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George P. Chrousos - One of the best experts on this subject based on the ideXlab platform.
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From Brain Organoids to Networking Assembloids: Implications for Neuroendocrinology and Stress Medicine
'Frontiers Media SA', 2021Co-Authors: Evanthia A. Makrygianni, George P. ChrousosAbstract:Brain organoids are three-dimensional cultures that contain multiple types of cells and cytoarchitectures, and resemble fetal human brain structurally and functionally. These organoids are being used increasingly to model brain development and disorders, however, they only partially recapitulate such processes, because of several limitations, including inability to mimic the distinct cortical layers, lack of functional neuronal circuitry as well as non-neural cells and gyrification, and increased cellular Stress. Efforts to create improved brain organoid culture Systems have led to region-specific organoids, vascularized organoids, glia-containing organoids, assembloids, sliced organoids and polarized organoids. Assembloids are fused region-specific organoids, which attempt to recapitulate inter-regional and inter-cellular interactions as well as neural circuitry development by combining multiple brain regions and/or cell lineages. As a result, assembloids can be used to model subtle functional aberrations that reflect complex neurodevelopmental, neuropsychiatric and neurodegenerative disorders. Mammalian organisms possess a highly complex neuroendocrine System, the Stress System, whose main task is the preservation of Systemic homeostasis, when the latter is threatened by adverse forces, the Stressors. The main central parts of the Stress System are the paraventricular nucleus of the hypothalamus and the locus caeruleus/norepinephrine-autonomic nervous System nuclei in the brainstem; these centers innervate each other and interact reciprocally as well as with various other CNS structures. Chronic dysregulation of the Stress System has been implicated in major pathologies, the so-called chronic non-communicable diseases, including neuropsychiatric, neurodegenerative, cardiometabolic and autoimmune disorders, which lead to significant population morbidity and mortality. We speculate that brain organoids and/or assembloids could be used to model the development, regulation and dysregulation of the Stress System and to better understand Stress-related disorders. Novel brain organoid technologies, combined with high-throughput single-cell omics and gene editing, could, thus, have major implications for precision medicine
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developmental trajectories of early life Stress and trauma a narrative review on neurobiological aspects beyond Stress System dysregulation
Frontiers in Psychiatry, 2019Co-Authors: Agorastos Agorastos, George P. Chrousos, Panagiota Pervanidou, Dewleen G BakerAbstract:Early life Stressors are highly prevalent in the general population and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life Stress (ELS) could represent a developmental risk factor and mediate risk for disease in adulthood, leading to increased physical and mental morbidity in later life. ELS during critical periods of brain development with elevated neuroplasticity could exert a programming effect on particular neuronal and molecular networks related to the Stress response and lead to enduring hyper- or hypo-activation of the Stress System, associated with adult hypothalamic-pituitary-adrenal axis and glucocorticoid signalling dysregulation. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the CNS, as well as immune and metabolic dysregulation have been lately identified as important risk factors for the development of a chronically impaired homeostatic balance after ELS. The diverse human genetic background and the later engraved epigenetic modifications through Stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to Stress. This paper reviews evidence from mainly human research on the most acknowledged neurobiological allostatic trajectories exerting enduring adverse effects of ELS even decades later. Future studies should focus on prospective investigation of putative mediators and their temporal sequence and interactions, while taking into account the potentially delayed time-frame for the expression of their effects. Screening strategies for ELS need therefore to be improved to better identify an individual’s risk for disease development and help prevention and treatment responses.
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developmental trajectories of early life Stress and trauma a narrative review on neurobiological aspects beyond Stress System dysregulation
Frontiers in Psychiatry, 2019Co-Authors: Agorastos Agorastos, George P. Chrousos, Panagiota Pervanidou, Dewleen G BakerAbstract:Early life Stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life Stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the Stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the Stress System and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through Stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to Stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous System, immune System and inflammation, oxidative Stress, cardiovascular System, gut microbiome, sleep and circadian System, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment.
