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{
"question": [
"what hormones do our brains release during stressful experiences?",
"what is the use of corticosterone?"
],
"answer": [
"During stressful experiences, our brains release hormones such as epinephrine, glucocorticoids, and corticosterone. The hypothalamic-pituitary-adrenal (HPA) axis also plays a significant role in this process, stimulating the release of these hormones.",
"Corticosterone, a type of glucocorticoid, is used in the body's response to stress. It initiates metabolic and physiological responses that help the body cope with stressors. It also provides negative feedback to inhibit activity in the hypothalamic-pituitary-adrenal (HPA) axis, which helps to dampen stress-activated defense reactions, including immune responses. Additionally, corticosterone can influence the expression of certain cytokines, potentially having anti-inflammatory effects."
],
"contexts": [
[
"40. Roozendaal B, McEwen BS, Chattarji S. Stress, memory and theamygdala. Nat Rev Neurosci 10: 426 433, 2009. 41. Sala M, Perez J, Soloff P, Ucelli di Nemi S, Caverzasi E, Soares JC,Brambilla P. Stress and hippocampal abnormalities in psychiatric disorders. Eur Neuropsychopharmacol 14: 393405, 2004. 42. Shiba T, Kakuda S, Ishiguro M, Morita I, Oka S, Kawaski T,Wakatsuki S, Kato R. Crystal structure of GlcAT-S, a human glucuronyltransferase, involved in the biosynthesis of the HNK-1 carbohydrateepitope. Proteins 65: 499 508, 2006. 43.",
"Sci. 132.ter Heegde, F., De Rijk, R.H., Vinkers, C.H. , 2015. The brain mineralocorticoid receptorand stress resilience. Psychoneuroendocrinology 52, 92110. ter Horst, J.P., van der Mark, M.H. , Arp, M., Berger, S., de Kloet, E.R. , Oitzl, M.S. , 2012. Stress or no stress: mineralocorticoid receptors in the forebrain regulate behavioraladaptation. Neurobiol. Learn. Mem. 98, 3340. van Leeuwen, N., Bellingrath, S., de Kloet, E.R. , Zitman, F.G., DeRijk, R.H., Kudielka,B.M. , Wust, S., 2011. Human mineralocorticoid receptor (MR) gene haplotypesmodulate MR expression and transactivation: implication for the stress response. Psychoneuroendocrinology 36, 699709. Waterham, H.R.",
"Acute stress and dexamethasone rapidly increase hippocampal somatostatin synthesis and release fromthe dentate gyrus hilus. Hippocampus 11, 469477. Aubry, J.-M., Bartanusz, V., Jezova, D., Belin, D., Kiss, J.Z. , 1999. Single stress induceslong-lasting elevations in vasopressin mRNA levels in CRF hypophysiotrophic neurones, but repeated stress is required to modify AVP immunoreactivity. J.Neuroendocrinol. 11, 377384. Baker, J.A. , Li, J., Zhou, D., Yang, M., Cook, M.N. , Jones, B.C. , Mulligan, M.K. , Hamre,K.M. , Lu, L., 2017. Analyses of dierentially expressed genes after exposure to acutestress, acute ethanol, or a combination of both in mice.",
"Chronic unpredictable stress beforepregnancy reduce the expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor inhippocampus of offspring rats associated with impairment of memory. Neurochem Res 35, 1038-49. Konig, P., Dedio, J., Oess, S., Papadakis, T., Fischer, A., Muller-Esterl, W. and Kummer, W., 2005. NOSIP and itsTinteracting protein, eNOS, in the rat trachea and lung. J Histochem Cytochem 53, 155-64. Longo, A., Oberto, A., Mele, P., Mattiello, L., Pisu, M.G. , Palanza, P., Serra, M. and Eva, C., 2015. NPY-Y1IPcoexpressed with NPY-Y5 receptors modulate anxiety but not mild social stress response in mice.Gynecol Endocrinol 12,61-7. MASajdyk, T.J., Schober, D.A. and Gehlert, D.R. , 2002. Neuropeptide Y receptor subtypes in the basolateral nucleusof the amygdala modulate anxiogenic responses in rats. Neuropharmacology 43, 1165-72. Shan, T., Ma, J., Ma, Q., Guo, K., Guo, J., Li, X., Li, W., Liu, J., Huang, C., Wang, F. and Wu, E., 2013.beta2-AR-HIF-1alpha: a novel regulatory axis for stress-induced pancreatic tumor growth and angiogenesis. DCurr Mol Med 13, 1023-34. TEShen, Q., Wang, X., Chen, Y., Xu, L., Wang, X. and Lu, L., 2009.",
