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Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ Cross-talk between nervous and immune systems: cytokines modulating morphology and function of both systems under stress conditions M.L. Cañavate, A. García de Galdeano, O. Arteaga, H. Montalvo, M. Revuelta, E. Hilario and A. Alvarez Department of Cell Biology and Histology. School of Medecine and Dentistry, University of the Basque Country, Leioa Spain A reciprocal regulation exists between the Central Nervous System (CNS) and the Immune System affecting the structure and function of both of them. It is a bidirectional interaction supported by anatomic connections but also mediated by different signals such as neurotransmitters, neuropeptides and cytokines released by nervous and immune cells. As has been recently shown, this interplay can be modulated by changes in the environment (stress) which in turn alters cellular responses in both systems. Particularly for the CNS, stressful conditions affect self-renewal and differentiation of the cells. Cytokines are a diverse group of glycopeptides produced immediately by immune cells in response to tissue injury, infection or inflammation. Upon binding to specific receptors (Rs), cytokines coordinate the complex network of cellular interactions. Cytokines are important neuroinflammatory mediators that are involved in the pathological processes resulting from brain trauma, ischemia and chronic neurodegenerative diseases. In this context, understanding when, where and how neuroimmune signaling mechanisms regulate the CNS lineage will help us better understand the interactions of cytokines with the elements in the brain that regulate CNS development, neuroprotection and repair in neurodegenerative diseases. Keywords: central nervous system; regulation; cytokines; neuroimmune signaling; CNS development; neuroprotection 1. Introduction During the course of evolution humans have developed neurobiological mechanisms allowing the adaptation to a changing environment and the ability to respond to new threats, being these physical, social or psychological. Our society today is characterized by technological changes occurring extremely fast. This, together with a growing complexity in the tasks to be achieved, demands from individuals a higher reaction potential, both physical and psychological. Stress can be viewed as the adaptation to the environment, the response of our body to triggers that modify the physiological equilibrium or homeostasis. The response to stressful situations is an intense adaptive reaction whose achievement needs an important amount of resources, requires energy mobilization and involves the triggering of several cognitive and physiological reactions in order to face up the stimuli. One of these adaptive responses is the Immune Response [1]. Humans live in permanent stress. As C. Bernard stated: “the physiological stimulus in excess is dangerous and, if the ability of adaptation of an individual is overridden, would produce illness“[2]. The correlation between psychological stress and susceptibility to infection had been observed from the beginnings of Immunology. Supporting this observation, a handful of data seemed to point out to the involvement of the Central Nervous System (CNS) in the triggering of the anaphylactic reaction (an acute systemic variant of immediate hypersensibility). However, it was not until 1919 that this correlation was scientifically demonstrated with the observations by Ishigami that the activity of phagocyte cells (cells of the innate immune system) from patients with tuberculosis was diminished during episodes of “emotional excitation“ and a that this effect was related to an increment in glucose or adrenaline levels in the blood [3]. During the last 30 years, a number of clinical, epidemiologic and experimental studies have focused on the fact that emotions modify an individual’s immunological functions and thus, the susceptibility to tumor [4,5], autoimmune [6] or infectious diseases [7]. There is a large amount of research work showing statistically significant association between different behaviors or emotional responses and parameters addressing the activity of the immune system [8]. Due to the relevance of the nervous, endocrine and immune systems for adaptation and survival, a great deal of research has been performed focused on the evolution and diversification of these systems, now supporting the idea that they constitute an integrated mechanism dealing with the maintenance of homeostasis. Even further, the existence of both functionally and structurally highly conserved molecules all through metazoan diversification supports the notion of a common evolutionary origin for the immune and neuroendocrine systems [9]. According to this, a large amount of knowledge on physiological mechanisms acquired during many years highlights that a bidirectional communication exists between the nervous, endocrine and immune systems. The interdisciplinary areas of neuroendocrinology-immunology, neuroimmune modulation and psychoneuroimmunology have experienced an increasing development. Two main evidences can be mentioned: 1) the anatomical and functional connections between nervous and immune systems; 2) the intercellular interactions among these systems as all of them express receptors and respond to a large number of common regulatory molecules (cytokines, steroids, neuropeptides), bearing