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early life Stress and trauma developmental neuroendocrine aspects of prolonged Stress System dysregulation
Hormones (Greece), 2018Co-Authors: Agorastos Agorastos, George P. Chrousos, Panagiota Pervanidou, Gerasimos KolaitisAbstract:Experience of early life Stress (ELS) and trauma is highly prevalent in the general population and has a high public health impact, as it can trigger a health-related risk cascade and lead to impaired homeostatic balance and elevated cacostatic load even decades later. The prolonged neuropsychobiological impact of ELS can, thus, be conceptualized as a common developmental risk factor for disease associated with increased physical and mental morbidity in later life. ELS during critical periods of brain development with elevated neuroplasticity could exert a programming effect on particular neuronal networks related to the Stress response and lead to enduring neuroendocrine alterations, i.e., hyper- or hypoactivation of the Stress System, associated with adult hypothalamic-pituitary-adrenal axis and glucocorticoid signaling dysregulation. This paper reviews the pathophysiology of the human Stress response and provides evidence from human research on the most acknowledged Stress axis-related neuroendocrine pathways exerting the enduring adverse effects of ELS and mediating the cumulative long-term risk of disease vulnerability in adulthood.
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salivary cortisol and alpha amylase diurnal profiles and Stress reactivity in children with attention deficit hyperactivity disorder
Psychoneuroendocrinology, 2018Co-Authors: Eleni Angeli, George P. Chrousos, Elizabeth O Johnson, Terpsichori Korpa, Filia Apostolakou, Ioannis Papassotiriou, Panagiota PervanidouAbstract:Abstract There is growing evidence for dysregulation of the Stress System in individuals with Attention Deficit Hyperactivity Disorder (ADHD). The Stress System includes neuroanatomical and functional components that function in concert to maintain homeostasis and its main effectors are the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic/adrenomedullary nervous System (SNS). As Stress System activity demonstrates a distinct circadian variation, we aimed to describe simultaneously, diurnal rhythms of both the HPA axis and the SNS in children with ADHD and a comparison group. Moreover, we attempted to investigate Stress responses to a physical Stressor, venipuncture, in both groups. Sixty-two prepubertal children with ADHD combined (ADHD-C) or inattentive (ADHD-I) type and 40 typically developing children provided saliva samples at six specific time points during a day, as well as before and 10 min after a scheduled morning venipuncture. Salivary cortisol and α- amylase were selected as reliable noninvasive biomarkers for HPA axis and SNS function and were measured in the samples obtained. Results revealed that children with ADHD-C had lower mean cortisol values both 30 min after awakening and at 18:00 h than controls (p = 0.002 and p = 0.018 respectively), as well as lower mean Cortisol Awakening Response (CAR) and Area Under the Curve for “wake to bed” period (AUC i ) values of cortisol (p = 0.004 and p = 0.001, respectively). Also, mean CAR and cortisol AUC i were lower in children with ADHD-I than the control group (p = 0.034 and p = 0.038 respectively). Alpha-amylase measurements showed an increase over time (p
Cristina Nunez - One of the best experts on this subject based on the ideXlab platform.
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Glucocorticoids Regulation of FosB/ΔFosB Expression Induced by Chronic Opiate Exposure in the Brain Stress System
PloS one, 2012Co-Authors: Daniel García-pérez, M. Luisa Laorden, M. Victoria Milanés, Cristina NunezAbstract:Chronic use of drugs of abuse profoundly alters Stress-responsive System. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFosB, particularly in brain areas associated with reward and Stress. The persistent effects of ΔFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that Stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain Stress System that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/ΔFosB in both hypothalamic and extrahypothalamic brain Stress Systems during morphine dependence. For that, expression of FosB/ΔFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FosB/ΔFosB was induced after chronic morphine administration in all the brain Stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FosB/ΔFosB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FosB/ΔFosB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FosB/ΔFosB) to opiates in brain areas associated with Stress is modulated by GC, supporting the evidence of a link between brain Stress hormones and addiction.