"CRH-expressing neurons located in the PVN of the hypothalamus play a pivotal role in orchestrating thecentral stress response. CRH stimulates the release of ACTH from the anterior pituitary gland. In turn, ACTH acts on the adrenal cortex to increase the production andrelease of GC hormones. Proper functioning of all of these neurons is essential formaintaining a homeostatic state following a stressful event. Several neuronal pathways modulate HPA axis activity. For example, the hippocampus and prefrontalcortex inhibit the HPA axis, and the amygdala and monoaminergic input from thebrainstem stimulate CRH production by PVN neurons.Norepinephrinergic activation leadsto afferent catecholaminergic signaling from the NTS and ventrolateral medulla tothe periventricular nucleus (PVN) [52], which in turn activates the hypothalamicpituitaryadrenal (HPA) axis. Thus, activation of stress response systems is initiated, which assists in directing mood and behavior. Blood-borne cytokines are also known to produce a central response by acting oncytokine receptors within the brain. However, given their size and hydrophilicnature, trafcking to the brain was once considered to be isolated to circumventricular organs. In 1983, Blatteis et al.They havedetermined that psychological stress results in decreased hippocampal neurogenesisalongside signicant increases in hippocampal IL-1b protein, depressive-likebehavior, and ACTH and corticosterone release [169, 170]. The importance of IL-1in producing these behavioral and HPA axis outcomes was conrmed both genetically using IL-1r knockout mice and pharmacologically using IL-1ra. In IL-1R1knockout mice stress-induced brain, behavioral and endocrine perturbationsobserved in the wild-type mice were all attenuated [169, 170]. More importantly,these perturbations were abolished if wild-type mice were adrenalectomized [170].Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105:751756118. Tanapat P, Hastings NB, Rydel TA, Galea LA, Gould E (2001) Exposure to fox odor inhibitscell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol 437:496504119. Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by uoxetine treatment. Neuropsychopharmacology 28:15621571120.RecentProg Horm Res 43:113173143. Rivier CL, Plotsky PM (1986) Mediation by corticotropin releasing factor (CRF) of adenohypophysial hormone secretion. Annu Rev Physiol 48:475494144. Jones MT, Gillham B (1988) Factors involved in the regulation of adrenocorticotropic hormone/beta-lipotropic hormone. Physiol Rev 68:743818145. Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids inuence stressresponses? Integrating permissive, suppressive, stimulatory, and preparative actions. EndocrRev 21:5589146. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balancein health and disease. Endocr Rev 19:269301147. McEwen BS, Stellar E (1993) Stress and the individual.The HPA axis mediates theneuroendocrine response to stressors, both systemic stressors that threaten homeostasis and/or survival and perceived threats or psychogenic stressors [141]. Inputs tothe HPA axis provided by stressors and the endogenous circadian rhythm [142] actthrough central neural pathways to the paraventricular nuclei (PVN) of the hypothalamus, where CRH is synthesized. CRH (potentiated by arginine vasopressin[AVP]) [143, 144] stimulates the release of adrenocorticotropin (ACTH) from theanterior pituitary, which in turn stimulates synthesis and secretion of glucocorticoids from the adrenal cortex.",
"(2007). Corticotropin releasing hormonereceptor alterations elicited byacute and chronic unpredictablestressor challenges in stressorsusceptible and resilient strainswww.frontiersin.orgof mice. Behav. Brain Res. 181,180190. Bartels, A., and Zeki, S. (2004). The neural correlates of maternaland romantic love. Neuroimage 21,11551166. Bennett, H. A., Einarson, A., Taddio, A., Koren, G., and Einarson, T. R. (2004). Prevalence ofdepression during pregnancy: systematic review. Obstet. Gynecol. 103,698709. Beuzen, A., and Belzung, C. (1995). Link between emotional memoryand anxiety states: a study by principal component analysis. Physiol. Behav. 58, 111118.",
