphisms linked to emotional and mnemonic processing and their influence on neuromodulator activity in the amygdala and other emotion-related structures. We discuss their potential roles in specific cognitive processes involved in memory formation, and review links between these genetic variants, brain activation, and specific patterns of attention, perception, and memory consolidation that may be linked to individual differences in memory vividness. Finally we propose a model predicting an influence of noradrenergic, serotonergic, and dopaminergic processes on emotional perception, as well as on memory consolidation and self-regulation. Outside of the laboratory, it is likely that real-life effects of arousal operate along a continuum that incorporates other "non-emotional" aspects of memory. For this reason we further discuss additional literature on genetic variations that influence general episodic memory processes, rather than being specific to emotional enhancement of memory. We conclude that specific neuromodulators contribute to an amygdala-driven memory system that is relatively involuntary, embodied, and sensorily vivid.
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A consensus exists that cholinesterase inhibitors (ChEIs) are efficacious for mild to moderate Alzheimer's Disease (AD). Unfortunately, the number of non-responders is large and the therapeutic effect is usually short-lasting. In experimental animals, ChEIs exert three main actions: inhibit cholinesterase (ChE), increase extracellular levels of brain acetylcholine (ACh), improve cognitive processes, particularly when disrupted in models of AD. In this overview we shall deal with the cognitive processes that are improved by ChEI treatment because they depend on the integrity of brain cholinergic pathways and their activation. The role of cholinergic system in cognition can be investigated using different approaches. Microdialysis experiments demonstrate the involvement of the cholinergic system in attention, working, spatial and explicit memory, information encoding, sensory-motor gating, skill learning. No involvement in long-term memory has yet been demonstrated. Conversely, memory consolidation is facilitated by low cholinergic activity. Experiments on healthy human subjects, notwithstanding caveats concerning age, dose, and different memory tests, confirm the findings of animal experiments and demonstrate that stimulation of the cholinergic system facilitates attention, stimulus detection, perceptual processing and information encoding. It is not clear whether information retrieval may be improved but memory consolidation is reduced by cholinergic activation. ChEI effects in AD patients have been extensively investigated using rating scales that assess cognitive and behavioural responses. Few attempts have been made to identify which scale items respond better to ChEIs and therefore, presumably, depend on the activity of the cholinergic system. Improvement in attention and executive functions, communication, expressive language and mood stability have been reported. Memory consolidation and retrieval may be impaired by high ACh levels. Therefore, considering that in AD the degeneration of the cholinergic system is associated with alteration of other neurotransmitter systems and a diffuse synaptic loss, a limited efficacy of ChEIs on memory processes should be expected.
The modifications in rat brain muscarinic acetylcholine receptors induced by acute immobilization stress lasting 10 min or 2 h were analyzed by quantitative in vitro autoradiography. [3H]N-Methylscopolamine ([3H]NMS) was used as a ligand. Immobilization stress for 10 min did not produce any significant change in the properties of [3H]NMS binding sites throughout the brain. In contrast, 2 h immobilization caused a significant increase in receptor affinity (Kd) without modification in the maximal number of receptors (Bmax) in several brain areas such as the caudate-putamen, cortical layers and CA1 field of the hippocampus, among others. These results, found even in animals killed immediately after the end of the immobilization sessions, suggest that immobilization stress induces supersensitivity of muscarinic receptors in certain cholinergic pathways in rat brain.
The effects of cold exposure on cholinergic binding sites in the rat adrenal gland were assessed by examining the binding of [125I]alpha-bungarotoxin (BTX), a nicotonic receptor antagonist and [3H]quinuclidinyl benzilate (QNB), a muscarinic receptor antagonist, to adrenal tissue homogenates. Cold exposure resulted in significant alterations in both nicotinic and muscarinic binding. Exposure to cold for 4 and 7 days resulted in a significant decrease in QNB binding. Scatchard analysis indicates that this alteration is due to a decrease in binding sites (Bmax) rather than a change in ligand affinity (Kd). In contrast, chronic cold exposure produced a significant increase in BTX binding sites. These results indicate that adrenal cholinergic receptors are altered in reciprocal fashion by chronic cold exposure, and that this change may represent a key event in the sympathoadrenal system's adaptive response to chronic cold stress.
The aim was to study the mechanism of the previously established decrease in acetylcholine (ACh) concentration in the rat hippocampus under cold stress. Male rats were exposed for 14 days to cold (5 degrees C) or kept (controls) at room temperature (24 degrees C). Acetylcholine content, release and muscarinic receptor binding were investigated in the hippocampus. Cold exposure resulted in a decrease of ACh concentration in the dorsal hippocampus. Moreover, the potassium-evoked release of ACh from hippocampal slices was increased and an increase of maximal binding capacity of [3H] (-) quinuclidinyl benzilate in the dorsal hippocampus of cold exposed animals was also observed. Thus the decrease of hippocampal ACh concentration under cold exposure is probably due to its increased release. On balance then, our results demonstrate that cold stress in the rat induces significant activation of the hippocampal cholinergic system.
