Advertisement

Establishing operant conflict tests for the translational study of anxiety in mice

  • Sara Oberrauch
  • Hannes Sigrist
  • Eva Sautter
  • Samuel Gerster
  • Dominik R. Bach
  • Christopher R. PryceEmail author
Original Investigation

Abstract

Rationale

In conflict-based anxiety tests, rodents decide between actions with simultaneous rewarding and aversive outcomes. In humans, computerised operant conflict tests have identified response choice, latency, and vigour as distinct behavioural components. Animal operant conflict tests for measurement of these components would facilitate translational study.

Objectives

In C57BL/6 mice, two operant conflict tests for measurement of response choice, latency, and vigour were established, and effects of chlordiazepoxide (CDZ) thereon investigated.

Methods

Mice were moderately diet-restricted to increase sucrose reward salience. A 1-lever test required responding under medium-effort reward/threat conditions of variable ratio 2–10 resulting in sucrose at p = 0.7 and footshock at p = 0.3. A 2-lever test mandated a choice between low-effort reward/threat with a fixed-ratio (FR) 2 lever yielding sucrose at p = 0.7 and footshock at p = 0.3 versus high-effort reward/no threat with a FR 20 lever yielding sucrose at p = 1.

Results

In the 1-lever test, CDZ (7.5 or 15 mg/kg i.p.) reduced post-trial pause (response latency) following either sucrose or footshock and reduced inter-response interval (increased response vigour) after footshock. In the 2-lever test, mice favoured the FR2 lever and particularly at post-reward trials. CDZ increased choice of FR2 and FR20 responding after footshock, reduced response latency overall, and increased response vigour at the FR2 lever and after footshock specifically.

Conclusions

Mouse operant conflict tests, especially 2-lever choice, allow for the translational study of distinct anxiety components. CDZ influences each component by ameliorating the impact of both previous punishment and potential future punishment.

Keywords

Anxiety Reward-aversion conflict Translational test Mouse Operant choice Response latency Response vigour Anxiolytic 

Notes

Acknowledgements

We are grateful to Björn Henz and Alex Osei for animal care. The experiments comply with the current laws of Switzerland.

Funding

This research was funded by the Swiss National Science Foundation (grant 31003A-160147 to CRP).

Compliance with ethical standards

Conflict of interest

ES is an employee of TSE Systems, Germany. All remaining authors declare no competing interests.