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glucocorticoids regulation of fosb δfosb expression induced by chronic opiate exposure in the brain Stress System
PLOS ONE, 2012Co-Authors: Daniel Garciaperez, Victoria M Milanes, Luisa M Laorden, Cristina NunezAbstract:Chronic use of drugs of abuse profoundly alters Stress-responsive System. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFosB, particularly in brain areas associated with reward and Stress. The persistent effects of ΔFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that Stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain Stress System that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/ΔFosB in both hypothalamic and extrahypothalamic brain Stress Systems during morphine dependence. For that, expression of FosB/ΔFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FosB/ΔFosB was induced after chronic morphine administration in all the brain Stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FosB/ΔFosB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FosB/ΔFosB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FosB/ΔFosB) to opiates in brain areas associated with Stress is modulated by GC, supporting the evidence of a link between brain Stress hormones and addiction.
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hypothalamic orexin a neurons are involved in the response of the brain Stress System to morphine withdrawal
PLOS ONE, 2012Co-Authors: Luisa M Laorden, Victoria M Milanes, Krisztina J Kovacs, Szilamer Ferenczi, Bernadett Pinterkubler, Laura Luz Gonzalezmartin, Carmen M Lasheras, Cristina NunezAbstract:Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain Stress System are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain Stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins' activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain Stress System to morphine withdrawal and suggest that all orexinergic subpopulations in the lateral hypothalamic area contribute in this response.
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induction of fosb δfosb in the brain Stress System related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Nunez, Luisa M Laorden, Fátima Martín, Anna Földes, Krisztina Kovács, Victoria M MilanesAbstract:J. Neurochem. (2010) 114, 475–487. Abstract The transcription factor ΔFosB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FosB/ΔFosB expression in both hypothalamic and extrahypothalamic brain Stress System during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FosB/ΔFosB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain Stress System in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FosB/ΔFosB in CRF-, TH- and DYN-positive neurons. FosB/ΔFosB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A2 noradrenergic part of the nucleus tractus solitarius (NTS-A2). Morphine dependence and withdrawal evoked an increase in FosB/ΔFosB-TH and FosB/ΔFosB-CRF double labelling in NTS-A2 and PVN, respectively, besides an increase in TH levels in NTS-A2 and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FosB/ΔFosB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain Stress System, which have been proposed to be directly related to addiction.
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induction of fosb δfosb in the brain Stress System related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Nunez, Luisa M Laorden, Fátima Martín, Anna Földes, Krisztina J Kovacs, Victoria M MilanesAbstract:The transcription factor DeltaFosB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FosB/DeltaFosB expression in both hypothalamic and extrahypothalamic brain Stress System during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FosB/DeltaFosB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain Stress System in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FosB/DeltaFosB in CRF-, TH- and DYN-positive neurons. FosB/DeltaFosB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A(2) noradrenergic part of the nucleus tractus solitarius (NTS-A(2)). Morphine dependence and withdrawal evoked an increase in FosB/DeltaFosB-TH and FosB/DeltaFosB-CRF double labelling in NTS-A(2) and PVN, respectively, besides an increase in TH levels in NTS-A(2) and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FosB/DeltaFosB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain Stress System, which have been proposed to be directly related to addiction.
Ilia J Elenkov - One of the best experts on this subject based on the ideXlab platform.
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Stress System activity innate and t helper cytokines and susceptibility to immune related diseases
Annals of the New York Academy of Sciences, 2006Co-Authors: Emanuele Calcagni, Ilia J ElenkovAbstract:Abstract: Associations between Stress and health outcomes have now been carefully documented, but the mechanisms by which Stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major Stress hormones, inhibit Systemically IL-12, TNF-α, and INF-γ, but upregulate IL-10, IL-4, and TGF-β production. Thus, during an immune and inflammatory response, the activation of the Stress System, through induction of a Th2 shift may protect the organism from Systemic “overshooting” with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, Stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-α, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive Stress System, and a dysfunctional neuroendocrine–immune interface associated with abnormalities of the “Systemic anti-inflammatory feedback” and/or “hyperactivity” of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in Stress System activity, such as acute or chronic Stress, cessation of chronic Stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the Systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, Stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which Stress affects disease susceptibility, activity, and outcome of various immune-related diseases.
