Abstract
Chronic psychosocial isolation (CPSI) is known to cause several maladaptive changes in the limbic brain structures, which regulate the hypothalamic–pituitary–adrenal (HPA) axis activity. In this study, we focused our investigation on CPSI effects in the hypothalamus (HT) since it is a major driver of HPA axis activity. We also investigated whether the exposure to CPSI could alter the response to subsequent acute stress (30-min immobilization). In the HT, we followed cytosolic and nuclear levels of the glucocorticoid receptor (GR), as a mediator of HPA axis feedback inhibition, and its chaperones, the heat shock proteins (HSPs), hsp70 and hsp90. The CPSI did not cause any changes in either GR or HSPs levels. However, we observed increase of the GR and hsp70 in both HT cellular compartments as a response of naïve rats to acute stress, whereas the response of CPSI rats to acute stress was associated with elevation of the GR in the cytosol and decrease of HSPs in the nucleus. Thus, our data indicated reduced availability of HSPs to GR in both cytosol and nucleus of the HT under acute stress of CPSI animals, and therefore, pointed out to potentially negative effects of CPSI on GR function in the HT.
Similar content being viewed by others
References
Adzic M, Djordjevic J, Djordjevic A, Niciforovic A, Demonacos C, Radojcic M, Krstic-Demonacos M (2009) Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain. J Endocrinol 202(1):87–97
Aronsson M, Fuxe K, Dong Y, Agnati LF, Okret S, Gustafsson JA (1988) Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization. Proc Natl Acad Sci USA 85(23):9331–9335
Bhatnagar S, Dallman M (1998) Neuroanatomical basis for facilitation of hypothalamic–pituitary–adrenal responses to a novel stressor after chronic stress. Neuroscience 84(4):1025–1039
Bhatnagar S, Vining C (2003) Facilitation of hypothalamic–pituitary–adrenal responses to novel stress following repeated social stress using the resident/intruder paradigm. Horm Behav 43(1):158–165
Cadepond F, Schweizer-Groyer G, Segard-Maurel I, Jibard N, Hollenberg SM, Giguere V, Evans RM, Baulieu EE (1991) Heat shock protein 90 as a critical factor in maintaining glucocorticosteroid receptor in a nonfunctional state. J Biol Chem 266(9):5834–5841
Chen S, Smith DF (1998) Hop as an adaptor in the heat shock protein 70 (Hsp70) and hsp90 chaperone machinery. J Biol Chem 273(52):35194–35200
de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6(6):463–475
DeFranco DB (2000) Role of molecular chaperones in subnuclear trafficking of glucocorticoid receptors. Kidney Int 57(4):1241–1249
Djordjevic A, Adzic M, Djordjevic J, Radojcic MB (2009) Stress type dependence of expression and cytoplasmic-nuclear partitioning of glucocorticoid receptor, hsp90 and hsp70 in Wistar rat brain. Neuropsychobiology 59(4):213–221
Elbi C, Walker DA, Romero G, Sullivan WP, Toft DO, Hager GL, DeFranco DB (2004) Molecular chaperones function as steroid receptor nuclear mobility factors. Proc Natl Acad Sci USA 101(9):2876–2881
Figueiredo HF, Bodie BL, Tauchi M, Dolgas CM, Herman JP (2003) Stress integration after acute and chronic predator stress: differential activation of central stress circuitry and sensitization of the hypothalamo-pituitary-adrenocortical axis. Endocrinology 144(12):5249–5258
Ford GK, Al-Barazanji KA, Wilson S, Jones DN, Harbuz MS, Jessop DS (2005) Orexin expression and function: glucocorticoid manipulation, stress, and feeding studies. Endocrinology 146(9):3724–3731
Furay AR, Murphy EK, Mattson MP, Guo Z, Herman JP (2006) Region-specific regulation of glucocorticoid receptor/HSP90 expression and interaction in brain. J Neurochem 98(4):1176–1184
Galigniana MD, Harrell JM, Murphy PJ, Chinkers M, Radanyi C, Renoir JM, Zhang M, Pratt WB (2002) Binding of hsp90-associated immunophilins to cytoplasmic dynein: direct binding and in vivo evidence that the peptidylprolyl isomerase domain is a dynein interaction domain. Biochemistry 41(46):13602–13610
Garcia A, Marti O, Valles A, Dal-Zotto S, Armario A (2000) Recovery of the hypothalamic–pituitary–adrenal response to stress. Effect of stress intensity, stress duration and previous stress exposure. Neuroendocrinology 72(2):114–125
Grad I, Picard D (2007) The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol 275(1–2):2–12
Grippo AJ, Gerena D, Huang J, Kumar N, Shah M, Ughreja R, Carter CS (2007) Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles. Psychoneuroendocrinology 32(8–10):966–980
Hall FS (1998) Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences. Crit Rev Neurobiol 12(1–2):129–162
