Skip to main content

Persistent disruption of overexpectation learning after inactivation of the lateral orbitofrontal cortex in male rats

A Correction to this article was published on 25 August 2022

This article has been updated

Abstract

Rationale and objective

Learning to inhibit acquired fear responses is fundamental to adaptive behavior. Two procedures that support such learning are extinction and overexpectation. In extinction, an expected outcome is omitted, whereas in overexpectation two individually trained cues are presented in compound to induce an expectation of a greater outcome than that delivered. Previously, we showed that inactivation of the lateral orbitofrontal cortex (lOFC) in experimentally naïve male rats causes a mild impairment in extinction learning but a profound one in overexpectation. The mild extinction impairment was also transient; that is, it was absent in a cohort of rats that had prior history of inhibitory training (overexpectation, extinction) and their associated controls. This raised the question whether lOFC involvement in overexpectation could likewise be attenuated by prior experience.

Methods

Using a muscimol/baclofen cocktail, we inactivated the lOFC during overexpectation training in rats with prior associative learning history (extinction, overexpectation, control) and examined its contribution to reducing learned fear.

Results

Inactivating the lOFC during compound training in overexpectation persistently disrupted fear reduction on test in naïve rats and regardless of prior experience. Additionally, we confirm that silencing the lOFC only resulted in a mild impairment in extinction learning in naïve rats.

Conclusion

We show that prior associative learning experience did not mitigate the deficit in overexpectation caused by lOFC inactivation. Our findings emphasize the importance of this region for this particular form of fear reduction and broaden our understanding of the conditions in which the lOFC modulates behavioral inhibition.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Change history

References

  • Anderson LC, Petrovich GD (2017) Sex specific recruitment of a medial prefrontal cortex-hippocampal-thalamic system during context-dependent renewal of responding to food cues in rats. Neurobiol Learn Mem 139:11–21. https://doi.org/10.1016/j.nlm.2016.12.004

    Article  PubMed  Google Scholar 

  • Baran SE, Armstrong CE, Niren DC, Hanna JJ, Conrad CD (2009) Chronic stress and sex differences on the recall of fear conditioning and extinction. Neurobiol Learn Mem 91(3):323–32. https://doi.org/10.1016/j.nlm.2008.11.005

    Article  PubMed  PubMed Central  Google Scholar 

  • Barker JM, Galea LA (2010) Males show stronger contextual fear conditioning than females after context pre-exposure. Physiol Behav 99(1):82–90. https://doi.org/10.1016/j.physbeh.2009.10.014

    CAS  Article  PubMed  Google Scholar 

  • Blanchard RJ, Blanchard DC (1969) Crouching as an index of fear. J Comp Physiol Psychol 67:370–375

    CAS  Article  Google Scholar 

  • Burke KA, Takahashi YK, Correll J et al (2009) Orbitofrontal inactivation impairs reversal of Pavlovian learning by interfering with “disinhibition” of responding for previously unrewarded cues. Eur J Neurosci 30:1941–1946

    Article  Google Scholar 

  • Cohen J (1988) Statistical power analysis for the behavioral sciences. Routledge Academic, New York, NY

    Google Scholar 

  • Dalla C, Shors TJ (2009) Sex differences in learning processes of classical and operant conditioning. Physiol Behav 97(2):229–38. https://doi.org/10.1016/j.physbeh.2009.02.035

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Day HLL, Suwansawang S, Halliday DM, Stevenson CW (2020) Sex differences in auditory fear discrimination are associated with altered medial prefrontal cortex function. Sci Rep 10(1):6300. https://doi.org/10.1038/s41598-020-63405-w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Delamater AR, Schneider K, Derman RC (2017) Extinction of specific stimulus-outcome (SO) associations in Pavlovian learning with an extended CS procedure. J Exp Psychol Anim Learn Cogn 43(3):243–261. https://doi.org/10.1037/xan0000138

    Article  PubMed  PubMed Central  Google Scholar 

  • Do-Monte FH, Quinones-Laracuente K, Quirk GJ (2015) A temporal shift in the circuits mediating retrieval of fear memory. Nature 519:460–463

    CAS  Article  Google Scholar 

  • Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15:177–182

    CAS  Article  Google Scholar 

  • Kreutzmann JC, Jovanovic T, Fendt M (2020) Infralimbic cortex activity is required for the expression but not the acquisition of conditioned safety. Psychopharm (Berl) 237(7):2161–2172. https://doi.org/10.1007/s00213-020-05527-7