the molecular base underlying this bidirectional interaction [10]. Cytokines 414 © FORMATEX 2014 Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ and other molecules released in the CNS by activated immune cells can affect neurotransmission and neurotransmitters induce also a reciprocal influence on the activity of the immune system [11]. Furthermore, it can be stated that immune cells from primary and secondary lymphoid organs are able to produce hormones and neuropeptides, whereas endocrine glands, neurons and glial cells are able to release cytokines. According to this, receptors for these molecules are expressed both on immune cells and cells from the neuroendocrine system. [12,13]. Nervous and immune systems are anatomically different and different types of cells can be found; however, the molecular mechanisms used have a lot in common. As an example, both systems sense changes in the environment and develop integrated responses altering the survival of the individual. Another resemblance is the concept of memory. Immunological memory acquired during childhood following certain infections persists during years, sometimes, a lifetime; similarly, neurological memory can last during all our life [14]. 2. Relationship between Neuroendocrine and Immune Systems Communication between neuroendocrine and immune systems requires anatomical connections with direct contact between nervous and immune cells, as well as the presence of receptors on the immune cells for the transmission of the signals. This interaction is mediated, at least in part, by neurotransmitters and peptide hormones. Neurotransmitters are secreted by symphathetic fibers innervating immune organs, while several neuropeptides and hormones are released through the portal-hypophysial system [15]. The presence of autonomous nervous fibers, mainly noradrenergic, has been demonstrated both in primary as in secondary organs and also in mucosa-associated lymphoid tissue. Into these organs and tissues the fibers are located in specific compartments and are associated with smooth muscle and certain immune cells such as lymphocytes, macrophages and mast cells [16]. An emotional response against different contingencies can induce the activation of the hippocampus, which, once activated, can affect the cells and organs of the immune system through the neuroendocrine and neurovegetative mediators. The activation of the neuroendocrine mediator leads to the production of neuropeptides by the hypothalamus, which in turn stimulates the anterior hypophysis to release of a large amount of hormones such as ACTH, inducers of the production of glucocorticoids in the suprarenal cortex. The increase in the plasma concentration of glucocorticoids is a usual response against adverse stimuli. Stressinduced glucocorticoids have been involved in cell death in the brain, leading to loss of memory and learning ability deficiencies associated to stress [17]. As regard to the effect of glucocorticoids on the immune system, higher levels have been currently associated to immunosupression both of cellular and humoral immunity, and therefore, to a higher susceptibility to infection. On the contrary, due to their anti-inflammatory properties, low levels of glucocorticoids are associated with inflammatory processes, autoimmunity and allergy [18]. However, at physiological levels, glucocorticoids rather than immunosupressors behave as immunomodulators inducing a shift in the pattern of cytokine production by T helper (TH) cells from TH1 to TH2. TH1 pathway involves the production of cytokines associated with cellular immunity (IL-2, IFNγ), whereas TH2 pathway is characterized by the release of cytokines associated to a humoral response with antibody production and an anti-inflammatory response [19]. Another consequence of the activation of the neuroendocrine system is the release of catecholamines by the adrenal medulla. It’s important to point out that the increased plasma concentration of catecholamines leads to a higher activity hormones not regulated by the anterior hypophysis (renin, calcitonin, parathyroid hormone, glucagon, erythropoietin, gastrin, insulin). The binding of catecholamines, parathyroid hormone and insulin to their respective receptors on the immune cells increases cAMP levels and has immunosuprresor effects on the activity of the cells, down regulating lymphocyte proliferation, cytotoxicity or antibody synthesis [20]. This means that lymphocytes and other immune cells as macrophages, mast cells or neutrophils do have specific receptors for hormones released in the neuroendocrine pathways during an emotional response. Both glucocorticoids and catecholamines supress immune activity although by different mechanisms [21]. The neurovegetative mediator link the CNS with the immune system through the sympathetic and parasympathetic pathways which originate in the hypothalamus. Lymphocytes and other immune cells have receptors for sympathetic (cathecolamines, mainly noradrenaline) and parasympathetic (acetylcholine) neurotransmitters: after binding to its receptors acetylcholine induces an increase in the intracellular cGMP with opposite effects as cAMP, and therefore stimulates proliferation of lymphocytes, cytotoxic activity, antibody synthesis and histamine release from basophils [20]. In summary, an emotional response against certain contingencies may lead to the activation of the hypothalamus