Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The anxiolytic effect of environmental enrichment is mediated via amygdalar CRF receptor type 1

Abstract

Environmental enrichment (EE) is known to have an anxiolytic effect in several animal models; however, the molecular mechanisms underlying these behavioral changes are not understood. In this study, we have shown that the anxiolytic effect of EE is associated with alterations in the corticotropin-releasing factor receptor type 1 (CRFR1) expression levels in the limbic system. We found that the decrease in anxiety-like behavior after housing in enriched conditions was associated with very low levels of CRFR1 mRNA expression in the basolateral amygdala of C57BL/6 mice. We further showed using a lentiviral-based system of RNA interference, that knockdown of CRFR1 mRNA expression in the basolateral amygdala induces a significant decrease in anxiety levels, similar to those achieved by EE nurture. Our data strongly suggest that reduced expression of CRFR1 mRNA levels in the basolateral amygdala mediates the effect of EE on anxiety-like behavior.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE . Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593–602.

    Article  PubMed  Google Scholar 

  2. Alonso J, Lépine JP . Overview of key data from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Clin Psychiatry 2007; 68: 3–9.

    Article  PubMed  Google Scholar 

  3. Fox C, Merali Z, Harrison C . Therapeutic and protective effect of environmental enrichment against psychogenic and neurogenic stress. Behav Brain Res 2006; 175: 1–8.

    Article  CAS  PubMed  Google Scholar 

  4. Rozenzweig MR, Bennet EL, Hebert M, Morimoto H . Social grouping cannot account for cerebral effects of enriched environments. Brain Res 1978; 153: 563–576.

    Article  Google Scholar 

  5. Hannan AJ . Huntington's disease: which drugs might help patients? IDrugs 2004; 7: 351–358.

    CAS  PubMed  Google Scholar 

  6. McOmish CE, Hannan AJ . Enviromimetics: exploring gene-environment interactions to identify therapeutic targets for brain disorders. Expert Opin Ther Targets 2007; 11: 899–913.

    Article  CAS  PubMed  Google Scholar 

  7. Vale W, Spiess J, Rivier C, Rivier J . Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981; 213: 1394–1397.

    Article  CAS  PubMed  Google Scholar 

  8. Rivier C, Vale W . Modulation of stress-induced ACTH release by corticotropin releasing factor, catecholamines and vasopressin. Nature 1983; 305: 325–327.

    Article  CAS  PubMed  Google Scholar 

  9. Muglia L, Jacobson L, Dikkes P, Majzoub JA . Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 1995; 373: 427–432.

    Article  CAS  PubMed  Google Scholar 

  10. de Kloet ER, Joels M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.

    Article  CAS  PubMed  Google Scholar 

  11. McEwen BS . Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005; 54: 20–23.

    Article  CAS  PubMed  Google Scholar 

  12. Zorrilla EP, Koob GF . The therapeutic potential of CRF1 antagonists for anxiety. Expert Opin Investig Drugs 2004; 137: 799–828.

    Article  Google Scholar 

  13. Heinrichs SC, Koob GF . Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J Pharmacol Exp Ther 2004; 311: 427–440.

    Article  CAS  PubMed  Google Scholar 

  14. Holsboer F . The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 1999; 33: 181–214.

    Article  CAS  PubMed  Google Scholar 

  15. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB . The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160: 1–12.

    Article  CAS  PubMed  Google Scholar 

  16. Holmes A, Heilig M, Rupniak NM, Steckler T, Griebel G . Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 2003; 24: 580–588.

    Article  CAS  PubMed  Google Scholar 

  17. Bale TL . Sensitivity to stress: dysregulation of CRF pathways and disease development. Horm Behav 2005; 48: 1–10.

    Article  CAS  PubMed  Google Scholar 

  18. Kuperman Y, Chen A . Urocortins: emerging metabolic and energy homeostasis perspectives. Trends Endocrinol Metabol 2008; 19: 122–129.

    Article  CAS  Google Scholar 

  19. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 1998; 20: 1093–1102.

    Article  CAS  PubMed  Google Scholar 

  20. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 1998; 19: 162–166.

