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The basis of the stress reaction

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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).

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... 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). ...
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... 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). ...
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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.
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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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
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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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.