"Yun SJ, Park HJ, Yeom MJ, Hahm DH, Lee HJ, et al. (2002) Effect ofelectroacupuncture on the stress-induced changes in brain-derived neurotrophicfactor expression in rat hippocampus. Neurosci Lett 318: 8588. 31. Bousios S, Karandrea D, Kittas C, Kitraki E (2001) Effects of gender and stresson the regulation of steroid receptor coactivator-1 expression in the rat brain andpituitary. J Steroid Biochem Mol Biol 78: 401407. 32. Thome J, Pesold B, Baader M, Hu M, Gewirtz JC, et al. (2001) Stressdifferentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol Psychiatry 50: 809812. 33.",
"Vyas A, Jadhav S, Chattarji S (2006) Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience 143:387393. Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, LeschKP, Murphy DL, Holmes A (2007) Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci 27:684 691. Wiedholz LM, Owens WA, Horton RE, Feyder M, Karlsson RM, Hefner K,Sprengel R, Celikel T, Daws LC, Holmes A (2008) Mice lacking the AMPAGluR1 receptor exhibit striatal hyperdopaminergia and schizophreniarelated behaviors. Mol Psychiatry 13:631 640.",
"Crhbp regulates the activity of CRH (corticotropin releasinghormone), a stress hormone in the HPA axis (Westphal andSeasholtz, 2006), and is upregulated following stress (McClennenet al. , 1998). The HPA axis has a complex relationship with learning and memory- transient activation results in enhancement oflearning and memory (de Kloet et al. , 1999), while persistent activation levels results in cognitive deficit (de Kloet et al. , 2005). Enoch et al. reported that dense whole genome linkage scan ofhippocampal activation assessed by EEG resulted in a linkagepeak containing crhbp (Enoch et al. , 2008).",
"First, the CRH or corticotrophin releasing factor(CRF) is the principal regulator of the stress response, whichhas receptor genes expressed in several organs including brainsand heart (here we used crhr1, which is the type 1 CRHreceptor). UCN I (urocortin I precursor), UCN II (urocortin Iprecursor, which is a stresscopin-related petide), and UCN III(stresscopin) were among the 10 genes. It has been shown thatthis gene group is a member of the CRH peptide family and isfound in many discrete brain regions and that it influencesfeeding, anxiety, and auditory processing behaviors (28).",
"It has beendemonstrated that stress and corticosterone release are important regulators of hippocampal 5-HT1A receptors [294], and thatprolonged corticosterone treatment alters the responsiveness of5-HT1A receptors to 8-OH-DPAT in rat CA1 hippocampal neurons [295]. Interestingly, changes in the hippocampally mediated5-HT1A receptor responses depend on whether stress or corticosterone predominantly activate the mineralocorticoid receptoror the glucocorticoid receptor [296]. Depression is characterized by a dysregulated response to stress, which may result inchanges in hippocampal 5-HT1A receptors in humans.",
"Herman JP & Cullinan WE Neurocircuitry of stress: central control of the hypothalamopituitaryadrenocortical axis. Trends in Neurosciences 20, 7884 (1997). [PubMed: 9023876]10. Barbazanges A, Piazza PV, Le Moal M & Maccari S Maternal glucocorticoid secretion mediateslong-term effects of prenatal stress. J. Neurosci 16, 39433949 (1996). [PubMed: 8656288]11. Montano MM, Wang MH, Even MD & vom Saal FS Serum corticosterone in fetal mice: sexdifferences, circadian changes, and effect of maternal stress. Physiol. Behav 50, 323329 (1991). [PubMed: 1745676]12.",
"He and othersconsidered that hormones released by stressful experiences couldenhance memory consolidation, indicating particularly the hormonesepinephrine and glucocorticoids as memory modulators (McGaugh &Roozendaal, 2009). It was suggested that several brain regions work insynergy to assure that emotionally significant experiences are wellremembered, and this could prepare the organism for future experiences by inducing long-term behavioral changes (Bahtiyar, Karaca,Henckens, & Roozendaal, 2020; McGaugh, 2013).",