    Article  CAS  PubMed  Google Scholar 

  21. Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P et al. Limbic corticotropin-releasing hormone receptor type 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 2003; 6: 1100–1107.

    Article  PubMed  Google Scholar 

  22. Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C et al. Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 2000; 428: 191–212.

    Article  CAS  PubMed  Google Scholar 

  23. Justice NJ, Yuan ZF, Sawchenko PE, Vale W . Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol 2008; 511: 479–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sajdyk TJ, Shekhar A . Excitatory amino acid receptors in the basolateral amygdala regulate anxiety responses in the social interaction test. Brain Res 1997; 704: 262–264.

    Article  Google Scholar 

  25. Sajdyk TJ, Shekhar A . Excitatory amino acid receptor antagonists block the cardiovascular and anxiety responses elicited by γ-aminobutyric acidA receptor blockade in the basolateral amygdala of rats. J Pharmacol Exp Ther 1997; 283: 969–977.

    CAS  PubMed  Google Scholar 

  26. Sanders SK, Shekhar A . Anxiolytic effects of chlordiazepoxide blocked by injections of GABAA and benzodiazepine receptors antagonists in the region of the anterior basolateral amygdala of rats. Biol Psychiatry 1995; 37: 473–476.

    Article  CAS  PubMed  Google Scholar 

  27. Sanders SK, Shekhar A . Regulation of anxiety by GABAA receptors in the rat amygdala. Pharm Biochem Behav 1995; 52: 1–6.

    Article  Google Scholar 

  28. Plakovits M . Punch sampling biopsy technique. Methods Enzymol 1983; 103: 368–376.

    Article  Google Scholar 

  29. Tiscornia G, Singer O, Ikawa M, Verma IM . A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 2003; 100: 1844–1848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chapillon P, Manneche C, Belzung C, Caston J . Rearing environmental enrichment in two inbred strains of mice: 1. Effects on emotional reactivity. Behav Genet 1999; 29: 41–46.

    Article  CAS  PubMed  Google Scholar 

  31. Friske JE, Gammie SC . Environmental enrichment alters plus maze, but not maternal defense performance in mice. Physiol Behav 2005; 85: 187–194.

    Article  CAS  PubMed  Google Scholar 

  32. Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, Wilf A et al. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci 2004; 20: 1341–1347.

    Article  CAS  PubMed  Google Scholar 

  33. Brenes Saenz JC, Villagra OR, Fornaguera Trias J . Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social and isolated reared rats. Behav Brain Res 2006; 169: 57–65.

    Article  PubMed  Google Scholar 

  34. Powell SB, Newman HA, McDonald TA, Bugenhagen P, Lewis MH . Development of spontaneous stereotyped behavior in deer mice: effects of early and late exposure to a more complex environment. Dev Psychobiol 2000; 37: 100–108.

    Article  CAS  PubMed  Google Scholar 

  35. Belz EE, Kennell JS, Czambel RK, Rubin RT, Rhodes ME . Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats. Biochem Behav 2003; 76: 481–486.

    Article  CAS  Google Scholar 

  36. Roy V, Belzung C, Delarue C, Chapillon P . Environmental enrichment in BALB/c mice: effects in classical tests of anxiety and exposure to a predatory odor. Physiol Behav 2001; 74: 313–320.

    Article  CAS  PubMed  Google Scholar 

  37. Francis DD, Diorio J, Plotsky PM, Meaney MJ . Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci 2002; 22: 7840–7843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Morley-Fletcher S, Rea M, Maccari S, Laviola G . Environmental enrichment during adolescence reverses the effects of prenatal stress on play behavior and HPA axis reactivity in rats. Eur J Neurosci 2003; 18: 3367–3374.

    Article  PubMed  Google Scholar 

  39. Marashi V, Barnekow A, Ossendorf E, Sachser N . Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice. Horm Behav 2003; 43: 281–292.

    Article  CAS  PubMed  Google Scholar 

  40. Gray TS, Bingaman EW . The amygdala: corticotropin-releasing factor, steroids and stress. Crit Rev Neurobiol 1996; 10: 155–168.