exerted by afferents from the cerebral cortex or the limbic system. Once activated the hypothalamus may act on cells of the immune system by means of the neuroendocrine and neurovegetative mediators. The neuroendocrine mediator will induce the release of several hormones, among them, glucocorticoids from the adrenal cortex and catecholamines from the adrenal medulla. These signals will bind to receptors on immune cells, so affecting their activity. Similarly, the activity of lymphoid cells will be regulated by the neurovegetative mediator through the release of catecholamines and acetylcholine from sympathetic and parasympathetic terminals respectively. All these interactions are the basis of regulatory entities known as the axis Hipothalamic-Pituitary-Adrenal (HPA) or the Sympathomedullary pathway (SAM) [22]. The HPA axis or stress axis is activated during a biological response to © FORMATEX 2014 415 Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ stress in the long run, and involves the hypothalamus-hipophysis-adrenal activation triggering the release of the stress hormone cortisol. This has a number of functions including releasing stored glucose from the liver (for energy) and controlling swelling after injury. The immune system is suppressed while this happens [23]. The Sympathomedullary Pathway (SAM) is engaged in the immediate response known as Fight or Flight response. In this case, the hypothalamus also activates the adrenal medulla which releases the catecholamine adrenaline, which, in turn, triggers the fight and flight response, with physiological changes in the body such as a rising in cardiac beating or the slowdown of digestion. Adrenaline leads to the arousal of the symphathetic nervous system and reduced activity in the parasympathetic nervous system. Once the threat is over the parasympathetic branch takes control and brings the body back into a balanced state. Pathologies affecting these systems involve malfunction of the immune system, especially relevant in inflammatory processes [24, 25] and autoimmunity [26]. 3. Cytokines and the neuroendocrine network Changes in the immune response related to psychosocial factors can be included as one of the physiological responses to stress. However, the immune system has also its own sensory role and is able to transmit signals to the neuroendocrine system. In fact, cells of the immune system can be stimulated by stimuli not detected by the nervous system. Virus, bacteria, parasites or tumors-like stimuli and other antigens are sensed by the immune system and transformed into information in the form of cytokines, hormones and neurotransmitters [27]. Cytokines are glycoproteins used for cell communication by a number of different cell types. These molecular signals are involved in the modulation of cell functions such as proliferation, differentiation, movement, survival and cell death. At the physiological level, once bound to their specific receptors, cytokines coordinate the complex network of cell interactions regulating processes such as the immune response, haematopoiesis, inflammation, wound-healing, energy metabolism, neuronal regulation and function, reproduction, pregnancy and embryogenesis. In spite of the large number of cytokines all of them have several properties in common: low molecular weight (overall lower than 80kD), highly potent as they exert their effect at the picomolar range, and just need a low concentration of receptors to induce a biological response. The binding of a cytokine to its receptor leads to the transduction of the signal inside the cell and usually modifies gene expression, thus inducing a change in cell behavior. Cytokines are pleiotropic, as one specific cytokine can exert many actions; redundant, as different cytokines can exert the same action; and also they may act synergistically. Furthermore, cytokines are frequently regulated in cascades where induction of the early cytokines serves to influence the synthesis of later ones. According to their regulatory effect on the immune and inflammatory response, cytokines can be classified as follows: 1- pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF-α) and interferons (IFNs); 2-Cytokines secreted by mutually exclusive populations of T helper (TH) cells, i.e., Th1 like IFNγ and IL-2 versus TH2 like IL-4 and IL-5; and, 3- Negative immunoregulatory cytokines such as IL-4, IL-10 and transforming growth factor (TGF) β which suppress TH1 effector functions [28]. In addition to regulate cellular interactions, cytokines are the molecular players that signal the brain to respond to the danger of viruses, bacteria, fungi and parasites through an elaborated coordination [29]. The information gets to the neuroendocrine system and induces a physiological response. In this context, cytokines work in two ways: as endogenous modulators of the immune system, and as carriers of information from de immune system to the neuroendocrine system. Cytokines in the brain are also regulated in cascades with evidence of feedback loops, both positive and negative, at different levels [30]. In general, cytocines have been shown to access the brain and interact with virtually every pathophysiologic domain, including neurotransmitter metabolism, neuroendocrine function and neural plasticity.