Rodent Models of Depression: Learned Helplessness Induced in Mice

Hymie Anisman1, Zul Merali2

1 Carleton University, Ottawa, Ontario, Canada, 2 University of Ottawa, Ottawa, Ontario, Canada
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 8.10C
DOI:  10.1002/0471142301.ns0810cs14
Online Posting Date:  May, 2001
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Uncontrollable stressors induce a variety of behavioral disturbances that are in many ways reminiscent of the symptoms that characterize clinical depression. These deficits are evident across a range of species, including mice. Given the increasing focus on genetic techniques involving mice to identify the mechanisms subserving these behavioral disturbances (e.g., recombinant, knockout, and transgenic strains), it is of particular interest to provide a detailed description of the method to induce behavioral deficits in response to uncontrollable stressors. This unit describes the procedure used to assess the effects of controllable and uncontrollable shock on subsequent shock escape performance in mice using an escape‚Äźdelay procedure.

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Table of Contents

  • Basic Protocol 1: Induction of a Learned Helplessness Effect in Mice
  • Alternate Protocol 1: Administration of Uncontrollable Shock
  • Support Protocol 1: Description and Fundamental Characteristics of Shuttle Boxes for Escape Testing
  • Commentary
  • Figures
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Basic Protocol 1: Induction of a Learned Helplessness Effect in Mice

  • Male or female mice, >60 days of age, housed individually if the procedure is to be carried over >1 day
  • 70% (v/v) ethanol
  • Drugs to be tested (optional)
  • Saline or appropriate vehicle
  • Syringes and needles 26 gauge, ⅜ in.
  • Shuttle boxes (Figure ; e.g., Stoelting, Coulbourn Instruments, or see protocol 3)
  • Sound‐attenuating chambers (ventilated) to house a shuttle box and accessory equipment (∼60 × 60 × 90 cm) (make in‐house or purchase, e.g., Coulbourn Instruments)
  • Shock generator and scrambler (or neon bulbs as an alternative to a shock scrambler) (Stoelting or Coulbourn Instruments)
  • Computer (to control trial delivery and record data). Software is available through equipment suppliers (e.g., Coulbourn Instruments) or can be written for specific uses
NOTE: There are marked differences between mouse strains (see ), and thus the specific procedures used will vary depending on the strain used.

Alternate Protocol 1: Administration of Uncontrollable Shock

  • Shock chambers (optional; Coulbourn Instruments)

Support Protocol 1: Description and Fundamental Characteristics of Shuttle Boxes for Escape Testing

  • Black Plexiglas (0.63 cm thick)
  • Red translucent Plexiglas
  • Stainless‐steel rods (0.32 cm in diameter)
  • Scrambler (available from virtually all companies that manufacture avoidance/escape equipment) or neon bulbs wired in series
  • Stainless‐steel sheets (0.1 cm thick)
  • Solenoid to control gate opening and closing
  • Photocells (e.g., Radio Shack)
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Literature Cited

