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

  • Amanda Crider
  • Tyler Nelson
  • Talisha Davis
  • Kiley Fagan
  • Kumar Vaibhav
  • Matthew Luo
  • Sunay Kamalasanan
  • Alvin V. TerryJr
  • Anilkumar Pillai


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.


ER stress Social behavior Estrogen IRE1 Connectivity 



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.

Compliance with Ethical Standards

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.

Supplementary material

12035_2018_929_Fig7_ESM.gif (192 kb)
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)

12035_2018_929_MOESM1_ESM.tif (46 kb)
High resolution image (TIFF 46 kb)
12035_2018_929_Fig8_ESM.gif (125 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)

12035_2018_929_MOESM2_ESM.tif (31 kb)
High resolution image (TIFF 31 kb)
12035_2018_929_MOESM3_ESM.xlsx (31 kb)
Table S1 (XLSX 30 kb)


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Authors and Affiliations

  1. 1.Department of Psychiatry and Health Behavior, Medical College of GeorgiaAugusta UniversityAugustaUSA
  2. 2.Department of Neurosurgery, and Department of Medical Laboratory Imaging and Radiologic Sciences (MLLIRS-CAHS)Augusta UniversityAugustaUSA
  3. 3.Department of Pharmacology and ToxicologyAugusta UniversityAugustaUSA

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