[31] Nevertheless, given that cytokines are relatively large polypeptides ( 15-25kD), experiments have conducted in laboratory animals to determine how peripheral cytokine signals reach the brain. Pathways that have been elucidated include1) cytokine passage through leaky regions in the blood-brain-barrier, 2) active transport via saturable transport molecules, 3) activation of endothelial and other cell types including perivascular macrophages lining the cerebral vasculature, and 4) binding to cytokine receptors associated with peripheral afferent nerve fibers that then relay cytokines signals to relevant brain regions including the nucleus of the solitary tract of hypothalamus [32]. Although much has been discussed about the passage of cytokines into the brain, many studies involving protein and mRNA expression determination show that cytokines are continuously expressed in the brain, including the hypothalamus. The constitutive expression of genes encoding a variety of cytokines and their receptors indicate that some cytokines sustain the normal functioning of the brain. It is well accepted the involvement of members of the IL-1 family in the modulation of brain functions such as sleeping, feeding, ovulation or physical exercising [33].The continuous expression of cytokine receptors on neural cells make these cells responsive to low or even undetectable levels of these molecules in the healthy adult brain. Under physiological conditions cytokines such as IL-1,IL-6 and TNF-α are important for providing trophic support to neurons and enhancing neurogenesis, while contributing to normal cognitive functions such as memory in laboratory animals [34] However, specific physiological stimuli can raise the low cytokine levels. In fact, many cytokines are induced in response to injury or infection. Altered expression of various cytokines in the brain is observed in a variety of CNS 416 © FORMATEX 2014 Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ disorders. This happens for instance in Alzheimer´s disease, multiple sclerosis, ischemia, stroke and various forms of encephalopathy [35]. Cell resident within the central nervous system (CNS) can synthesize, secrete and respond to inflammatory cytokines not only contributing to the response to injury or immunological challenge within the CNS, but also regulating their own growth and differential potential. The actions and cell communication via cytokines in the CNS are designated as the “CNS cytokine network“, in with microglia and astrocytes play the central roles, and under certain conditions, neurons can also produce cytokines [36,37]. Astrocytes and microglia are thought to be immune surveillant cells of the nervous system, control unbalancing situations and protect the integrity of the CNS. Moreover, cytokine production and cytokine responses in astrocytes and microglia are very similar, however, the role of these cells in the CNS is different: microglia is engaged in the elimination of death cells or their remnants by phagocytosis in brain injury, are considered “ the CNS professional macrophages” which can perform APC and proinflammatory effector functions following activation. Microglia is myeloid lineage cells and owing to their phenotype and reactivity following injury and inflammation [38] Astrocytes providing structural and environmental support for neurons and are essential for brain homeostasis and neuronal function. Astrocytes, the most abundant glial cell population are neuroectodermal origin. They form the glia limitants around blood vessels restricting the access of immune cells to CNS parenchyma. In contrast to other brain cells, astrocytes are resistant to death receptor-induced apoptosis, indicating that are well equipped to survive inflammatory insults [39]. 4. The role of the proinflammatory cytokines in neurogenesis, neural plasticity, memory and learning The formation of new neurons, a process termed neurogenesis is a complex process which includes continuous renewal of the hippocampal stem cell pool and generation of new neurons in the dentate gyrus (DG) of the hippocampus during adult life [40]. Recent research indicates that adult hippocampal neurogenesis is indeed extensively affected by elements of the immune response such as activated microglia and cytokine release. Immune activation has been shown to play an important role in many neuropsychiatric diseases such as Alzheimer´s disease, schizophrenia, autism and depression. A number of research studies have shown that activation of the immune system in early life can augment the risk of some psychiatric disorders in adulthood, such as a schizophrenia and depression [41]. Other studies supported the role of individual cytokines in neurogenesis, demonstrating that over expression of IL-6 and IL-1β in the brain as well as systemic administration of TNF-α can reduce cell proliferation and neuronal differentiation in the adult hippocampus, stimuling more progenitor cells to differentiate into astrocytes [42]. This further suggest that neurogenesis might be responsible for the cognitive deficits seen in infectious accompanied by inflammation. Currently microglia activation and cytokine release are also suggested to be a mechanism of neurogenic decline in non-infectious conditions such Alzheimer´s disease and normal aging. In vitro findings indicate that IL-6 is a key factor released by microglia that reduces neuron survival, proliferation, and neuronal differentiation of new cells. Similar anti-neurogenic effects of TNF-α have also been reported [43]. A highly active area of