    CAS  Article  Google Scholar 

  • Laurent V, Westbrook RF (2009) Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. Learn Mem 16:520–529

    Article  Google Scholar 

  • Lay BPP, Nicolosi M, Usypchuk AA et al (2019) Dissociation of appetitive overexpectation and extinction in the infralimbic cortex. Cereb Cortex 29:3687–3701

    Article  Google Scholar 

  • Lay BP, Pitaru AA, Boulianne N, Esber GR, Iordanova MD (2020) Different methods of fear reduction are supported by distinct cortical substrates. Elife 9:e55294. https://doi.org/10.7554/eLife.55294

  • Matsuda S, Matsuzawa D, Ishii D, Tomizawa H, Sutoh C, Shimizu E (2015) Sex differences in fear extinction and involvements of extracellular signal-regulated kinase (ERK). Neurobiol Learn Mem 123:117–24. https://doi.org/10.1016/j.nlm.2015.05.009

    CAS  Article  PubMed  Google Scholar 

  • Mendoza J, Sanio C, Chaudhri N (2015) Inactivating the infralimbic but not prelimbic medial prefrontal cortex facilitates the extinction of appetitive Pavlovian conditioning in Long-Evans rats. Neurobiol Learn Mem 118:198–208

    CAS  Article  Google Scholar 

  • Pavlov IP (1927) Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford Univ. Press, Oxford, England

    Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press, Sydney

    Google Scholar 

  • Quirk GJ, Russo GK, Barron JL et al (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20:6225–6231

    CAS  Article  Google Scholar 

  • Rhodes SE, Killcross AS (2007a) Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding. Eur J Neurosci 25:2498–2503

    CAS  Article  Google Scholar 

  • Rhodes SE, Killcross AS (2007b) Lesions of rat infralimbic cortex result in disrupted retardation but normal summation test performance following training on a Pavlovian conditioned inhibition procedure. Eur J Neurosci 26:2654–2660

    CAS  Article  Google Scholar 

  • Rhodes SE, Killcross S (2004) Lesions of rat infralimbic cortex enhance recovery and reinstatement of an appetitive Pavlovian response. Learn Mem 11:611–616

    Article  Google Scholar 

  • Sierra-Mercado D Jr, Corcoran KA, Lebrón-Milad K et al (2006) Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. Eur J Neurosci 24:1751–1758

    Article  Google Scholar 

  • Smiley CE, McGonigal JT, Valvano T, Newsom RJ, Otero N, Gass JT (2020) The infralimbic cortex and mGlu5 mediate the effects of chronic intermittent ethanol exposure on fear learning and memory. Psychopharmacology 237(11):3417–3433. https://doi.org/10.1007/s00213-020-05622-9 (Epub 2020 Aug 7)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Takahashi YK, Roesch MR, Stalnaker TA et al (2009) The orbitofrontal cortex and ventral tegmental area are necessary for learning from unexpected outcomes. Neuron 62:269–280

    CAS  Article  Google Scholar 

  • Villaruel FR, Lacroix F, Sanio C et al (2018) Optogenetic activation of the infralimbic cortex suppresses the return of appetitive Pavlovian-conditioned responding following extinction. Cereb Cortex 28:4210–4221

    Article  Google Scholar 

Download references

Funding

This work was supported by FRQNT Nouveaux Chercheurs grant (MDI; 2017-NC-198182), a NARSAD Young Investigator grant (MDI; Grant # 24748), a CIHR Project Grant (MDI; Grant # PJT-155927), the Canada Research Chairs program (MDI; Grant # 950–230456), and a FRQS post-doctoral fellowship (to BPPL; #276908).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mihaela D. Iordanova.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article belongs to a Special Issue on Conditioned Determinants of Reward Seeking.

The original version of this article was revised: This article was originally published with an added data at the beginning of the article title.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lay, B.P.P., Choudhury, R., Esber, G.R. et al. Persistent disruption of overexpectation learning after inactivation of the lateral orbitofrontal cortex in male rats. Psychopharmacology (2022). https://doi.org/10.1007/s00213-022-06198-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00213-022-06198-2

Keywords

  • Fear
  • Learning
  • Memory
  • Rat
  • Extinction