"Keywords: stress, hippocampus, microarray, C57BL/6J, DBA/2J, C57BL/6NJINTRODUCTIONStress is a generic term used to describe physiological and behavioral responses to realor perceived challenges (Wang et al. , 2013). These responses are integrated over multiplesystems (e.g. , autonomic, behavioral, endocrine, and immune) with the hypothalamic-pituitaryadrenal (HPA) axis being a main pillar of the neuroendocrine response to stress. Ultimately,stimulation of the HPA axis results in glucocorticoid hormone [corticosterone (CORT) in miceand cortisol in humans] release."
],
[
"Cortisol has widespread effects on the body, but its major roleis to counteract the stress response and attempt to return the body to homeostasis. Once this is achieved, cortisol can negatively regulate its own production throughinhibitory feedback loops at the level of secretion of both CRH and ACTH. Thisbiochemical pathway is known as the hypothalamic-pituitary-adrenal (HPA) axis.",
"Gulf War and Health: Volume 10: Update of HealthEffects of Serving in the Gulf War, 2016. National Academies Press. O'Callaghan, J.P., Kelly, K.A. , Locker, A.R. , Miller, D.B. , Lasley, S.M. , 2015a. Corticosterone primes theneuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness. Journal ofneurochemistry 133, 708-721. O'Callaghan, J.P., Kelly, K.A. , Locker, A.R. , Miller, D.B. , Lasley, S.M. , 2015b. Corticosterone primes theneuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness. J Neurochem133, 708-721. O'Callaghan, J.P., Michalovicz, L.T. , Kelly, K.A. , 2016.",
"The glucocorticoids, cortisol in humans and corticosterone in most rodents, have numerous metabolic and physiological effects andprovide negative feedback to inhibit HPA activity at the level of the pituitary, PVN,hippocampus, prefrontal cortex, and other brain areas [142144]. Glucocorticoids,acting on their receptors (mineralocorticoid receptors, MR; glucocorticoid receptors, GR), initiate metabolic and physiological responses that facilitate response toand coping with the stressor and, ultimately, dampen stress-activated defense reactions, including immune responses, to prevent them from overshooting and themselves causing harm [145, 146].In the short term, the metabolic and physiologicalchanges induced by the glucocorticoids promote survival (increased gluconeogenesis and blood pressure, suppressed immune and reproductive function). However,prolonged exposure to glucocorticoids can result in metabolic, cognitive, andimmune dysfunction [147]. Thus, it is important that the HPA axis be tightlycontrolled through efcient feedback and efcient termination of the stress response;the ability to turn off the stress response is as important as the ability to respondinitially [145].[45, 54] or by injection of glucocorticoid synthesis inhibitors [58] enhances theexpression of IL-1 and other cytokines in brain as a result of stress exposure. Thesendings parallel earlier studies showing that ADX enhanced the plasma IL-6response evoked by exposure to a novel environment [78] and t with the canonicalviewpoint that glucocorticoids have powerful anti-inammatory properties. Whilewe do not wish to dispute this viewpoint, it is interesting to note that antiinammatory actions of CORT are most pronounced at high and supraphysiologicalconcentrations, whereas lower concentrations of CORT appear to have someimmune-potentiating effects (e.g. , [6]).As such, an immunological stressor, such as infection or a mimetic such asLPS which works to activate the HPA axis, will result in downstream glucocorticoidrelease. This secretion of glucocorticoids should, in turn, attenuate the originatinginammation. However, this is often not the case when studying for patients ofdepression showing enhanced immune activation, and hence, additional processesmust also be at play such as the