Skip to main content
SpringerLink
Log in

Behavioral Despair and Home-Cage Activity in Mice with Chronically Elevated Baseline Corticosterone Concentrations

  • BRIEF COMMUNICATION
  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

Dysfunction of the hypothalamic-pituitary-adrenal axis resulting in elevated baseline glucocorticoid concentrations is a hallmark of stress-related human anxiety and affective disorders, including depression. Mice from four replicate lines bred for high voluntary wheel running (HR lines) run almost three times as much as four non-selected control (C) lines, and exhibit two fold elevated baseline circulating corticosterone levels throughout the 24 h cycle. Although elevated baseline CORT may be beneficial for high locomotor activity, chronic elevations can have deleterious effects on multiple systems, and may predispose for affective disorders. Because stressful events often precede a depressive bout, we quantified depressive-like behavior in the forced-swim (FST; generation 41) and tail-suspension tests (TST; generation 47) in HR and C mice that had wheel access for 6 days and then were deprived of wheels on day seven prior to the FST or TST. Male HR spent significantly more time immobile in the FST than C, suggesting that HR males have a predisposition for depression-like behavior. Both male and female HR (generation 43) were more active than same-sex controls in both wheel running and home-cage activity across 22 h (pooling the sexes, HR/C = 2.28 and 2.66, respectively).

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

References

  • Aidman EV, Woollard S (2003) The influence of self-reported exercise addiction on acute emotional and physiological responses to brief exercise deprivation. Psychol Sport Exerc 4:225–236. doi:10.1016/S1469-0292(02)00003-1

    Article  Google Scholar 

  • Amsterdam JD, Maislin G, Gold P, Winokur A (1989) The assessment of abnormalities in hormonal responsiveness at multiple levels of the hypothalmic-pituitary-adrenocortical axis in depressive illness. Psychoneuroendocrinology 14:43–62. doi:10.1016/0306-4530(89)90055-3

    Article  PubMed  CAS  Google Scholar 

  • Antonijevic IA, Steiger A (2003) Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis. Psychoneuroendocrinology 28:780–795. doi:10.1016/S0306-4530(02)00085-9

    Article  PubMed  CAS  Google Scholar 

  • Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “Behavioral despair”. Pharmacol Biochem Behav 70:187–192. doi:10.1016/S0091-3057(01)00599-8

    Article  PubMed  CAS  Google Scholar 

  • Barden N, Reul JM, Holsboer F (1995) Do antidepressants stabilize mood through actions on the hypothalamic-pituitary-adrenocortical system? Trends Neurosci 18:6–11. doi:10.1016/0166-2236(95)93942-Q

    Article  PubMed  CAS  Google Scholar 

  • Belke TW, Garland T Jr (2007) A brief opportunity to run does not function as a reinforcer for mice selectively bred for high daily wheel-running rates. J Exp Anal Behav 88:199–213. doi:10.1901/jeab.2007.62-06

    Article  PubMed  Google Scholar 

  • Board F, Persky H, Hamburg DA (1956) Psychological stress and endocrine functions. Psychosom Med 18:324–333

    PubMed  CAS  Google Scholar 

  • Boyle MP, Brewer JA, Funatsu M, Wozniak DF, Tsien JZ, Izumi Y, Muglia LJ (2005) Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc Natl Acad Sci USA 102:473–478. doi:10.1073/pnas.0406458102

    Article  PubMed  CAS  Google Scholar 

  • Brené S, Bjǿrnebekk A, Ǻberg E, Mathé A, Olson L, Werme M (2007) Running is rewarding and antidepressive. Physiol Behav 92:136–140. doi:10.1016/j.physbeh.2007.05.015

    Article  PubMed  CAS  Google Scholar 

  • Brown GW, Bifulco A, Harris TO (1987) Life events, vulnerability and onset of depression. Br J Psychiatry 150:30–42. doi:10.1192/bjp.150.1.30

    Article  PubMed  CAS  Google Scholar 

  • Brown ES, Khan DA, Nejtek VA (1999) The psychiatric side effects of corticosteroids. Asthma Immunol 83:495–503

    CAS  Google Scholar 

  • Brown ES, Woolston D, Frol A, Bobadilla L, Khan DA, Hanczyc M (2004) Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiatry 55:538–545. doi:10.1016/j.biopsych.2003.09.010

    Article  PubMed  CAS  Google Scholar 

  • Dallman MF, Strack AM, Akana SF, Bradbury MJ, Hanson ES, Scribner KA, Smith M (1993) Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol 14:303–347. doi:10.1006/frne.1993.1010

    Article  PubMed  CAS  Google Scholar 

  • de Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease. Endocr Rev 19:269–301. doi:10.1210/er.19.3.269

    Article  PubMed  Google Scholar 

  • Dishman RK, Berthoud H-R, Booth FW, Cotman CW, Edgerton VR, Fleshner MR, Gandevia SC, Gomez-Pinilla F, Greenwood BN, Hillman CH, Kramer AF, Levin BE, Moran TH, Russo-Neustadt AA, Salamone JD, Van Hoomissen JD, Wade CE, York DA, Zigmond MJ (2006) Neurobiology of Exercise. Obesity 14:345–356. doi:10.1038/oby.2006.46 (Silver Spring, Md.)

