Skip to main content

Advertisement

SpringerLink
Log in

Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Impaired social interaction is a key feature of several major psychiatric disorders including depression, autism, and schizophrenia. While, anatomically, the prefrontal cortex (PFC) is known as a key regulator of social behavior, little is known about the cellular mechanisms that underlie impairments of social interaction. One etiological mechanism implicated in the pathophysiology of the aforementioned psychiatric disorders is cellular stress and consequent adaptive responses in the endoplasmic reticulum (ER) that can result from a variety of environmental and physical factors. The ER is an organelle that serves essential roles in protein modification, folding, and maturation of proteins; however, the specific role of ER stress in altered social behavior is unknown. In this study, treatment with tunicamycin, an ER stress inducer, enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X-box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ERβ) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERβ specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in social behavior, and activation of IRE1/XBP1 pathway in mouse PFC. Moreover, ERB-041 inhibited tunicamycin-induced increases in functional connectivity between PFC and hippocampus in male mice. Together, these results show that ERβ agonist attenuates ER stress-induced deficits in social behavior through the IRE-1/XBP1 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Arlington

    Book  Google Scholar 

  2. Kundakovic M, Champagne FA (2015) Early-life experience, epigenetics, and the developing brain. Neuropsychopharmacology 40(1):141–153. https://doi.org/10.1038/npp.2014.140

    Article  PubMed  Google Scholar 

  3. Bicks LK, Koike H, Akbarian S, Morishita H (2015) Prefrontal cortex and social cognition in mouse and man. Front Psychol 6:1805

    Article  PubMed  PubMed Central  Google Scholar 

  4. Calabrese F, Riva MA, Molteni R (2016) Synaptic alterations associated with depression and schizophrenia: potential as a therapeutic target. Expert Opin Ther Targets 20(10):1195–1207. https://doi.org/10.1080/14728222.2016.1188080

    Article  PubMed  CAS  Google Scholar 

  5. Chen J, Yu S, Fu Y, Li X (2014) Synaptic proteins and receptors defects in autism spectrum disorders. Front Cell Neurosci 8:276

    PubMed  PubMed Central  Google Scholar 

  6. Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC, Jurjus GJ, Dieter L et al (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16(01):69–82. https://doi.org/10.1017/S1461145712000016

    Article  PubMed  CAS  Google Scholar 

  7. Dichter GS (2012) Functional magnetic resonance imaging of autism spectrum disorders. Dialogues Clin Neurosci 14(3):319–351

    PubMed  PubMed Central  Google Scholar 

  8. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, Berman KF (2005) Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 62(4):379–386. https://doi.org/10.1001/archpsyc.62.4.379

    Article  PubMed  Google Scholar 

  9. Marchand WR, Lee JN, Suchy Y, Johnson S, Thatcher J, Gale P (2012) Aberrant functional connectivity of cortico-basal ganglia circuits in major depression. Neurosci Lett 514(1):86–90. https://doi.org/10.1016/j.neulet.2012.02.063

    Article  PubMed  CAS  Google Scholar 

  10. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A et al (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17(3):400–406. https://doi.org/10.1038/nn.3641

    Article  PubMed  CAS  Google Scholar 

  11. Vetter-O'Hagen CS, Spear LP (2012) The effects of gonadectomy on sex- and age-typical responses to novelty and ethanol-induced social inhibition in adult male and female Sprague-Dawley rats. Behav Brain Res 227(1):224–232. https://doi.org/10.1016/j.bbr.2011.10.023

    Article  PubMed  CAS  Google Scholar 

  12. Crider A, Pillai A (2017) Estrogen signaling as a therapeutic target in neurodevelopmental disorders. J Pharmacol Exp Ther 360(1):48–58. https://doi.org/10.1124/jpet.116.237412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Crider A, Thakkar R, Ahmed AO, Pillai A (2014) Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects. Mol Autism 5(1):46. https://doi.org/10.1186/2040-2392-5-46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Wong J, Weickert CS (2009) Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia. J Biol Chem 284(28):18824–18832. https://doi.org/10.1074/jbc.M109.013243