    Article  CAS  PubMed  Google Scholar 

  41. Roozendaal B, Schelling G, McGaugh JL . Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta-adrenoceptor-cAMP pathway: dependence on glucocorticoid receptor activation. J Neuorsci 2008; 28: 6642–6651.

    Article  CAS  Google Scholar 

  42. Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J . Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol Psychiatry 2008; 64: 708–717.

    Article  CAS  PubMed  Google Scholar 

  43. Nithianantharajah J, Hannan AJ . Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 2006; 7: 697–709.

    Article  CAS  PubMed  Google Scholar 

  44. Mohammed AH, Henriksson BG, Söderström S, Ebendal T, Olsson T, Seckl JR . Environmental influences on the central nervous system and their implications for the aging rat. Behav Brain Res 1993; 57: 183–191.

    Article  CAS  PubMed  Google Scholar 

  45. Olsson T, Mohammed AH, Donaldson LF, Henriksson BG, Seckl JR . Glucocorticoid receptor and NGFI-A gene expression are induced in the hippocampus after environmental enrichment in adult rats. Brain Res Mol Brain Res 1994; 23: 349–353.

    Article  CAS  PubMed  Google Scholar 

  46. Larsson F, Winblad B, Mohammed AH . Psychological stress and environmental adaptation in enriched vs impoverished housed rats. Pharmacol Biochem Behav 2002; 73: 193–207.

    Article  CAS  PubMed  Google Scholar 

  47. Skelton KH, Nemeroff CB, Knight DL, Owens MJ . Chronic administration of the triazolobenzodiazepine Alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. J Neurosci 2000; 20: 1240–1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jochman KA, Newman SM, Kalin NH, Bakshi VP . Corticotropin-releasing factor-1 receptors in the basolateral amygdala mediate stress-induced anorexia. Behav Neurosci 2005; 119: 1448–1458.

    Article  CAS  PubMed  Google Scholar 

  49. Sajdyk TJ, Schober DA, Gehlert DR, Shekhar A . Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses. Behav Brain Res 1999; 100: 207–215.

    Article  CAS  PubMed  Google Scholar 

  50. Spiga F, Lightman SL, Shekhar A, Lowry CA . Injections of urocortin 1 into the basolateral amygdala induce anxiety-like behavior and c-Fos expression in brainstem serotonergic neurons. Neuroscience 2006; 138: 1265–1276.

    Article  CAS  PubMed  Google Scholar 

  51. Gehlert DR, Shekhar A, Morin SM, Hipskind PA, Zink C, Gackenheimer SL et al. Stress and central urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor. Eur J Pharmacol 2005; 509: 145–153.

    Article  CAS  PubMed  Google Scholar 

  52. Kempermann G, Kuhn HG, Gage FH . More hippocampal neurons in adult mice living in an enriched environment. Nature 1997; 386: 493–495.

    Article  CAS  PubMed  Google Scholar 

  53. Olsson IA, Sherwin CM . Behaviour of laboratory mice in different housing conditions when allowed to self-administer an anxiolytic. Lab Anim 2006; 40: 392–399.

    Article  CAS  PubMed  Google Scholar 

  54. Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 2006; 9: 268–275.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

AC is incumbent of the Philip Harris and Gerald Ronson Career Development Chair. This work is supported by research grants from the Israel Science Foundation; The National Institute for Psychobiology in Israel—founded by The Charles E. Smith Family; the Israel Ministry of Health; Roberto and Renata Ruhman; Mr and Mrs Mike Kahn; Mr Jorge David Ashkenazi; Mr and Mrs Barry Wolfe; and Nella and Leon Benoziyo Center for Neurosciences and Neurological Diseases.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Chen.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sztainberg, Y., Kuperman, Y., Tsoory, M. et al. The anxiolytic effect of environmental enrichment is mediated via amygdalar CRF receptor type 1. Mol Psychiatry 15, 905–917 (2010). https://doi.org/10.1038/mp.2009.151

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2009.151

Keywords

This article is cited by

Search

Quick links