CoChat
Sign Up
Cited by 72Stress Responses and CortisolMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

Glucocorticoid receptor signaling in astrocytes is required for aversive memory formation

Open access
Tertil, Magdalena, Skupio, Urszula, Barut, Justyna, Dubovyk, Valentyna, Wawrzczak-Bargiela, Agnieszka, Soltys, Zbigniew, Golda, Slawomir, Kudla, Lucja +5 more·2018·Translational Psychiatry
DOI 10.1038/s41398-018-0300-xPMC PMC6261947
Open this paper in CoChat — free accountOpen PDF

Abstract

Stress elicits the release of glucocorticoids (GCs) that regulate energy metabolism and play a role in emotional memory. Astrocytes express glucocorticoid receptors (GR), but their contribution to cognitive effects of GC's action in the brain is unknown. To address this question, we studied how astrocyte-specific elimination of GR affects animal behavior known to be regulated by stress. Mice with astrocyte-specific ablation of GR presented impaired aversive memory expression in two different paradigms of Pavlovian learning: contextual fear conditioning and conditioned place aversion. These mice also displayed compromised regulation of genes encoding key elements of the glucose metabolism pathway upon GR stimulation. In particular, we identified that the glial, but not the neuronal isoform of a crucial stress-response molecule, Sgk1, undergoes GR-dependent regulation in vivo and demonstrated the involvement of SGK1 in regulation of glucose uptake in astrocytes. Together, our results reveal astrocytes as a central element in GC-dependent formation of aversive memory and suggest their relevance for stress-induced alteration of brain glucose metabolism. Consequently, astrocytes should be considered as a cellular target of therapies of stress-induced brain diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41398-018-0300-x

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Astrocytes play a signaling hub in stress-induced changes in brain glucose metabolism, with SGK1 being a factor in formation of aversive memories.

    “It’s noteworthy that astrocytes play a signaling hub in stress-induced changes in brain glucose metabolism, with SGK1 being a factor in formation of aversive memories”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Tertil et al., 2018

    The Abstract and Results identify astrocytes as important for glucocorticoid-dependent aversive memory and show that SGK1 regulates glucose uptake in astrocytes. The Discussion proposes that this pathway may affect stress-induced memory formation, but does not establish SGK1 itself as a factor in aversive memory formation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • SGK1 is present in microglia, oligodendrocytes, and astrocytes.

    “Currently, reports indicate that SGK1 is present in microglia (Inoue et al., 2016b), oligodendrocytes (Hinds et al., 2017), and astrocytes (Tertil et al., 2018).”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Tertil et al., 2018