proinammatory nature of cytokines and glucocorticoid resistance (discussed below). It is important to recognize that cytokine regulation of HPA axis function is complex and requires a multifaceted approach to studying such complexity.CORT, on the other hand, appears to negatively inuence the expression of IL-1 and other cytokines throughinteraction with glucocorticoid responsive elements (GREs) in the promoter region of cytokine genes. There are also reciprocal interactions between NE andCORT, whereby NE is a key driver in central regulation of the HPA axis (via a1-adrenergic receptors) and CORT tempers the release of NE.[45] also demonstrated the profound impact of endogenous CORT to inhibit brain cytokine responses evoked by stress, showing that boththe magnitude and spatial distribution of IL-1 changes provoked by stress wereaugmented in ADX rats. Since then, our lab and others have gone on to successfullyexamine cytokine expression using gross dissections and ELISA detection (e.g. ,[22, 5557]) or at the level of gene expression using RT-PCR [5861], whichtogether further support the view that stress challenges have the ability to drivecytokine changes in the uninjured brain.The HPA axis has been shown to regulate immune responses. The main hormones involved in the HPA axis are corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), andglucocorticoids (GC), which are also called stress hormones. These hormones contribute to the regulation of immune responses and can also affect neuronal survival,neurogenesis, synaptic plasticity, and behavioral responses [1, 2]. The HPA axis isa three-tiered biological system that begins at the highest level with the release ofCRH from the hypothalamic paraventricular nucleus (PVN).Whether these low-dose facilitation effectsrelate more directly to the timing of CORT injection relative to cytokine measurements, or represent differential tissue sensitivity to glucocorticoids, remains to bedetermined [79, 80]. Moreover, ambient levels of CORT taken during or immediately after stress exposure do not appear to be predictive of central IL-1 expression[63, 65]. Regardless, the point here is that the long-held assumption that glucocorticoids exert unilateral, anti-inammatory actions does not broadly account for theliterature writ large.During theresolution phase of disease, hormone levels did not differ among the three prenatalgroups, and if anything, corticosterone and ACTH levels were somewhat lower inPAE compared to control animals with clinical signs of arthritis. It has been suggested [227] that low levels of glucocorticoid hormones in the context of high levelsof inammation may reect a disconnect between the immune and endocrine systems. As noted above, we have evidence for such a disconnect in our previous work.As such, CORT can interfere with IL-1 gene expression (and expression of othercytokines) through numerous pathways. When taken together, a simple framework for understanding the interactionbetween the major stress-responsive systems (SNS and HPA axis) and inammatoryconsequences of stress is that neuroinammatory consequences of stress are mechanistically intertwined between the stimulatory actions of the SNS and the inhibitoryactions of CORT (see [84] for a review), though much work remains to be done inthis area. This concept is depicted in Fig.The HPA response is slower, and the secretion of the glucocorticoid hormones initiates numerous metabolic and behavioral effects that mediateeffective coping with a stressor in the longer term. The HPA and autonomic systemsappear to be regulated by similar neurotransmitters (e.g. , acetylcholine, serotonin,norepinephrine, GABA). In addition, there is reciprocal stimulation of HPA andautonomic activity by CRH and norepinephrine and reciprocal actions of the glucocorticoids and catecholamines. The glucocorticoids are thought to feed back torestrain activity of both systems. Further, the activity and sensitivity of both systemsare modulated by stress