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Choleris E, Ogawa S, Kavaliers M, Gustafsson JA, Korach KS, Muglia LJ, Pfaff DW (2006) Involvement of estrogen receptor alpha, beta and oxytocin in social discrimination: a detailed behavioral analysis with knockout female mice. Genes Brain Behav 5(7):528–539. https://doi.org/10.1111/j.1601-183X.2006.00203.x

    Article  PubMed  CAS  Google Scholar 

  16. Tang AC, Nakazawa M, Romeo RD, Reeb BC, Sisti H, McEwen BS (2005) Effects of long-term estrogen replacement on social investigation and social memory in ovariectomized C57BL/6 mice. Horm Behav 47(3):350–357. https://doi.org/10.1016/j.yhbeh.2004.10.010

    Article  PubMed  CAS  Google Scholar 

  17. Castillo K, Rojas-Rivera D, Lisbona F, Caballero B, Nassif M, Court FA, Schuck S, Ibar C et al (2011) BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response. EMBO J 30(21):4465–4478. https://doi.org/10.1038/emboj.2011.318

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Zhang K, Kaufman RJ (2004) Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 279(25):25935–25938. https://doi.org/10.1074/jbc.R400008200

    Article  PubMed  CAS  Google Scholar 

  19. Fujita E, Dai H, Tanabe Y, Zhiling Y, Yamagata T, Miyakawa T, Tanokura M, Momoi MY et al (2010) Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1. Cell Death Dis 1(6):e47. https://doi.org/10.1038/cddis.2010.23

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Schröder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569(1-2):29–63. https://doi.org/10.1016/j.mrfmmm.2004.06.056

    Article  PubMed  CAS  Google Scholar 

  21. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415(6867):92–96. https://doi.org/10.1038/415092a

    Article  PubMed  CAS  Google Scholar 

  22. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  23. Dey S, Baird TD, Zhou D, Palam LR, Spandau DF, Wek RC (2010) Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem 285(43):33165–33174. https://doi.org/10.1074/jbc.M110.167213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K (2000) ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol 20(18):6755–6767. https://doi.org/10.1128/MCB.20.18.6755-6767.2000

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Ai D, Baez JM, Jiang H, Conlon DM, Hernandez-Ono A, Frank-Kamenetsky M, Milstein S, Fitzgerald K et al (2012) Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice. J Clin Invest 122(5):1677–1687. https://doi.org/10.1172/JCI61248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13(3):385–392. https://doi.org/10.1038/sj.cdd.4401778

    Article  PubMed  CAS  Google Scholar 

  27. Momoi T, Fujita E, Senoo H, Momoi M (2010) Genetic factors and epigenetic factors for autism: endoplasmic reticulum stress and impaired synaptic function. Cell Biol Int 34:13–19

    CAS  Google Scholar 

  28. Timberlake MA 2nd, Dwivedi Y (2016) Altered expression of endoplasmic reticulum stress associated genes in hippocampus of learned helpless rats: relevance to depression pathophysiology. Front Pharmacol 6:319

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Rubio MD, Wood K, Haroutunian V, Meador-Woodruff JH (2013) Dysfunction of the ubiquitin proteasome and ubiquitin-like systems in schizophrenia. Neuropsychopharmacology 38(10):1910–1920. https://doi.org/10.1038/npp.2013.84

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Elbein AD (1987) Inhibitors of the biosynthesis and processing of N-linked oligosaccharide chains. Annu Rev Biochem 56(1):497–534. https://doi.org/10.1146/annurev.bi.56.070187.002433

    Article  PubMed  CAS  Google Scholar 

  31. Steele KE, Seth P, Catlin-Lebaron KM, Schoneboom BA, Husain MM, Grieder F et al (2006) Tunicamycin enhances neuroinvasion and encephalitis in mice infected with Venezuelan equine encephalitis virus. Vet Pathol 43(6):904–913. https://doi.org/10.1354/vp.43-6-904