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 49

  1. [1]de Kloet ER Joels M Holsboer F Stress and the brain: from adaptation to disease Nat. Rev. Neurosci. 2005 6 463 475 10.1038/nrn1683 15891777 · DOI · Paper page
  2. [2]de Quervain D Schwabe L Roozendaal B Stress, glucocorticoids and memory: implications for treating fear-related disorders Nat. Rev. Neurosci. 2017 18 7 19 10.1038/nrn.2016.155 27881856 · DOI · Paper page
  3. [4]Joëls M Baram TZ The neuro-symphony of stress Nat. Rev. Neurosci. 2009 10 459 466 10.1038/nrn2632 19339973 PMC2844123 · DOI · Paper page
  4. [5]McEwen BS Mechanisms of stress in the brain Nat. Neurosci. 2015 18 1353 1363 10.1038/nn.4086 26404710 PMC4933289 · DOI · Paper page
  5. [7]Boyle MP Kolber BJ Vogt SK Wozniak DF Muglia LJ Forebrain glucocorticoid receptors modulate anxiety-associated locomotor activation and adrenal responsiveness J. Neurosci. 2006 26 1971 1978 10.1523/JNEUROSCI.2173-05.2006 16481429 PMC6674945 · DOI
  6. [8]Tronche F Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety Nat. Gen. 1999 23 99 103 10.1038/12703 10471508 · DOI
  7. [9]Wei Q Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability Proc. Natl. Acad. Sci. USA 2004 101 11851 11856 10.1073/pnas.0402208101 15280545 PMC511063 · DOI
  8. [10]Joëls M Sarabdjitsingh RA Karst H Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes Pharmacol. Rev. 2012 64 901 938 10.1124/pr.112.005892 23023031 · DOI
  9. [11]Mongrain V Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis Sleep 2010 33 1147 1157 10.1093/sleep/33.9.1147 20857860 PMC2938796 · DOI
  10. [13]van Rossum EF Polymorphisms of the glucocorticoid receptor gene and major depression Biol. Psychiatry 2006 59 681 688 10.1016/j.biopsych.2006.02.007 16580345 · DOI
  11. [14]Carrillo-Roa T Common genes associated with antidepressant response in mouse and man identify key role of glucocorticoid receptor sensitivity PLoS Biol. 2017 15 e2002690 10.1371/journal.pbio.2002690 29283992 PMC5746203 · DOI
  12. [16]Fitzsimons CP Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior Mol. Psychiatry 2013 18 993 1005 10.1038/mp.2012.123 22925833 · DOI
  13. [17]Hartmann J Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor Mol. Psychiatry 2017 22 466 475 10.1038/mp.2016.87 27240530 · DOI
  14. [18]Kolber BJ Central amygdala glucocorticoid receptor action promotes fear-associated CRH activation and conditioning Proc. Natl. Acad. Sci. USA 2008 105 12004 12009 10.1073/pnas.0803216105 18695245 PMC2575312 · DOI
  15. [19]Korostynski M Novel drug-regulated transcriptional networks in brain reveal pharmacological properties of psychotropic drugs BMC Genom. 2013 14 606 10.1186/1471-2164-14-606 PMC3844597 24010892 · DOI
  16. [20]Allaman I Pellerin L Magistretti PJ Glucocorticoids modulate neurotransmitter-induced glycogen metabolism in cultured cortical astrocytes J. Neurochem. 2004 88 900 908 10.1046/j.1471-4159.2003.02235.x 14756811 · DOI
  17. [21]Carter BS Meng F Thompson RC Glucocorticoid treatment of astrocytes results in temporally dynamic transcriptome regulation and astrocyte-enriched mRNA changes in vitro Physiol. Genom. 2012 44 1188 1200 10.1152/physiolgenomics.00097.2012 PMC3544487 23110767 · DOI
  18. [23]Piechota M Transcriptional signatures of steroid hormones in the striatal neurons and astrocytes BMC Neurosci 2017 18 37 10.1186/s12868-017-0352-5 28381250 PMC5381047 · DOI
  19. [24]Simard M Glucocorticoids-potent modulators of astrocytic calcium signaling Glia 1999 28 1 12 10.1002/(SICI)1098-1136(199910)28:1<1::AID-GLIA1>3.0.CO;2-4 10498817 · DOI
  20. [25]Zschocke J Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions J. Biol. Chem. 2005 280 34924 34932 10.1074/jbc.M502581200 16079146 · DOI
  21. [26]Slezak M Astrocytes are a neural target of morphine action via glucocorticoid receptor-dependent signaling Glia 2013 61 623 635 10.1002/glia.22460 23339081 · DOI
  22. [27]Carter BS Hamilton DE Thompson RC Acute and chronic glucocorticoid treatments regulate astrocyte-enriched mRNAs in multiple brain regions in vivo Front. Neurosci. 2013 7 139 23966905 PMC3736049
  23. [28]Alberini CM Cruz E Descalzi G Bessieres B Gao V Astrocyte glycogen and lactate: new insights into learning and memory mechanisms Glia 2018 66 1244 1262 10.1002/glia.23250 29076603 PMC5903986 · DOI
  24. [29]Jouroukhin Y DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders Transl. Psychiatry 2018 8 76 10.1038/s41398-018-0123-9 29643356 PMC5895599 · DOI
  25. [30]Dienel GA The metabolic trinity, glucose-glycogen-lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression Neurosci. Lett. 2017 637 18 25 10.1016/j.neulet.2015.02.052 25725168 · DOI
  26. [32]Yuen EY Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory Mol. Psychiatry 2010 16 156 170 10.1038/mp.2010.50 20458323 PMC3108461 · DOI · Paper page
  27. [34]Deroche-Gamonet V The glucocorticoid receptor as a potential target to reduce cocaine abuse J. Neurosci. 2003 23 4785 4790 10.1523/JNEUROSCI.23-11-04785.2003 12805318 PMC6740779 · DOI
  28. [35]Garcia-Perez D Different contribution of glucocorticoids in the basolateral amygdala to the formation and expression of opiate withdrawal-associated memories Psychoneuroendocrinology 2016 74 350 362 10.1016/j.psyneuen.2016.09.020 27728875 · DOI
  29. [36]Slezak M Transgenic mice for conditional gene manipulation in astroglial cells Glia 2007 55 1565 1576 10.1002/glia.20570 17823970 · DOI
  30. [37]Saab AS Bergmann glial AMPA receptors are required for fine motor coordination Science 2012 337 749 753 10.1126/science.1221140 22767895 · DOI
  31. [38]Szklarczyk K Endogenous opioids regulate glucocorticoid-dependent stress-coping strategies in mice Neuroscience 2016 330 121 137 10.1016/j.neuroscience.2016.05.034 27235740 · DOI
  32. [39]Schindelin J Fiji: an open-source platform for biological-image analysis Nat. Meth. 2012 9 676 682 10.1038/nmeth.2019 PMC3855844 22743772 · DOI · Paper page
  33. [40]Arteaga MF Alvarez de la Rosa D Alvarez JA Canessa CM Multiple translational isoforms give functional specificity to serum- and glucocorticoid-induced kinase 1 Mol. Biol. Cell 2007 18 2072 2080 10.1091/mbc.e06-10-0968 17377066 PMC1877090 · DOI · Paper page
  34. [42]Wiltgen BJ Context fear learning in the absence of the hippocampus J. Neurosci. 2006 26 5484 5491 10.1523/JNEUROSCI.2685-05.2006 16707800 PMC6675287 · DOI
  35. [43]Donley MP Schulkin J Rosen JB Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear Behav. Brain Res. 2005 164 197 205 10.1016/j.bbr.2005.06.020 16107281 · DOI
  36. [44]Ambroggi F Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking Nat. Neurosci. 2009 12 247 249 10.1038/nn.2282 19234455 · DOI
  37. [45]Johansen Joshua P Cain Christopher K Ostroff Linnaea E LeDoux Joseph E Molecular mechanisms of fear learning and memory Cell 2011 147 509 524 10.1016/j.cell.2011.10.009 22036561 PMC3215943 · DOI · Paper page
  38. [48]Allen NJ Eroglu C Cell biology of astrocyte-synapse interactions Neuron 2017 96 697 708 10.1016/j.neuron.2017.09.056 29096081 PMC5687890 · DOI
  39. [49]Koyanagi S Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia Nat. Commun. 2016 7 13102 13102 10.1038/ncomms13102 27739425 PMC5067584 · DOI
  40. [50]Tian G Translational control of glial glutamate transporter EAAT2 expression J. Biol. Chem. 2007 282 1727 1737 10.1074/jbc.M609822200 17138558 · DOI
  41. [51]Pannasch U Connexin 30 sets synaptic strength by controlling astroglial synapse invasion Nat. Neurosci. 2014 17 549 558 10.1038/nn.3662 24584052 · DOI
  42. [52]Gao V Astrocytic beta2-adrenergic receptors mediate hippocampal long-term memory consolidation Proc. Natl. Acad. Sci. USA 2016 113 8526 8531 10.1073/pnas.1605063113 27402767 PMC4968707 · DOI · Paper page
  43. [53]Krugers HJ Karst H Joels M Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance Front. Cell. Neurosci. 2012 6 15 10.3389/fncel.2012.00015 22509154 PMC3321636 · DOI
  44. [54]Simon P Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription Cell. Physiol. Biochem. 2007 20 715 728 10.1159/000110432 17982254 · DOI
  45. [55]Hinds LR Dynamic glucocorticoid-dependent regulation of Sgk1 expression in oligodendrocytes of adult male rat brain by acute stress and time of day PLoS ONE 2017 12 1 17 10.1371/journal.pone.0175075 PMC5380358 28376115 · DOI · Paper page
  46. [56]Miyata S Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum PLoS ONE 2011 6 e19859 10.1371/journal.pone.0019859 21655274 PMC3104997 · DOI
  47. [58]Lovallo WR Robinson JL Glahn DC Fox PT Acute effects of hydrocortisone on the human brain: an fMRI study Psychoneuroendocrinology 2010 35 15 20 10.1016/j.psyneuen.2009.09.010 19836143 PMC2795004 · DOI
  48. [59]Osborne DM Pearson-Leary J McNay EC The neuroenergetics of stress hormones in the hippocampus and implications for memory Front. Neurosci. 2015 9 164 10.3389/fnins.2015.00164 25999811 PMC4422005 · DOI
  49. [60]Maatouk et al. Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity. Cell Death & Differentiation. (2018). 10.1038/s41418-018-0150-3. PMC6370798 30006609 · DOI