    Article  PubMed  CAS  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127. doi:10.1016/j.biopsych.2006.02.013

    Article  PubMed  CAS  Google Scholar 

  • Duman CH, Schlesinger L, Russell DS, Duman RS (2008) Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice. Brain Res 1199:148–158

    PubMed  CAS  Google Scholar 

  • Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO (2005) Exercise treatment for depression: efficacy and dose response. Am J Prev Med 28:1–8. doi:10.1016/j.amepre.2004.09.003

    Article  PubMed  Google Scholar 

  • Dunner D, Patrick V, Fieve RR (1979) Life events at the onset of bipolar affective illness. Am J Psychiatry 136:508–511

    PubMed  CAS  Google Scholar 

  • El Yacoubi M, Bouali S, Popa D, Naudon L, Leroux-Nicollet I, Hamon M, Costentin J, Adrien J, Vaugeois JM (2003) Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression. Proc Nat Acad Sci USA, 100:6227–6232. doi:10.1073/pnas.1034823100

    Article  PubMed  CAS  Google Scholar 

  • Garland T Jr (2003) Selection experiments: An underutilized tool in biomechanics and organismal biology. In: Bels VL, Gasc J-P, Casinos A (eds) Vertebrate biomechanics and evolution. BIOS Scientific Publishers, Oxford, pp 23–56

    Google Scholar 

  • Garland T Jr, Rose MR (eds) (2009) Experimental evolution: concepts, methods, and applications of selection experiments. University of California Press, Berkeley (in press)

  • Garland T Jr, Morgan MT, Swallow JG, Rhodes JS, Girard I, Belter JG, Carter PA (2002) Evolution of a small-muscle polymorphism in lines of house mice selected for high activity levels. Evol Int J Org Evol 56:1267–1275

    Google Scholar 

  • Girard I, Garland T Jr (2002) Plasma corticosterone response to acute and chronic voluntary exercise in female house mice. J Appl Physiol 92:1553–1561

    PubMed  CAS  Google Scholar 

  • Gold P, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, Nieman LK, Post RM, Pickar D, Gallucci W, Averginos P, Paul S, Oldfield EH, Cutler GB, Chrousos GP (1986) Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. N Engl J Med 314:1329–1335

    Article  PubMed  CAS  Google Scholar 

  • Gomes FR, Rezende EL, Malisch JL, Lee SK, Rivas DA, Kelly SA, Lytle C, Yaspelkis BB III, Garland T Jr (2009) Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running. J Exp Biol (in press)

  • Greenwood BN, Foley TE, Day HEW, Campisi J, Hammack SH, Campeau S, Maier SF, Fleshner M (2003) Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons. J Neurosci 23:2889–2898

    PubMed  CAS  Google Scholar 

  • Greenwood BN, Foley TE, Burhans D, Maier SF, Fleshner M (2005) The consequences of uncontrollable stress are sensitive to duration of prior wheel running. Brain Res 1033:164–178. doi:10.1016/j.brainres.2004.11.037

    Article  PubMed  CAS  Google Scholar 

  • Gregus A, Wintink AJ, Davis AC, Kalynchuk LE (2005) Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res 156:105–114. doi:10.1016/j.bbr.2004.05.013

    Article  PubMed  CAS  Google Scholar 

  • Hammen C, Davila J, Brown GW, Ellicott A, Gitlin M (1992) Psychiatric history and stress: predictors of severity of unipolar depression. J Abnorm Psychiatry 101:45–52. doi:10.1037/0021-843X.101.1.45

    Article  CAS  Google Scholar 

  • Henderson ND (1989) Interpreting studies that compare high- and low-selected lines on new characters. Behav Genet 19:473–502. doi:10.1007/BF01066250

    Article  PubMed  CAS  Google Scholar 

  • Henderson ND (1997) Spurious associations in unreplicated selected lines. Behav Genet 27:145–154. doi:10.1023/A:1025689425738

    Article  PubMed  CAS  Google Scholar 

  • Holmes P (2003) Rodent models of depression: reexamining validity without anthropomorphic inference. Crit Rev Neurobiol 15:143–174. doi:10.1615/CritRevNeurobiol.v15.i2.30