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Stress System activity innate and t helper cytokines and susceptibility to immune related diseases
Annals of the New York Academy of Sciences, 2006Co-Authors: Emanuele Calcagni, Ilia J ElenkovAbstract:Associations between Stress and health outcomes have now been carefully documented, but the mechanisms by which Stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major Stress hormones, inhibit Systemically IL-12, TNF-alpha, and INF-gamma, but upregulate IL-10, IL-4, and TGF-beta production. Thus, during an immune and inflammatory response, the activation of the Stress System, through induction of a Th2 shift may protect the organism from Systemic "overshooting" with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, Stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive Stress System, and a dysfunctional neuroendocrine-immune interface associated with abnormalities of the "Systemic anti-inflammatory feedback" and/or "hyperactivity" of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in Stress System activity, such as acute or chronic Stress, cessation of chronic Stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the Systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, Stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which Stress affects disease susceptibility, activity, and outcome of various immune-related diseases.
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Stress hormones proinflammatory and antiinflammatory cytokines and autoimmunity
Annals of the New York Academy of Sciences, 2002Co-Authors: Ilia J Elenkov, George P. ChrousosAbstract:Recent evidence indicates that glucocorticoids and catecholamines, the major Stress hormones, inhibit the production of proinflammatory cytokines, such as interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, whereas they stimulate the production of antiinflammatory cytokines, such as IL-10, IL-4, and transforming growth factor (TGF)-beta. Thus, Systemically, an excessive immune response, through activation of the Stress System, stimulates an important negative feedback mechanism, which protects the organism from an "overshoot" of proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential. Conversely, in certain local responses and under certain conditions, Stress hormones actually may boost regional immune responses, through induction of TNF-alpha, IL-1, and IL-8, and by inhibiting TGF-beta production. Therefore, conditions that are associated with significant changes in Stress System activity, such as acute or chronic Stress, cessation of chronic Stress, severe exercise, and pregnancy and the postpartum period, through modulation of the Systemic or local pro/antiinflammatory cytokine balance, may suppress or potentiate autoimmune diseases activity and/or progression.
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Stress hormones proinflammatory and antiinflammatory cytokines and autoimmunity
Annals of the New York Academy of Sciences, 2002Co-Authors: Ilia J Elenkov, George P. ChrousosAbstract:Abstract: Recent evidence indicates that glucocorticoids and catecholamines, the major Stress hormones, inhibit the production of proinflammatory cytokines, such as interleukin (IL)-12, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, whereas they stimulate the production of antiinflammatory cytokines, such as IL-10, IL-4, and transforming growth factor (TGF)-β. Thus, Systemically, an excessive immune response, through activation of the Stress System, stimulates an important negative feedback mechanism, which protects the organism from an “overshoot” of proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential. Conversely, in certain local responses and under certain conditions, Stress hormones actually may boost regional immune responses, through induction of TNF-α, IL-1, and IL-8, and by inhibiting TGF-β production. Therefore, conditions that are associated with significant changes in Stress System activity, such as acute or chronic Stress, cessation of chronic Stress, severe exercise, and pregnancy and the postpartum period, through modulation of the Systemic or local pro/antiinflammatory cytokine balance, may suppress or potentiate autoimmune diseases activity and/or progression.
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Stress corticotropin releasing hormone glucocorticoids and the immune inflammatory response acute and chronic effectsa
Annals of the New York Academy of Sciences, 1999Co-Authors: Ilia J Elenkov, Elizabeth L Webster, David J Torpy, George P. ChrousosAbstract:: Corticotropin-releasing hormone (CRH) influences the immune System indirectly, through activation of the hypothalamic-pituitary-adrenal axis and sympathetic System, and directly, through local modulatory actions of peripheral (immune) CRH. We recently demonstrated that catecholamines and histamine potently inhibited interleukin (IL)-12 and stimulated IL-10, whereas glucocorticoids suppressed IL-12, but did not affect IL-10 production ex vivo. Thus, both glucocorticoids and catecholamines, the end products of the Stress System, and histamine, a product of activated mast cells, may selectively suppress cellular immunity and favor humoral immune responses. We localized immunoreactive CRH in experimental carrageenin-induced aseptic inflammation and, in humans, in inflamed tissues from patients with several autoimmune diseases. In addition, we demonstrated that CRH activated mast cells via a CRH receptor type 1-dependent mechanism, leading to release of histamine and hence vasodilatation and increased vascular permeability. Thus, activation of the Stress System, through direct and indirect effects of CRH, may influence the susceptibility of an individual to certain autoimmune, allergic, infectious or neoplastic diseases. Antalarmin, a novel nonpeptide CRH antagonist, prevented several proinflammatory effects of CRH, thus revealing its therapeutic potential in some forms of inflammation.