    Article  PubMed  CAS  Google Scholar 

  32. Lee S, Shang Y, Redmond SA, Urisman A, Tang AA, Li KH, Burlingame AL, Pak RA et al (2016) Activation of HIPK2 promotes ER stress-mediated neurodegeneration in amyotrophic lateral sclerosis. Neuron 91(1):41–55. https://doi.org/10.1016/j.neuron.2016.05.021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jo F, Jo H, Hilzendeger AM, Thompson AP, Cassell MD, Rutkowski DT, Davisson RL, Grobe JL et al (2015) Brain endoplasmic reticulum stress mechanistically distinguishes the saline-intake and hypertensive response to deoxycorticosterone acetate-salt. Hypertension 65(6):1341–1348. https://doi.org/10.1161/HYPERTENSIONAHA.115.05377

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Walf AA, Rhodes ME, Frye CA (2006) Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats. Neurobiol Learn Mem 86(1):35–46. https://doi.org/10.1016/j.nlm.2006.01.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Frye CA, Duffy CK, Walf AA (2007) Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task. Neurobiol Learn Mem 88(2):208–216. https://doi.org/10.1016/j.nlm.2007.04.003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Pisani SL, Neese SL, Katzenellenbogen JA, Schantz SL, Korol DL (2016) Estrogen receptor-selective agonists modulate learning in female rats in a dose- and task-specific manner. Endocrinology 157(1):292–303. https://doi.org/10.1210/en.2015-1616

    Article  PubMed  CAS  Google Scholar 

  37. Pandya CD, Hoda N, Crider A, Peter D, Kutiyanawalla A, Kumar S, et al (2017) Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice. Mol Psychiatry 22(5):745–753

  38. Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, Saudek V, Gaston JSH (2010) Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci U S A 107(41):17698–17703. https://doi.org/10.1073/pnas.1011736107

    Article  PubMed  PubMed Central  Google Scholar 

  39. Etherton MR, Tabuchi K, Sharma M, Ko J, Südhof TC (2011) An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J 30:2908–2919

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Mitsuda T, Omi T, Tanimukai H, Sakagami Y, Tagami S, Okochi M, Kudo T, Takeda M (2011) Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress. Biochem Biophys Res Commun 415(3):519–525. https://doi.org/10.1016/j.bbrc.2011.10.113

    Article  PubMed  CAS  Google Scholar 

  41. Hwang HJ, Jung TW, Ryu JY, Hong HC, Choi HY, Seo JA, Kim SG, Kim NH et al (2014) Dipeptidyl petidase-IV inhibitor (gemigliptin) inhibits tunicamycin-induced endoplasmic reticulum stress, apoptosis and inflammation in H9c2 cardiomyocytes. Mol Cell Endocrinol 392(1-2):1–7. https://doi.org/10.1016/j.mce.2014.04.017

    Article  PubMed  CAS  Google Scholar 

  42. Quan X, Wang J, Liang C, Zheng H, Zhang L (2015) Melatonin inhibits tunicamycin-induced endoplasmic reticulum stress and insulin resistance in skeletal muscle cells. Biochem Biophys Res Commun 463:1102–1107

    Article  PubMed  CAS  Google Scholar 

  43. Skropeta D (2009) The effect of individual N-glycans on enzyme activity. Bioorg Med Chem 17(7):2645–2653. https://doi.org/10.1016/j.bmc.2009.02.037

    Article  PubMed  CAS  Google Scholar 

  44. Dennis JW, Lau KS, Demetriou M, Nabi IR (2009) Adaptive regulation at the cell surface by N-glycosylation. Traffic 10(11):1569–1578. https://doi.org/10.1111/j.1600-0854.2009.00981.x

    Article  PubMed  CAS  Google Scholar 

  45. Bodo C, Rissman EF (2006) New roles for estrogen receptor beta in behavior and neuroendocrinology. Front Neuroendocrinol 27(2):217–232. https://doi.org/10.1016/j.yfrne.2006.02.004