Glucose-sensitive neural elements exist in the hypothalamus, the nucleus of the solitary tract (NTS) and autonomic afferents from visceral organs such as liver and gastrointestinal tract. Glucose affects neural activity through these central and peripheral chemosensors. Glucose is generally suppressive in the liver, the NTS and the lateral hypothalamic area (LHA), and generally excitatory in the small intestine and ventromedial hypothalamic nucleus (VMH). The hypothalamus is involved in the control of pancreatic hormone secretion through autonomic efferent nerves. Stimulation or lesion of the hypothalamus induces various changes in pancreatic autonomic nerve activity. The VMH, the dorsomedial hypothalamic nucleus and the paraventricular nucleus have inhibitory effects on vagal nerve activity and excitatory effects on splanchnic nerve activity. The LHA is excitatory to the vagal nerve, and both excitatory and inhibitory to the splanchnic nerve. These findings suggest that the neural network of the glucose monitoring system, which also analyzes and integrates information concerning other metabolites and peptides in the blood and cerebrospinal fluid, contributes to regulation of peripheral metabolism and endocrine activity as well as feeding behavior. The physiological function and input-output organization of this network are discussed.
Three decades ago, results from a proportionate scaling study of life change events was published in this journal. The events, listed by rank order of their mean life change values, comprised the Social Readjustment Rating Scale (SRRS). Ten years later, 42 of the 43 original events were rescaled. In this second study, an additional 44 events were added to the original list. In the present report, the original plus the later-developed events were scaled once again by persons chosen to closely approximate subjects enrolled in the initial study. Comparing the average life change intensity scores across 30 years, a 45% increase in mean values was seen. These recently derived life change magnitudes, for both the original list of events plus the later-developed events, provide values appropriate for use in the 1990s. In the original study, effects of subjects' demographic characteristics were noted briefly in a table. In the present investigation, varying influences of gender, age, marital status, and education were explored in more detail. Several significant differences were discovered, with gender showing a very pronounced influence on scaling results. Discussion of these results included composition requirements for a life changes questionnaire.
Responses of central catecholaminergic systems as well as the Hypothalamic-Pituitary-Adrenocortical (HPA) axis vary during exposure to different stressors. Extracellular norepinephrine (NE) levels in the paraventricular nucleus (PVN) increase markedly with immobilization (IMMO) or with formalin (FORM)-induced pain and relatively little with insulin (INS)-induced hypoglycemia, cold (COLD) stress, or hemorrhage (HEM). Levels of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, increase in the locus ceruleus with IMMO or ether but are unchanged during INS-induced hypoglycemia. These and other findings have led to the hypothesis of the existence of stressor-specific central noradrenergic pathways participating in regulation of the HPA axis. In the study described in this chapter, conscious rats have been exposed to one of several stressors-HEM, i.v. INS, s.c. FORM, COLD, or IMMO. Fos immunoreactivity of the immediate early gene c-fos was used to investigate changes in the activity of brain stem neurons. The results were correlated with previous findings about stress-induced central noradrenergic activation in the PVN using in vivo microdialysis and simultaneous measurements of plasma adrenocorticotropic hormone (ACTH) levels. The present results indicate that the magnitude of activation of c-fos in brain catecholaminergic regions and of PVN corticotrophin releasing hormone (CRH) neurons varies widely across stressors. The findings support the notion of stressor-specificity of responses of central catecholaminergic systems and the HPA axis and indicate that different central pathways regulate HPA reactivity.
Animals exposed to chronic stress exhibit normal or enhanced hypothalamic-pituitary-adrenal responses to novel, acute stimuli despite the inhibitory endogenous corticosterond response to the chronic stressor. Prior stress is thought to induce a central facilitatory trace that, upon exposure to a novel stimulus, balances or overcomes the inhibitory effects of corticosterone. The neuroanatomical basis for this facilitation of hypothalamic-pituitary-adrenal responses is unknown. In this study, we first show increased adrenocorticotropin and corticosterone responses to the novel stressor of restraint in rats exposed to intermittent cold for seven days. We then compared numbers of Fos-immunoreactive cells in 26 sites in control and chronically stressed rats at various times after onset of a 30 min restraint. At 60 min, density of Fos-stained cells was significantly higher in chronically stressed than in control rats in the parabrachial/Kölliker-Fuse area, posterior paraventricular thalamus, central, basolateral and basomedial nuclei of the amygdala and parvocellular paraventricular hypothalamus. The posterior paraventricular nucleus of the thalamus receives projections from the parabrachial nucleus and projects heavily to the differentially stained subnuclei of the amygdala, which in turn project to the parvocellular paraventricular nucleus of the hypothalamus.
Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This has been called "allostasis" or "stability through change" by Sterling and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component of maintaining homeostasis. When these adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993; 153: 2093.). Allostatic load can lead to disease over long periods. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. Examples will be given for each type of allostatic load from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity. The relationship of allostatic load to genetic and developmental predispositions to disease is also considered.