    Article  PubMed  Google Scholar 

  • Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23:477–501. doi:10.1016/S0893-133X(00)00159-7

    Article  PubMed  CAS  Google Scholar 

  • Johnson RA, Rhodes JS, Jeffrey SL, Garland T Jr, Mitchell GS (2003) Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience 121:1–7. doi:10.1016/S0306-4522(03)00422-6

    Article  PubMed  CAS  Google Scholar 

  • Johnson SA, Fournier NM, Kalynchuk LE (2006) Effect of different doses of corticosterone in depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res 168:280–288. doi:10.1016/j.bbr.2005.11.019

    Article  PubMed  CAS  Google Scholar 

  • Kalynchuk LE, Gregus A, Boudreau D, Perrot-Sinal TS (2004) Corticosterone increases depression-like behavior, with some effects on predator odor-induced defensive behavior, in male and female rats. Behav Neurosci 118:1365–1377. doi:10.1037/0735-7044.118.6.1365

    Article  PubMed  CAS  Google Scholar 

  • Kaneko M, Hoshino Y, Hashimoto S, Okano T, Kumashiro H (1993) Hypothalamic-pituitary-adrenal axis function in children with attentrion-deficit hyperactivity disorder. J Autism Dev Disord 23:59–65. doi:10.1007/BF01066418

    Article  PubMed  CAS  Google Scholar 

  • Kelly WF, Checkley SA, Bender DA, Mashiter K (1983) Cushing’s syndrome and depression- a prospective study of 26 patients. Br J Psychiatry 142:16–19. doi:10.1192/bjp.142.1.16

    Article  PubMed  CAS  Google Scholar 

  • Malisch JL (2007) Micro-evolutionary change in the hypothalamic-pituitary-adrenal axis in mice selectively bred for high voluntary wheel running. Ph.D. Dissertation, University of California, Riverside

  • Malisch JL, Saltzman W, Gomes FR, Rezende EL, Jeske DR, Garland T Jr (2007) Baseline and stress-induced plasma corticosterone concentrations of mice selectively bred for high voluntary wheel running. Physiol Biochem Zool 80:146–156. doi:10.1086/508828

    Article  PubMed  CAS  Google Scholar 

  • Malisch JL, Breuner CW, Gomes FR, Chappell MA, Garland T Jr (2008) Circadian pattern of total and free corticosterone concentrations, corticosteroid-binding globulin, and physical activity in mice selectively bred for high voluntary wheel-running behavior. Gen Comp Endocrinol 156:210–217

    Article  PubMed  CAS  Google Scholar 

  • Malisch JL, Kelly SA, Bhanvadia A, Blank KM, Marsik RL, Platzer EG, Garland T Jr (2009) Lines of mice with chronically elevated baseline corticosterone are more susceptible to a parasitic nematode infection. Zoology (Jena, Germany) (in press)

  • Morgan WP (1985) Affective beneficence of vigorous physical activity. Med Sci Sports Exerc 17:94–100

    PubMed  CAS  Google Scholar 

  • Nehrenberg DL, Hua K, Estrada-Smith D, Garland Jr T, Pomp D (2008) Voluntary exercise and its effects on body composition depend on genetic selection history. Obesity (in review)

  • Parker KJ, Schatzberg AF, Lyons DM (2003) Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav 43:60–66. doi:10.1016/S0018-506X(02)00016-8

    Article  PubMed  CAS  Google Scholar 

  • Pecoraro N, Gomez F, Dallman MF (2005) Glucocorticoids dose-dependently remodel energy stores and amplify incentive relativity effects. Psychoneuroendocrinol 30:815–825. doi:10.1016/j.psyneuen.2005.03.010

    Article  CAS  Google Scholar 

  • Pecoraro N, Dallman MF, Warne JP, Ginsberg AB, Laugero KD, la Fleur SE, Houshyar H, Gomez F, Bhargava A, Akana SF (2006) From Malthus to motive: how the HPA axis engineers the phenotype, yoking needs to wants. Prog Neurobiol 79:247–340. doi:10.1016/j.pneurobio.2006.07.004

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Bertain A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    PubMed  CAS  Google Scholar 

  • Post F (1962) The significance of affective syptoms in old age, Maudsley monograph 10. Oxford University Press, London

    Google Scholar 

  • Ransford CP (1982) A role for amines in the antidepressant effect of exercise: a review. Med Sci Sports Exerc 14:1–10. doi:10.1249/00005768-198214010-00001