research focuses on the extent to which adult neurogenesis contributes to learning and memory [44] or it merely reflects development and maintenance of brain regions where it occurs [45]. The learning and memory theory is in part based on the idea that new neurons which are not yet fully integrated into the circuitry could mold their connections to experiences more extensively as compared to older neurons that are already incorporated into circuitry. Old neurons can modify their synapsis in response to experiences, but younger neurons may display a greater degree of malleability or plasticity. Most of the research on the role of immune system in learning and memory process focused on the involvement of inflammatory cytokines, particularly IL-1, Il-6 and TNF-α. Several lines of evidence indicate that IL-1 is required for some learning and memory process, particularly for the consolidation of memory that depends on proper functioning of the hippocampus. It is now clear that the role of IL-6 in memory is quite complex and that IL-6 may influence learning and memory in different, and even opposite ways under various conditions. In addition to the extensive literature on the detrimental effects of TNF-α in learning and memory, there is some evidence for its beneficial effects under certain conditions [46]. The term “neuronal plasticity” was already used by the “father of neuroscience” Santiago Ramón y Cajal (18521934) who described nonpathological changes in the structure of adult brains. The term stimulated a controversial discussion as some neuropathologists favored the “old dogma” that there is a fixed number of neurons in the adult brain that cannot be replaced when the cells die [47, 48]. As Fuchs comments [48]: “today it is generally accepted that the adult brain is far from being fixed. A number of factors such as stress, adrenal and gonadal hormones, neurotransmitters, growth factors, certain drugs, environmental stimulation, learning, and aging change neuronal structures and functions. In a wider sense, plasticity of the brain can be regarded as “the ability to make adaptive changes related to the structure and function of the nervous system”. Accordingly, “neuronal plasticity” can stand not only for morphological changes in brain areas, for alterations in neuronal networks including changes in neuronal connectivity as well as the generation of new neurons (neurogenesis), but also for neurobiochemical changes” . © FORMATEX 2014 417 Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ The formation of long-term memory and neural plasticity depends on a process of consolidation, in which new memories, which in the short term exist in a relatively fragile state, undergo a process of stabilization. Consolidation of memories enables the modulation of memory strength by endogenous processes activated by an experience. Such modulation is particularly relevant for memory associated with emotionally arousing experiences, which are modulated by stress-induced activation of the HPA axis (and the secretion of glucocorticoids), as well as the activation of the SNS in the periphery. It should be noted, however, that under severe stressful conditions over-activation of the HPA axis can disrupt memory consolidation [49]. Most research on these interactions was conducted in the context of the detrimental role of inflammation in neurobehavioral plasticity. However under certain conditions, mild emotional stimulation/stress, interactions between immunity, HPA and SNS activation may be beneficial for memory and plasticity. For example, the emotional stimulation that is an integral part of many cognitive processes (such as examination or public speaking in humans or various learning paradigms in rodents) is associated with cytokines (particularly IL-1) production [50]. On the other hand, cytokine production, particularly in the hippocampus and hypothalamus, is important for mild stressinduced activation of the HPA axis and SNS [51]. 5. Microscopy contribution to the study of tissue and cellular damage induced by stress in the nervous system In the field of neurosciences imaging techniques are especially relevant for the assessment of morphological changes in the brain at the microscopic level, and therefore, can also be used for the monitoring of changes induced as part of the response to the environment. In fact, it was thanks to observations made under the microscope that Santiago Ramón y Cajal developed in the XIX century the “Neuronal Theory” which is considered to be the foundation of neurosciences. The microscopic structure of nervous cells and tissue can be studied on thin tissue slices previously fixed, directly in fresh, or, alternatively, on sections frozen immediately after extraction. Sections are then stained with specific methods, such as Nissl staining (cresyl violet staining), allowing the visualization of Nissl bodies that reflect the location of the rough endoplasmic reticulum. The Golgi techniques, and silver impregnation among them, allow the staining of cell bodies and ramifications of neurons. Tracing techniques are useful for the identification of long distance connections between neurons, whereas electron microscopy is especially interesting for studying the peripheral nervous system; for instance, it can be used in order to evaluate the ultrastructure of myelin sheets which may appear damaged in neurodegenerative diseases. Immunohistochemistry is