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.
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Change history
25 August 2022
A Correction to this paper has been published: https://doi.org/10.1007/s00213-022-06215-4
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
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
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
Blanchard RJ, Blanchard DC (1969) Crouching as an index of fear. J Comp Physiol Psychol 67:370–375
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
Cohen J (1988) Statistical power analysis for the behavioral sciences. Routledge Academic, New York, NY
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
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
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
Do-Monte FH, Quinones-Laracuente K, Quirk GJ (2015) A temporal shift in the circuits mediating retrieval of fear memory. Nature 519:460–463
Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15:177–182
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
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
Lay BPP, Nicolosi M, Usypchuk AA et al (2019) Dissociation of appetitive overexpectation and extinction in the infralimbic cortex. Cereb Cortex 29:3687–3701
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
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
Pavlov IP (1927) Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford Univ. Press, Oxford, England
Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press, Sydney
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
Rhodes SE, Killcross AS (2007a) Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding. Eur J Neurosci 25:2498–2503
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
Rhodes SE, Killcross S (2004) Lesions of rat infralimbic cortex enhance recovery and reinstatement of an appetitive Pavlovian response. Learn Mem 11:611–616
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
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)
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
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
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).
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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 240, 501–511 (2023). https://doi.org/10.1007/s00213-022-06198-2
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DOI: https://doi.org/10.1007/s00213-022-06198-2