Cited by

Sorted by citations

Authors
Tertil, M., Skupio, U., Barut, J., Dubovyk, V., Wawrzczak-Bargiela, A., Soltys, Z., Golda, S., Kudla, L., Wiktorowska, L., Szklarczyk, K., Korostynski, M., Przewlocki, R., & Slezak, M.
Affiliations
  • Maj Institute of Pharmacology (PL)
  • BioMed X (DE)
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-11-28
Volume
8
Issue
1
Pages
255-255
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-018-0300-x
PMC
PMC6261947
OpenAlex
W2903122394
Cited by
72
References
11
Citations by year
2026: 5 · 2025: 15 · 2024: 11 · 2023: 8 · 2022: 10 · 2021: 13 · 2020: 6 · 2019: 4
FWCI
3.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Narodowe Centrum Nauki (OPUS, 2011/03/B/NZ3/01683, MAESTRO, 013/08/A/NZ3/00848)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
glucocorticoid receptor, astrocytes, aversive memory, stress, contextual fear conditioning, conditioned place aversion, Pavlovian learning, glucose metabolism, SGK1, glucose uptake
MeSH terms
Serum-Glucocorticoid Regulated Kinases, Animals, Astrocytes, Behavior, Animal, Conditioning, Classical, Fear, Male, Memory, Mice, Transgenic, Receptors, Glucocorticoid, Stress, Psychological, Signal Transduction, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Mice, Nociception

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review