another important tool related to microscopy. Today, using tissue sections and monoclonal antibodies designed to target specific molecular components in neurons, it is possible to visualize the nervous tissue as a molecular map where neurons can be identified by the presence of their own components such as neurotransmitters. Neurons and glial cells arranged in complex functional domains process information and are mediators of behavior change. A usual problem in the observation of neuronal networks remains in the fact that one unique neuron may spread across the whole tissue section, allowing only to get limited information from just one section. Confocal microscopy, tissue serial sectioning and 3D reconstruction are powerful techniques that allow to bypass/overcome this problem. Using these methods the visualization of whole nervous cells from the brain and also from other tissues can be achieved. In confocal microscopy a specific point in the tissue is focused by a beam of light which is simultaneously captured by a camera. In this way6 high resolution images are generated. Moreover, by using confocal microscopy images of the nervous system can be obtained “in vivo”, as well as the monitoring of molecular movements inside the cell, the visualization of secretion processes using tracers, or the location of antibodies in immunohistochemistry studies, with a higher resolution than conventional microscopy and allowing the use of several tracers on the same sample. In addition, “in situ” hybridization can be performed for the identification of specific nucleid acids sequences, avoiding the use of radioisotopes. When using microscopy techniques in the field of cell responses to stress, we must take into account that cells are active and dynamic microcosmos, constantly adapting to changes in the environment and so, modifying their structure and function. In this context, nerve cells are not an exception and suffer structural changes in response to environmental demands. Under pathological or an excess of stress, nerve cells can be driven through a process of adaptation leading to morphological changes that can become stable, and so that, the cell remains healthy. If the demanded response overcomes the ability of the cell for adaptation, cell damage may occur and can be monitored under the microscope. Up to a point cellular damage may be reversed but, after a continuous and high level of stress irreversible damage occurs and the cell will die. One of the best studied stress agents, both in humans and in experimental models, which is able to induce morphological changes is hypoxia. Lack of oxygen affects the aerobic respiration and therefore, the mitochondrial oxidative phosphorilation process. As a consequence the generation of ATP decreases or even will be blocked which in the end alters all cellular systems, involving the generation of irreversible lesions in the cell and also in the individual. Inflammation is an important factor that determines the severity of the damage following brain ischemia [52,53]. In the nervous system inflammation involves cell responses triggered by microglia and astroglia and the ongoing increase in the synthesis of inflammatory molecules such as proinflammatory cytokines (IL-1, IL-6 and TNFα). Overall these responses lead to exacerbate damage. 418 © FORMATEX 2014 Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ In the next two figures it can be observed morphological brain damage induced in a rat after hypoxic ischemia. In figure 1 we can observe a hippocampus of a control and hipoxic-ischemic rat. Both are been immunostained for Glial fibrillary acidic protein(GFAP) to visualize astrocytes and contrastained with hematoxilin-eosin. In the right image we can appreciate an increase of the GFAP immunostaining consequence of the reactive astrogliosis. Similarly, now using confocal microscopy (Figure 2) we can also observe the astroglial reactivity in the right image in the parietal cortex of a rat after an injury. 6. Conclusions Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters and hormones (e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFα. It became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis, facilitating many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases. Fig. 1 Represetative light microphotographs of brain sections of control and hypoxic-ischemic (HI) group. The images showed astrocytes immunolabeled with glial fibrilary acid protein (GFAP) from dentated gyrus (DG) of hippocampus area. Original magnification x200. Fig. 2 Represetative confocal microphotographs of brain sections of control and hypoxic-ischemic (HI) group. The images showed astrocytes immunolabeled with glial fibrilary acid protein (GFAP) from parietal cortex. Original magnification x200. © FORMATEX 2014 419 Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.) __________________________________________________________________ References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] 420 Segerstrom SC, Miller GE. Psychological Stress and the Human Immune System: A Meta- Analytic Sudy of 30 Years of Inquiry. Psychological Bulletin. 2004; 130:601-630. Benard C. Les phenomenes de la vie. Librarie et fils,editors. Paris. 1878. 1:879-893 Ishigami T. The influence of psychic acts on the progress of pulmonary tuberculosis, American Review of Tuberculosis. 1919; 2:470-478. 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