and circadian inuences [140].Regardless, the evidence todate suggests that NE release is a key driver of inammatory processes in at leastsome brain structures during times of stress. In contrast to the actions of NE, which appear to stimulate the expression of IL-1and other cytokines, CORT appears to constrain cytokine gene and protein expression during times of stress, at least in broad strokes. Indeed, there is a plethora ofstudies demonstrating that removal of endogenous glucocorticoids through ADX142T. Deak et al.With that said, there are a variety of cellular mechanisms by which glucocorticoids impact gene expression for cytokines during times of stress, particularly in thecase of IL-1 gene expression. Many of these effects are produced through interaction of the CORT-receptor complex with repressor sites in the promoter region ofthe IL-1 gene, including the nGRE repressor site and interference with nuclear factor k-light chain-enhancer of activated B cells (NFkB) signaling. In addition, CORThas been shown to block cAMP response element-binding (CREB) phosphorylation, prevent NFkB binding to the DNA, and destabilize mRNA for IL-1 [8183].Similarly,paradigms involving neonatal immune activation have demonstrated increased propensities to develop stress-related behaviors alongside hypersecretion of corticosterone, elevated hippocampal cytokines, and altered GR abundance in adulthood[184186]. Such animal studies have been useful in dissociating the relationshipbetween the actions of cytokines and the HPA axis in the brain to provide a moredirect account of how these factors may inuence behavior. Raz Yirmiyas laboratory has been particularly inuential in this regard, reporting brain IL-1b to beresponsible for depressive-like behavior in relation to stress physiology.",
"Corticosterone primes theneuroinflammatory response to DFP in mice: Potential animal model of Gulf War Illness. J. Neurochem. 2015,133, 708721. OCallaghan, J.P.; Miller, D.B. Neuroinflammation disorders exacerbated by environmental stressors. Metabolism 2019, 100, 153951. [CrossRef] [PubMed]Ashbrook, D.G. ; Arends, D.; Prins, P.; Mulligan, M.K. ; Roy, S.; Williams, E.G. ; Lutz, C.M. ; Valenzuela, A.;Bohl, C.J. ; Ingels, J.F. ; et al. The expanded BXD family of mice: A cohort for experimental systems geneticsand precision medicine. BioRxiv 2019. [CrossRef]Peirce, J.L. ; Lu, L.; Gu, J.; Silver, L.M. ; Williams, R.W.",
"For example, the measurement of plasma cortisol, the main glucocor-ticoid secreted by the interrenal tissue of theteleosts in response to stress and the most usedindication of a stress status, may not be sufcient to assess physiological conditions under chronic stress, in particular due to theacclimation of the interrenal gland and theinuence of negative feedback mechanismson the hypothalamuspituitaryinterrenal axis(Rotllant et al. , 2000).Otherworks have assessed the changes in gene expression by microarray using an in vitro approach with cultured cells treated with animmune stressor (LPS) and compared the transcriptomic response when adding cortisol. Theresults showed that cortisol is able to counteract the immune activation, but other responseswere taking place anyway, such as the recoveryof cell activity, increase of protein synthesis, andenergetic metabolism (Mackenzie et al. , 2006).",
"Pruett SB, Fan R, Myers LP, Wu WJ, Collier S. Quantitative analysis of the neuroendocrine-immune axis: linearmodeling of the effects of exogenous corticosterone and restraint stress on lymphocyte subpopulations in thespleen and thymus in female B6C3F1 mice. Brain Behav Immun 2000 Dec;14(4):270-287. 56. Pruett SB, Fan R. Quantitative modeling of suppression of IgG1, IgG2a, IL-2, and IL-4 responses to antigen inmice treated with exogenous corticosterone or restraint stress. J Toxicol Environ Health A 2001 Feb9;62(3):175-189. 57. Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation topharmacological actions."
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