Heinrich LM, Gullone E (2006) The clinical significance of loneliness: a literature review. Clin Psychol Rev 26(6):695–718
Kang KI, Meng X, Devin-Leclerc J, Bouhouche I, Chadli A, Cadepond F, Baulieu EE, Catelli MG (1999) The molecular chaperone Hsp90 can negatively regulate the activity of a glucocorticosteroid-dependent promoter. Proc Natl Acad Sci USA 96(4):1439–1444
Kregel KC (2002) Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 92(5):2177–2186
Kultz D (2005) Molecular and evolutionary basis of the cellular stress response. Annu Rev Physiol 67:225–257
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685
Lam CK, Chari M, Lam TK (2009) CNS regulation of glucose homeostasis. Physiology (Bethesda) 24:159–170
Liu J, DeFranco DB (1999) Chromatin recycling of glucocorticoid receptors: implications for multiple roles of heat shock protein 90. Mol Endocrinol 13(3):355–365
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275
Morimoto M, Morita N, Ozawa H, Yokoyama K, Kawata M (1996) Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study. Neurosci Res 26(3):235–269
Murphy EK, Spencer RL, Sipe KJ, Herman JP (2002) Decrements in nuclear glucocorticoid receptor (GR) protein levels and DNA binding in aged rat hippocampus. Endocrinology 143(4):1362–1370
Noguchi T, Makino S, Matsumoto R, Nakayama S, Nishiyama M, Terada Y, Hashimoto K (2010) Regulation of glucocorticoid receptor transcription and nuclear translocation during single and repeated immobilization stress. Endocrinology 151(9):4344–4355
Nollen EA, Morimoto RI (2002) Chaperoning signaling pathways: molecular chaperones as stress-sensing ‘heat shock’ proteins. J Cell Sci 115(Pt 14):2809–2816
Patchev VK, Brady LS, Karl M, Chrousos GP (1994) Regulation of HSP90 and corticosteroid receptor mRNA by corticosterone levels in vivo. Mol Cell Endocrinol 103(1–2):57–64
Pratt WB, Galigniana MD, Harrell JM, DeFranco DB (2004) Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement. Cell Signal 16(8):857–872
Radojcic M, Adzic M, Niciforovic A, Djordjevic J, Djordjevic A, Demonacos C, Krstic-Demonacos M (2012) Effects of chronic psychosocial isolation on limbic brain structures of Wistar rats. In: Costa A, Villalba E (eds) Horizons in neuroscience research, vol 5. Nova Science Publishers, New York, pp 97–126
Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21(1):55–89
Smith DF, Toft DO (1993) Steroid receptors and their associated proteins. Mol Endocrinol 7(1):4–11
Spencer RL, Kalman BA, Cotter CS, Deak T (2000) Discrimination between changes in glucocorticoid receptor expression and activation in rat brain using western blot analysis. Brain Res 868(2):275–286
Stavreva DA, Muller WG, Hager GL, Smith CL, McNally JG (2004) Rapid glucocorticoid receptor exchange at a promoter is coupled to transcription and regulated by chaperones and proteasomes. Mol Cell Biol 24(7):2682–2697
Stevens A, Begum G, Cook A, Connor K, Rumball C, Oliver M, Challis J, Bloomfield F, White A (2010) Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology 151(8):3652–3664
Stricker-Krongrad A, Beck B (2002) Modulation of hypothalamic hypocretin/orexin mRNA expression by glucocorticoids. Biochem Biophys Res Commun 296(1):129–133
Swaab DF, Bao AM, Lucassen PJ (2005) The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4(2):141–194
Tasker JG (2006) Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration. Obesity (Silver Spring) 14(Suppl 5):259S–265S
Vamvakopoulos NC, Fukuhara K, Patchev V, Chrousos GP (1993) Effect of single and repeated immobilization stress on the heat shock protein 70/90 system of the rat: glucocorticoid-independent, reversible reduction of Hsp90 in the liver and spleen. Neuroendocrinology 57(6):1057–1065
Wallace DL, Han MH, Graham DL, Green TA, Vialou V, Iniguez SD, Cao JL, Kirk A, Chakravarty S, Kumar A, Krishnan V, Neve RL, Cooper DC, Bolanos CA, Barrot M, McClung CA, Nestler EJ (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12(2):200–209
Acknowledgments
The authors are gratefully appreciative of the support provided by the Ministry of Education and Sciences of Serbia for this study (Grant III41029).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Simic, I., Mitic, M., Djordjevic, J. et al. Chronic Stress Decreases Availability of Heat Shock Proteins to Glucocorticoid Receptor in Response to Novel Acute Stress in Wistar Rat Hypothalamus. Cell Mol Neurobiol 32, 625–632 (2012). https://doi.org/10.1007/s10571-012-9811-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-012-9811-9