Victoria M Milanes - One of the best experts on this subject based on the ideXlab platform.
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glucocorticoids regulation of fosb δfosb expression induced by chronic opiate exposure in the brain Stress System
PLOS ONE, 2012Co-Authors: Daniel Garciaperez, Victoria M Milanes, Luisa M Laorden, Cristina NunezAbstract:Chronic use of drugs of abuse profoundly alters Stress-responsive System. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFosB, particularly in brain areas associated with reward and Stress. The persistent effects of ΔFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that Stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain Stress System that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/ΔFosB in both hypothalamic and extrahypothalamic brain Stress Systems during morphine dependence. For that, expression of FosB/ΔFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FosB/ΔFosB was induced after chronic morphine administration in all the brain Stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FosB/ΔFosB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FosB/ΔFosB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FosB/ΔFosB) to opiates in brain areas associated with Stress is modulated by GC, supporting the evidence of a link between brain Stress hormones and addiction.
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hypothalamic orexin a neurons are involved in the response of the brain Stress System to morphine withdrawal
PLOS ONE, 2012Co-Authors: Luisa M Laorden, Victoria M Milanes, Krisztina J Kovacs, Szilamer Ferenczi, Bernadett Pinterkubler, Laura Luz Gonzalezmartin, Carmen M Lasheras, Cristina NunezAbstract:Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain Stress System are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain Stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins' activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain Stress System to morphine withdrawal and suggest that all orexinergic subpopulations in the lateral hypothalamic area contribute in this response.
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induction of fosb δfosb in the brain Stress System related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Nunez, Luisa M Laorden, Fátima Martín, Anna Földes, Krisztina J Kovacs, Victoria M MilanesAbstract:The transcription factor DeltaFosB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FosB/DeltaFosB expression in both hypothalamic and extrahypothalamic brain Stress System during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FosB/DeltaFosB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain Stress System in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FosB/DeltaFosB in CRF-, TH- and DYN-positive neurons. FosB/DeltaFosB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A(2) noradrenergic part of the nucleus tractus solitarius (NTS-A(2)). Morphine dependence and withdrawal evoked an increase in FosB/DeltaFosB-TH and FosB/DeltaFosB-CRF double labelling in NTS-A(2) and PVN, respectively, besides an increase in TH levels in NTS-A(2) and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FosB/DeltaFosB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain Stress System, which have been proposed to be directly related to addiction.
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induction of fosb δfosb in the brain Stress System related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Nunez, Luisa M Laorden, Fátima Martín, Anna Földes, Krisztina Kovács, Victoria M MilanesAbstract:J. Neurochem. (2010) 114, 475–487. Abstract The transcription factor ΔFosB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FosB/ΔFosB expression in both hypothalamic and extrahypothalamic brain Stress System during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FosB/ΔFosB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain Stress System in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FosB/ΔFosB in CRF-, TH- and DYN-positive neurons. FosB/ΔFosB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A2 noradrenergic part of the nucleus tractus solitarius (NTS-A2). Morphine dependence and withdrawal evoked an increase in FosB/ΔFosB-TH and FosB/ΔFosB-CRF double labelling in NTS-A2 and PVN, respectively, besides an increase in TH levels in NTS-A2 and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FosB/ΔFosB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain Stress System, which have been proposed to be directly related to addiction.