Tract-tracing techniques in combination with immunohistochemistry and in situ hybridization were used in intact and operated rats (hypothalamic lesions, transections of neuronal pathways) to localize and characterize neuronal connections between the hypothalamus and autonomic centers. Viscerosensory and somatosensory signals which relay in the spinal cord and the medulla oblongata reach the hypothalamus through various catecholaminergic and noncatecholaminergic neuronal pathways. Vice versa, the hypothalamus influences autonomic activities through humoral and neurohumoral pathways. Descending hypothalamic efferents carry feedback signals to viscerosensory and brainstem catecholaminergic neurons and regulatory inputs to parasympathetic (dorsal vagal nucleus) and sympathetic (thoracolumbar intermediolateral cell column) preganglionic neurons. These fibers arise mainly from neurons of the paraventricular, arcuate, perifornical, and dorsomedial nuclei and the lateral hypothalamus. The major neuroanatomical observations are the following: (1) pathways between the hypothalamus and autonomic centers are bidirectional: the ascending and descending fibers may use the same avenues; (2) the descending axons are mainly peptidergic (CRF, vasopressin, oxytocin, somatostatin, enkephalin, POMC, and cANP), while the ascending fibers are both peptidergic (enkephalin, NPY, neurotensin, dynorphins) and catecholaminergic; (3) descending hypothalamic axons terminate directly on the sensory, preganglionic, and catecholaminergic neurons in the medulla and the spinal cord; (4) hypothalamic projections to the autonomic centers are always bilateral; (5) while medullary autonomic and catecholaminergic fibers innervate hypothalamic neurons directly, spinohypothalamic axons are relayed on neurons in the lateral hypothalamus.
The primary hormonal mediators of the stress response, glucocorticoids and catecholamines, have both protective and damaging effects on the body. In the short run, they are essential for adaptation, maintenance of homeostasis, and survival (allostasis). Yet, over longer time intervals, they exact a cost (allostatic load) that can accelerate disease processes. The concepts of allostasis and allostatic load center around the brain as interpreter and responder to environmental challenges and as a target of those challenges. In anxiety disorders, depressive illness, hostile and aggressive states, substance abuse, and post-traumatic stress disorder (PTSD), allostatic load takes the form of chemical imbalances as well as perturbations in the diurnal rhythm, and, in some cases, atrophy of brain structures. In addition, growing evidence indicates that depressive illness and hostility are both associated with cardiovascular disease (CVD) and other systemic disorders. A major risk factor for these conditions is early childhood experiences of abuse and neglect that increase allostatic load later in life and lead individuals into social isolation, hostility, depression, and conditions like extreme obesity and CVD. Animal models support the notion of lifelong influences of early experience on stress hormone reactivity. Whereas, depression and childhood abuse and neglect tend to be more prevalent in individuals at the lower end of the socioeconomic ladder, cardiovascular and other diseases follow a gradient across the full range of socioeconomic status (SES). An SES gradient is also evident for measures of allostatic load. Wide-ranging SES gradients have also been described for substance abuse and affective and anxiety disorders as a function of education. These aspects are discussed as important, emerging public health issues where the brain plays a key role.
Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep after hyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H3) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors. Histamine activates four types of receptors. H1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium-calcium exchanger. H2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel. H3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels. Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.
Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.
This review highlights new information gained from studies using recently developed animal models that harbor specific alterations in corticotropin-releasing hormone (CRH) pathways. We discuss features of a transgenic mouse model of chronic CRH overexpression and two mouse models that lack either CRH receptor type 1 (CRH-R1) or type 2 (CRH-R2). Together these models provide new insights into the role of CRH pathways in promoting stability through adaptive changes, a process known as allostasis.
The effects of both REM sleep deprivation and its recovery on pontine and hippocampus muscarinic M2 receptors were investigated in synaptosomes using [3H]-AF-DX 384 as a ligand. Animals were divided into three groups: REM sleep deprivation group (small platforms 6.5 cm of diameter); stress group (large platforms 14 cm of diameter) and cage control group. In a second experiment REM sleep-deprived animals were allowed 48 h of recovery. REM sleep-deprived rats showed a reduction in M2 receptors compared with both intact and stress groups. Changes in M2 receptors were also observed after 48 h of recovery from REM sleep deprivation only in hippocampus. The enhancement of acetylcholine release during both REM sleep deprivation and recovery could explain the present findings.
Although much evidence supports a major role of brain cholinergic transmission in memory consolidation processes, little is known about cholinergic functioning under environmental pressure.
The present experiments were aimed at investigating possible functional adaptation of muscarinic receptors promoted by a chronic stressful procedure in an inbred strain of mice highly susceptible to stress.
We tested the effects of post-trial administration of a cholinergic agonist and a muscarinic antagonist on the retention of a passive avoidance task in control animals and compared these effects with those observed following food restriction.
Food restriction enhanced the facilitatory effects of oxotremorine and reduced the impairing effects of atropine on memory consolidation.
Our results support the view that chronic sensitization of muscarinic receptors occurs following chronic stress.