    Article  PubMed  CAS  Google Scholar 

  • Rhodes JS, Hosack GR, Girard I, Kelly AE, Mitchell GS, Garland T Jr (2001) Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selected for hyperactive wheel-running behavior. Psychopharmacology 158:120–131. doi:10.1007/s002130100857

    Article  PubMed  CAS  Google Scholar 

  • Rhodes JS, Gammie SC, Garland T Jr (2003) Patterns of brain activity associated with variation in voluntary wheel-running behavior. Behav Neurosci 117:1243–1256. doi:10.1037/0735-7044.117.6.1243

    Article  PubMed  Google Scholar 

  • Rhodes JS, Gammie SC, Garland T Jr (2005) Neurobiology of mice selected for high voluntary wheel-running activity. Integrative Comp Biol 45:438–455. doi:10.1093/icb/45.3.438

    Article  Google Scholar 

  • Ridder S, Chourbaji S, Hellweg R, Urani A, Zacher C, Schmid W, Zink M, Hortnagl H, Flor H, Henn FA, Schutz G, Gass P (2005) Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. J Neurosci 25:6243–6250. doi:10.1523/JNEUROSCI.0736-05.2005

    Article  PubMed  CAS  Google Scholar 

  • Sapolsky RM, Plotsky PM (1990) Hypercortisolism and its possible neural bases. Biol Psychiatry 27:937–952. doi:10.1016/0006-3223(90)90032-W

    Article  PubMed  CAS  Google Scholar 

  • Sokal RR, Rohlf FJ (1981) Biometry, 2nd edn. W. H. Freeman and Co., San Francisco

    Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370. doi:10.1007/BF00428203

    Article  PubMed  CAS  Google Scholar 

  • Stone EA, Lin Y (2008) An anti-immobility effect of exogenous corticosterone in mice. Eur J Pharmacol 580:135–142. doi:10.1016/j.ejphar.2007.10.045

    Article  PubMed  CAS  Google Scholar 

  • Strohle A, Holsboer F (2003) Stress responsive neurohormones in depression and anxiety. Pharmacopsychiatry 36:S207–S214

    PubMed  Google Scholar 

  • Swallow JG, Carter PA, Garland T Jr (1998) Artificial selection for increased wheel-running behavior in house mice. Behav Genet 28:227–237. doi:10.1023/A:1021479331779

    Article  PubMed  CAS  Google Scholar 

  • Swallow JG, Koteja P, Carter PA, Garland T Jr (1999) Artificial selection for increased wheel-running activity in house mice results in decreased body mass at maturity. J Exp Biol 202:2513–2520

    PubMed  CAS  Google Scholar 

  • Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL, Mason JW (1990) Low urinary cortisol excretion in patients with posttraumatic stress disorder. J Nerv Ment Dis 187:366–369. doi:10.1097/00005053-199006000-00004

    Google Scholar 

  • Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (2003) Mineralocorticoid receptor function in major depression. Arch Gen Psychiatry 60:24–28

    Article  PubMed  CAS  Google Scholar 

  • Zheng H, Liu Y, Li W, Yang B, Chen D, Wang X, Jiang Z, Wang H, Wang Z, Cornelisson G, Halberg F (2006) Beneficial effects of exercise and its molecular mechanisms on depression in rats. Behav Brain Res 168:47–55. doi:10.1016/j.bbr.2005.10.007

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Leslie Karpinski and Jim Sinclair for their help maintaining the mouse colony. This work was supported by US NSF grants IOB-0543429 (T.G.) and IBN-0202676 (C.W.B.). J.M. was partially supported by a Graduate Assistantship in Areas of National Need grant to the Department of Biology and a U. C. Office of the President Dissertation Year Fellowship Award.

Author information

Author notes

  1. Kevin M. Middleton

    Present address: Department of Biology, California State University, San Bernardino, San Bernardino, CA, 92407, USA

Authors and Affiliations

  1. Department of Biology, University of California, Riverside, Riverside, CA, 92521, USA

    Jessica L. Malisch, Erik M. Kolb, Robert M. Hannon, Mark A. Chappell, Kevin M. Middleton & Theodore Garland Jr

  2. Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA

    Creagh W. Breuner & Haruka Wada

Authors
  1. Jessica L. Malisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Creagh W. Breuner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erik M. Kolb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haruka Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert M. Hannon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark A. Chappell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kevin M. Middleton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Theodore Garland Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodore Garland Jr.

Additional information

Edited by Stephen Maxson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Malisch, J.L., Breuner, C.W., Kolb, E.M. et al. Behavioral Despair and Home-Cage Activity in Mice with Chronically Elevated Baseline Corticosterone Concentrations. Behav Genet 39, 192–201 (2009). https://doi.org/10.1007/s10519-008-9246-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-008-9246-8

Keywords

Search

Navigation