    Article  PubMed  CAS  Google Scholar 

  46. Rocha BA, Fleischer R, Schaeffer JM, Rohrer SP, Hickey GJ (2005) 17 Beta-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-beta knockout (BERKO) mice. Psychopharmacology 179(3):637–643. https://doi.org/10.1007/s00213-004-2078-1

    Article  PubMed  CAS  Google Scholar 

  47. Walf AA, Frye CA (2007) Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats. Pharmacol Biochem Behav 86(2):407–414. https://doi.org/10.1016/j.pbb.2006.07.003

    Article  PubMed  CAS  Google Scholar 

  48. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2(6):326–332. https://doi.org/10.1038/35014014

    Article  PubMed  CAS  Google Scholar 

  49. Guo YS, Sun Z, Ma J, Cui W, Gao B, Zhang HY, Han YH, Hu HM et al (2014) 17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts. Lab Investig 94(8):906–916. https://doi.org/10.1038/labinvest.2014.63

    Article  PubMed  CAS  Google Scholar 

  50. Grice SJ, Spratling MW, Karmiloff-Smith A, Halit H, Csibra G, de Haan M, Johnson MH (2001) Disordered visual processing and oscillatory brain activity in autism and Williams syndrome. Neuroreport 12(12):2697–2700. https://doi.org/10.1097/00001756-200108280-00021

    Article  PubMed  CAS  Google Scholar 

  51. Gandal MJ, Edgar JC, Ehrlichman RS, Mehta M, Roberts TP, Siegel SJ (2010) Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry 68(12):1100–1106. https://doi.org/10.1016/j.biopsych.2010.09.031

    Article  PubMed  PubMed Central  Google Scholar 

  52. McNally JM, McCarley RW (2016) Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities. Curr Opin Psychiatry 29(3):202–210. https://doi.org/10.1097/YCO.0000000000000244

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ye AX, Leung RC, Schäfer CB, Taylor MJ, Doesburg SM (2014) Atypical resting synchrony in autism spectrum disorder. Hum Brain Mapp 35(12):6049–6066. https://doi.org/10.1002/hbm.22604

    Article  PubMed  Google Scholar 

  54. Anticevic A, Hu X, Xiao Y, Hu J, Li F, Bi F, Cole MW, Savic A et al (2015) Early-course unmedicated schizophrenia patients exhibit elevated prefrontal connectivity associated with longitudinal change. J Neurosci 35(1):267–286. https://doi.org/10.1523/JNEUROSCI.2310-14.2015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Delmonte S, Gallagher L, O’Hanlon E, McGrath J, Balsters JH (2013) Functional and structural connectivity of frontostriatal circuitry in autism spectrum disorder. Front Hum Neurosci 7:430

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ et al (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477(7363):171–178. https://doi.org/10.1038/nature10360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287(5453):664–666. https://doi.org/10.1126/science.287.5453.664

    Article  PubMed  CAS  Google Scholar 

  58. Win S, Than TA, Fernandez-Checa JC, Kaplowitz N (2014) JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis 5(1):e989. https://doi.org/10.1038/cddis.2013.522

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN (2013) The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153(2):348–361. https://doi.org/10.1016/j.cell.2013.02.054

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Nilsen J, Brinton RD (2004) Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord 3(4):297–313. https://doi.org/10.2174/1568007043337193

    Article  PubMed  CAS  Google Scholar 

  61. Irwin RW, Yao J, To J, Hamilton RT, Cadenas E, Brinton RD (2012) Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function. J Neuroendocrinol 24(1):236–248. https://doi.org/10.1111/j.1365-2826.2011.02251.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Oslowski CM, Hara T, O'Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ et al (2012) Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab 16(2):265–273. https://doi.org/10.1016/j.cmet.2012.07.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Kim SY (2006) Transglutaminase 2 in inflammation. Front Biosci 11(1):3026–3035. https://doi.org/10.2741/2030