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effects of corticotropin releasing factor receptor 1 antagonists on the brain Stress System responses to morphine withdrawal
Molecular Pharmacology, 2010Co-Authors: Javier Navarrozaragoza, Cristina Nunez, Luisa M Laorden, Victoria M MilanesAbstract:The role of Stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain Stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain Stress System to morphine withdrawal. The effects of naloxone-precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A2 cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF Systems in mediating morphine withdrawalactivation of brain Stress neurocircuitry.
Luisa M Laorden - One of the best experts on this subject based on the ideXlab platform.
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Hypothalamic Orexin-A Neurons Are Involved in the Response of the Brain Stress System to Morphine Withdrawal
2016Co-Authors: Luisa M Laorden, Laura L. González-martı́n, Carmen Lasheras, Krisztina J. Kovács, Victoria M. MilanésAbstract:Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain Stress System are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain Stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins ’ activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain Stress System to morphine withdrawal and suggest that all orexinergic subpopulations in the latera
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glucocorticoids regulation of fosb δfosb expression induced by chronic opiate exposure in the brain Stress System
PLOS ONE, 2012Co-Authors: Daniel Garciaperez, Victoria M Milanes, Luisa M Laorden, Cristina NunezAbstract:Chronic use of drugs of abuse profoundly alters Stress-responsive System. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFosB, particularly in brain areas associated with reward and Stress. The persistent effects of ΔFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that Stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain Stress System that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/ΔFosB in both hypothalamic and extrahypothalamic brain Stress Systems during morphine dependence. For that, expression of FosB/ΔFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FosB/ΔFosB was induced after chronic morphine administration in all the brain Stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FosB/ΔFosB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FosB/ΔFosB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FosB/ΔFosB) to opiates in brain areas associated with Stress is modulated by GC, supporting the evidence of a link between brain Stress hormones and addiction.
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hypothalamic orexin a neurons are involved in the response of the brain Stress System to morphine withdrawal
PLOS ONE, 2012Co-Authors: Luisa M Laorden, Victoria M Milanes, Krisztina J Kovacs, Szilamer Ferenczi, Bernadett Pinterkubler, Laura Luz Gonzalezmartin, Carmen M Lasheras, Cristina NunezAbstract:Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain Stress System are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain Stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins' activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain Stress System to morphine withdrawal and suggest that all orexinergic subpopulations in the lateral hypothalamic area contribute in this response.
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Glucocorticoids Regulation of FosB/DFosB Expression Induced by Chronic Opiate Exposure in the Brain Stress System
2012Co-Authors: Luisa M Laorden, Victoria M. MilanésAbstract:Chronic use of drugs of abuse profoundly alters Stress-responsive System. Repeated exposure to morphine leads to accumulation of the transcription factor DFosB, particularly in brain areas associated with reward and Stress. The persistent effects of DFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that Stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain Stress System that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/DFosB in both hypothalamic and extrahypothalamic brain Stress Systems during morphine dependence. For that, expression of FosB/DFosB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FosB/DFosB was induced after chronic morphine administration in all the brain Stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FosB/DFosB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FosB/DFosB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FosB/DFosB) t
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induction of fosb δfosb in the brain Stress System related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Nunez, Luisa M Laorden, Fátima Martín, Anna Földes, Krisztina Kovács, Victoria M MilanesAbstract:J. Neurochem. (2010) 114, 475–487. Abstract The transcription factor ΔFosB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FosB/ΔFosB expression in both hypothalamic and extrahypothalamic brain Stress System during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FosB/ΔFosB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain Stress System in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FosB/ΔFosB in CRF-, TH- and DYN-positive neurons. FosB/ΔFosB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A2 noradrenergic part of the nucleus tractus solitarius (NTS-A2). Morphine dependence and withdrawal evoked an increase in FosB/ΔFosB-TH and FosB/ΔFosB-CRF double labelling in NTS-A2 and PVN, respectively, besides an increase in TH levels in NTS-A2 and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FosB/ΔFosB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain Stress System, which have been proposed to be directly related to addiction.