Literature Cited
   Anisman, H. and Zacharko, R.M. 1982. Depression: The predisposing influence of stress. Behav. Brain Sci. 5:89‐137.
   Anisman, H., deCatanzaro, D., and Remington, G. 1978. Escape performance following exposure to inescapable shock: Deficits in motor response maintenance. J. Exp. Psychol. Anim. Behav. Process. 4:197‐218.
   Anisman, H., Remington, G., and Sklar, L.S. 1979. Effects of inescapable shock on subsequent escape performance: Catecholaminergic and cholinergic mediation of response initiation and maintenance. Psychopharmacology 61:107‐124.
   Anisman, H., Suissa, A., and Sklar, L.S. 1980. Escape deficits induced by uncontrollable stress: Antagonism by dopamine and norepinephrine agonists. Behav. Neural Biol. 28:34‐4.
   Anisman, H., Glazier, S., and Sklar, L.S. 1981. Modification by cholinergic manipulation of escape deficits produced by inescapable shock. Psychopharmacology 74:81‐87.
   Anisman, H., Shanks, N., Zalcman, S., and Zacharko, R.M. 1992. Multisystem regulation of performance deficits induced by stressors: An animal model of depression. In Animal Models in Psychiatry, Vol.II (M.T. Martin‐Iverson, ed.) pp. 1‐55. Humana Press, Clifton, N.J.
   Anisman, H., Zalcman, S., and Zacharko, R.M. 1993. The impact of stressors on immune and central neurotransmitter activity: Bidirectional communication. Rev. Neurosci. 4:147‐180.
   Crabbe, J.C., Wahlsten, D., and Dudek, B.C. 1999. Genetics of mouse behavior: Interactions with laboratory environment. Science. 284:1670‐1672.
   Glazer, H.I. and Weiss, J.M. 1976a. Long‐term and transitory interference effects. J. Exp. Psychol. Anim. Behav. Process. 2:191‐201.
   Glazer, H.I. and Weiss, J.M. 1976b. Long‐term interference effect: An alternative to learned helplessness. J. Exp. Psychol.Anim. Behav. Process. 2:202‐213.
   Irwin, J., Suissa, A., and Anisman, H. 1980. Differential effects of inescapable shock on escape performance and discrimination learning in a water escape task. J. Exp. Psychol. Anim. Behav. Process. 6:21‐40.
   Kalivas, P.W. and Stewart, J. 1991. Dopamine transmission in the initiation and expression of drug‐ and stress‐induced sensitization of motor activity. Brain Res. Brain Res. Rev. 16:223‐244.
   Maier, S.F. and Seligman, M.E.P. 1976. Learned helplessness: Theory and evidence . J. Exp. Psychol. Gen. 105:3‐46.
   Petty, F., Kramer, G.L., and Wu, J. 1997. Serotonergic modulation of learned helplessness. Ann. N.Y. Acad. Sci. 821:538‐541.
   Prince, C.R. and Anisman, H. 1984. Acute and chronic stress effects on performance in a forced swim task. Behav. Neural Biol. 42:99‐119.
   Schulkin, J., Gold, P.W., and McEwen, B.S. 1998. Induction of corticotropin‐releasing hormone gene expression by glucocorticoids: Implication for understanding the states of fear and anxiety and allostatic load. Psychoneuroendocrinology. 23:219‐243.
   Seligman, M.E.P. 1975. Helplessness: On depression, development and death. Freeman, San Francisco.
   Shanks, N. and Anisman, H. 1988. Stressor‐provoked behavioral changes in six strains of mice. Behav. Neurosci. 102:894‐905.
   Shanks, N. and Anisman, H. 1989. Strain‐specific effects of antidepressants on escape deficits induced by inescapable shock. Psychopharmacology. 99:122‐128.
   Sherman, A.D. and Petty, F. 1980. Neurochemical basis of the action of antidepressants on learned helplessness. Behav. Neural Biol. 30:119‐134.
   Szostak, C. and Anisman, H. 1985. Stimulus perseveration in a water‐maze following exposure to controllable and uncontrollable shock. Behav. Neural Biol. 43:178‐198.
   Tilders, F.J.H., Schmidt, E.D., and De Goeij, D.C.E. 1993. Phenotypic plasticity of CRF neurons during stress. Ann. N.Y. Acad. Sci. 697:39‐52.
   Wahlsten, D. 1972. Genetic experiments with animal learning: A critical review. Behav. Biol. 7:143‐182.
   Weiss, J.M. and Simson, P.G. 1984. Neurochemical mechanisms underlying stress‐induced depression. In Stress and Coping (T. Field, P. McCabe, and N. Schneiderman, eds.) pp. 93‐116. Lawrence‐Erlbaum, New York.
   Weiss, J.M., Glazer, H.I., Pohorecky, L.A., Brick, J., and Miller, N.E. 1975. Effects of chronic exposure to stressors on avoidance‐escape behavior and on brain norepinephrine. Psychosom. Med. 37:522‐534.
   Weiss, J.M., Glazer, H.I., and Pohorecky, L.M. 1976. Coping behavior and neurochemical changes: An alternative explanation for the original “Learned Helplessness” experiments. In Animal Models in Human Psychobiology (G. Serban and A. Kling, eds.) pp. 141‐173. Plenum Press, New York.
   Weiss, J.M., Goodman, P.A., Losito, B.G., Corrigan, S., Charry, J.M., and Bailey, W.H. 1981. Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine and serotonin levels in various regions of rat brain. Brain Res. Brain Res. Rev. 3:161‐191.
   Zacharko, R.M. and Anisman, H. 1991. Stressor‐induced anhedonia in the mesocorticolimbic system. Neurosci. Biobehav. Rev. 15:391‐405.
   Zaharia, M., Kulczycki, J., Shanks, N., and Anisman, H. 1996. The effects of early postnatal stimulation on Morris water‐maze acquisition in adult mice: Genetic and maternal factors. Psychopharmacology. 128:227‐239.
Key References
   Anisman et al., 1978. See above.
  Provides detailed procedures to induce an interference effect in mice.
   Anisman et al., 1992. See above.
  Describes a variety of behavioral effects and theoretical positions, emphasizing the proposition that the effects of uncontrollable stressors can be accommodated on the basis of central neurochemical changes.
   Maier and Seligman, 1976. See above.
  Provides an overview of the work supporting the position that the interference effect induced by inescapable shock reflects cognitive changes (learned helplessness).
   Weiss et al., 1981. See above.
  Relates neurochemical and behavioral effects of uncontrollable stressors; includes paradigms such as swim rather than shock escape.
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