    Article  PubMed  CAS  Google Scholar 

  64. Lélu K, Laffont S, Delpy L, Paulet PE, Périnat T, Tschanz SA et al (2011) Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J Immunol 187(5):2386–2393. https://doi.org/10.4049/jimmunol.1101578

    Article  PubMed  Google Scholar 

  65. Spence RD, Wisdom AJ, Cao Y, Hill HM, Mongerson CR, Stapornkul B et al (2013) Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERβ signaling on astrocytes or neurons. J Neurosci 33(26):10924–10933. https://doi.org/10.1523/JNEUROSCI.0886-13.2013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Saijo K, Collier JG, Li AC, Katzenellenbogen JA, Glass CK (2011) An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145(4):584–595. https://doi.org/10.1016/j.cell.2011.03.050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

We acknowledge the funding support from US National Institute of Mental Health (MH 097060) to A.P. The funding agencies had no involvement in the research other than financial support.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, 997 St. Sebastian Way, Augusta, GA, 30912, USA

    Amanda Crider, Tyler Nelson, Talisha Davis, Kiley Fagan, Matthew Luo, Sunay Kamalasanan & Anilkumar Pillai

  2. Department of Neurosurgery, and Department of Medical Laboratory Imaging and Radiologic Sciences (MLLIRS-CAHS), Augusta University, Augusta, GA, 30912, USA

    Kumar Vaibhav

  3. Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, 30912, USA

    Alvin V. Terry Jr

Authors
  1. Amanda Crider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tyler Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Talisha Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kiley Fagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kumar Vaibhav
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthew Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sunay Kamalasanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alvin V. Terry Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anilkumar Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anilkumar Pillai.

Ethics declarations

All experiments were in compliance with the US National Institute of Health guidelines and approved by Augusta University animal welfare guidelines.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Electronic Supplementary Material

Figure S1

IRE1 in hippocampus does not mediate tunicamycin-induced deficits in social behavior in mice. Control or IRE1 shRNA lentiviral particles were stereotaxically administered into mouse hippocampus, and tunicamycin (1 mg/kg; i,.p) was administered 2 weeks following shRNA administration. Social behavior was examined at 12 h after tunicamycin treatment. IRE1 shRNA administration failed to attenuate tunicamycin-induced deficits in social behavior. A) The three-chamber social interaction test. Left, time in chamber. ***p < 0.001 vs. stranger mouse chamber. Two-way ANOVA. Right, the discrimination index calculated as the difference in the time spent in the social and non-social chambers, divided by the sum of the time spent in both chambers. *p < 0.05 vs. con shRNA group; One-way ANOVA. B) Reciprocal social interaction test. *p < 0.05 vs. con shRNA group; One-way ANOVA. Data are expressed as mean ±s.e.m. (n = 4 per group). M, chamber housing stranger mouse; E, chamber housing an empty cage; C, center. ns, non-significant. (GIF 192 kb)

High resolution image (TIFF 46 kb)

Figure S2

IRE1 shRNA in PFC does not attenuate tunicamycin-induced decrease in ERβ protein levels. Control or IRE1 shRNA lentiviral particles were stereotaxically administered into mouse prefrontal cortex (PFC), and tunicamycin (1 mg/kg; i.p) was administered 2 weeks following shRNA administration. ERβ protein levels were determined in mouse PFC 12 h after tunicamycin injection. Top. Representative blot. Bottom. Quantification of ERβ protein. Protein levels were measured by western blot analysis and normalized to tubulin. Data are expressed as mean ±s.e.m. *p < 0.05 vs. con shRNA group; One-way ANOVA. (GIF 125 kb)

High resolution image (TIFF 31 kb)

Table S1

(XLSX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Crider, A., Nelson, T., Davis, T. et al. Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice. Mol Neurobiol 55, 7606–7618 (2018). https://doi.org/10.1007/s12035-018-0929-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-0929-8

Keywords

Search

Navigation