References

  1. Amemori K, Amemori S, Graybiel AM (2015) Motivation and affective judgments differentially recruit neurons in the primate dorsolateral prefrontal and anterior cingulate cortex. J Neurosci 35:1939–1953CrossRefGoogle Scholar
  2. Azzinnari D, Sigrist H, Staehli S, Palme R, Hildebrandt T, Leparc G, Hengerer B, Seifritz E, Pryce CR (2014) Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology 85:328–341CrossRefGoogle Scholar
  3. Bach DR (2015) Anxiety-like behavioural inhibition is normative under environmental threat-reward correlations. PLoS Comput Biol 11:e1004646CrossRefGoogle Scholar
  4. Bach DR, Dayan P (2017) Algorithms for survival: a comparative perspective on emotions. Nat Rev Neurosci 18:311–319CrossRefGoogle Scholar
  5. Bach DR, Guitart-Masip M, Packard PA, Miro J, Falip M, Fuentemilla L, Dolan RJ (2014) Human hippocampus arbitrates approach-avoidance conflict. Curr Biol 24:541–547CrossRefGoogle Scholar
  6. Bach DR, Korn CW, Vunder J, Bantel A (2018) Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial. Transl Psychiatry 8:157CrossRefGoogle Scholar
  7. Britton KT, Morgan J, Rivier J, Vale W, Koob GF (1985) Chlordiazepoxide attenuates response suppression induced by corticotropin-releasing factor in the conflict test. Psychopharmacology 86:170–174CrossRefGoogle Scholar
  8. Calhoon GG, Tye KM (2015) Resolving the neural circuits of anxiety. Nat Neurosci 18:1394–1404CrossRefGoogle Scholar
  9. Coutinho CB, Cheripko JA, Carbone JJ (1969) Relationship between the duration of anticonvulsant activity of chlordiazepoxide and systemic levels of the parent compound and its major metabolites in mice. Biochem Pharmacol 18:303–316CrossRefGoogle Scholar
  10. Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. TiPS 16:33–36Google Scholar
  11. Evenden J, Ross L, Jonak G, Zhou J (2009) A novel operant conflict procedure conflict procedure using incrementing shock intensities to assess the anxiolytic and anxiogeneic effects of drugs. Behav Pharmacol 20:226–236CrossRefGoogle Scholar
  12. File SE, Lippa AS, Beer B, Lippa MT (2004) Animal tests of anxiety. In: Current protocols in neuroscience Chapter 8, Unit 8.3Google Scholar
  13. Gray JA, McNaughton N (2000) The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system, 2nd edn. Oxford University Press, OxfordGoogle Scholar
  14. Gray JA, Davis N, Feldon J, Rawlins NP, Owen SR (1981) Animal models of anxiety. Prog Neuro-Psychopharmacol 5:143–157CrossRefGoogle Scholar
  15. Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687CrossRefGoogle Scholar
  16. Ito R, Lee AC (2016) The role of the hippocampus in approach-avoidance conflict decision-making: evidence from rodent and human studies. Behav Brain Res 313:345–357CrossRefGoogle Scholar
  17. Jean-Richard-Dit-Bressel P, McNally GP (2015) The role of the basolateral amygdala in punishment. Learn Mem 22:128–137CrossRefGoogle Scholar
  18. Jean-Richard-Dit-Bressel P, Killcross S, McNally GP (2018) Behavioral and neurobiological mechanisms of punishment: implications for psychiatric disorders. Neuropsychopharmacology 43:1639–1650CrossRefGoogle Scholar
  19. Khemka S, Barnes G, Dolan RJ, Bach DR (2017) Dissecting the function of hippocampal oscillations in a human anxiety model. J Neurosci 37:6869–6876CrossRefGoogle Scholar
  20. Kirlic N, Young J, Aupperle RL (2017) Animal to human translational paradigms relevant for approach avoidance conflict decision making. Behav Res Ther 96:14–29CrossRefGoogle Scholar
  21. Korn CW, Vunder J, Miro J, Fuentemilla L, Hurlemann R, Bach DR (2017) Amygdala lesions reduce anxiety-like behavior in a human benzodiazepine-sensitive approach-avoidance conflict test. Biol Psychiatry 82:522–531CrossRefGoogle Scholar
  22. Lopez-Aumatell R, Guitart-Masip M, Vicens-Costa E, Gimenez-Llort L, Valdar W, Johannesson M, Flint J, Tobena A, Fernandez-Teruel A (2008) Fearfulness in a large N/Nih genetically heterogeneous rat stock: differential profiles of timidity and defensive flight in males and females. Behav Brain Res 188:41–55CrossRefGoogle Scholar
  23. Lu SX, Higgins GA, Hodgson RA, Hyde LA, Del Vecchio RA, Guthrie DH, Kazdoba T, McCool MF, Morgan CA, Bercovici A, Ho GD, Tulshian D, Parker EM, Hunter JC, Varty GB (2011) The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxami de (SCH 655842): comparison of efficacy and side effects across rodent species. Eur J Pharmacol 661:63–71CrossRefGoogle Scholar
  24. Rodgers RJ, Johnson NJ (1995) Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol Biochem Behav 52:297–303CrossRefGoogle Scholar
  25. Rodgers RJ, Cao BJ, Dalvi A, Holmes A (1997) Animal models of anxiety: an ethological perspective. Braz J Med Biol Res 30:289–304CrossRefGoogle Scholar
  26. Shimp KG, Mitchell MR, Beas BS, Bizon JL, Setlow B (2015) Affective and cognitive mechanisms of risky decision making. Neurobiol Learn Mem 117:60–70CrossRefGoogle Scholar
  27. Simon NW, Setlow B (2012) Modeling risky decision making in rodents. Methods Mol Biol 829:165–175CrossRefGoogle Scholar
  28. Tajima S, Drugowitsch J, Pouget A (2016) Optimal policy for value-based decision-making. Nat Commun 7:12400CrossRefGoogle Scholar
  29. Tovote P, Fadok JP, Luthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331CrossRefGoogle Scholar
  30. Varty GB, Hyde LA, Hodgson RA, Lu SX, McCool MF, Kazdoba TM, Del Vecchio RA, Guthrie DH, Pond AJ, Grzelak ME, Xu X, Korfmacher WA, Tulshian D, Parker EM, Higgins GA (2005) Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species. Psychopharmacology 182:132–143CrossRefGoogle Scholar
  31. Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1–7CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric HospitalUniversity of ZurichZurichSwitzerland
  2. 2.TSE Systems GmbHBad HomburgGermany
  3. 3.Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric HospitalUniversity of ZurichZurichSwitzerland

Personalised recommendations