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Neuroscience and Behavioral Physiology

, Volume 46, Issue 8, pp 964–970 | Cite as

Activity of the Nitrergic System of the Medial Prefrontal Cortex in Rats with High and Low Levels of Generalization of a Conditioned Reflex Fear Reaction

  • N. B. Saul’skayaEmail author
  • P. V. Sudorgina
Article
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In vivo intracerebral microdialysis/HPLC studies on Sprague–Dawley rats showed that acquisition of a conditioned reflex fear reaction (combined conditioned sound stimulus and unavoidable electrocutaneous shock) was accompanied by an increase in the level of extracellular citrulline (a coproduct of NO synthesis) in the medial area of the prefrontal cortex. This increase was almost completely blocked by administration of the neuronal NO synthase inhibitor Nω-propyl-L-arginine (1 mM) into this area of the cortex and was not seen in animals of the control group. These increases were large in animals subsequently showing low levels of freezing (a measure of fear) in response to the differential signal not previously combined with the pain stimulus and low in rats with high levels of freezing in response to the differential signal, though they did not correlate with the level of freezing in response to the conditioned signal. These data provide the first evidence that the formation of a conditioned reflex fear reaction is accompanied by activation of the nitrergic system of the medial prefrontal cortex, reflected in the extent of subsequent generalization but not expression of this conditioned reflex reaction.

Keywords

citrulline nitric oxide medial prefrontal cortex microdialysis conditioned reflex fear reaction generalization of fear differential inhibition 

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References

  1. 1.
    Dusmoor, J. E., Mitroff, S. R., and LaBar, K. S., “Generalization of conditioned fear along a dimension of increasing fear intensity,” Learn. Mem., 16, No. 7, 460–469 (2009).CrossRefGoogle Scholar
  2. 2.
    Gabott, P. L. and Bacon, S. J., “Co-localisation of NADPH diaphorase and GABA immunoreactivity in local circuit neurons in the medial prefrontal cortex (mPFC) of the rat,” Brain. Res., 699, No. 2, 321–328 (1995).CrossRefGoogle Scholar
  3. 3.
    Garthwaite, J., “Glutamate, nitric oxide and cell-cell signaling in the nervous system, “Trends Neurosci., 14, No. 1, 60–67 (1991).Google Scholar
  4. 4.
    Gotlib, I. H. and Joormann, J., “Cognition and depression: current status and future directions,” Annu. Rev. Clin. Psychol., 6, 285–312 (2010).CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Greenberg, T., Carlson, J. M., Cha, J., et al., “Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization,” Depress. Anxiety, 30, No. 3, 242–250 (2013).CrossRefPubMedGoogle Scholar
  6. 6.
    Huang, C. C. and Hsu, K. S., “Activation of muscarinic acetylcholine receptors induces a nitric oxide-dependent long-term depression in rat medial prefrontal cortex,” Cereb. Cortex, 20, No. 4, 982–996 (2010).CrossRefPubMedGoogle Scholar
  7. 7.
    Jovanovic, T., Kazama, A., Bachevalier, J., and Davis, M., “Impaired safety signal learning may be a biomarker of PTSD,” Neuropharmacology, 62, No. 2, 695–704 (2012).Google Scholar
  8. 8.
    Kim, J. J. and Jung, W. J., “Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review,” Neurosci. Biobehav. Rev., 30, No. 2, 188–202 (2006).CrossRefPubMedGoogle Scholar
  9. 9.
    LeDoux, J. E., “Emotional circuits in the brain,” Annu. Rev. Neurosci., 23, 155–184 (2000).CrossRefPubMedGoogle Scholar
  10. 10.
    Likhtik, E., Stuenske, J. M., Topivala, M. A., et al., “Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety,” Nat. Neurosci., 17, No. 1, 106–113 (2014).CrossRefPubMedGoogle Scholar
  11. 11.
    Lissek, S., Bradford, D. E., Alvarez, R. P., et al., “Neural substrates of classically conditioned fear-generalization in human: a parametric fMRI study,” Soc. Cogn. Affect. Neurosci., 9, No. 8, 1134–1142 (2014).CrossRefPubMedGoogle Scholar
  12. 12.
    Lu, Y., Simpson, K. L., Weaver, K. J., and Lin, R. C., “Coexpression of serotonin and nitric oxide in the raphe complex: cortical versus subcortical circuit,” Anat. Rec. (Hoboken), 293, No. 11, 1954–1965 (2010).CrossRefGoogle Scholar
  13. 13.
    Maren, S. and Quirk, G. J., “Neuronal signaling of fear memory,” Nat. Rev. Neurosci., 5, No. 11, 844–852 (2004).CrossRefPubMedGoogle Scholar
  14. 14.
    Nasif, E. J., Hu, X. T., Ramirez, O. A., and Perez, M. F., “Inhibition of neuronal nitric oxide synthase prevents alterations in medial prefrontal cortex excitability induced by repeated cocaine administration,” Psychopharmacology (Berlin), 218, No. 2, 323–330 (2011).Google Scholar
  15. 15.
    Orsini, C. A. and Maren, S., “Neural and cellular mechanisms of fear and extinction memory formation,” Neurosci. Biobehav. Rev., 36, No. 7, 1773–1803 (2012).CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pavesi, E., Heldt, S. A., and Fletcher, M. L., “Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear and increases odor generalization,” Learn. Mem., 20, No. 9, 482–490 (2013).CrossRefPubMedGoogle Scholar
  17. 17.
    Resstel, L. B., Correa, E. M., and Guimaraes, F. S., “The expression of contextual fear conditioning involves activation of an NMDA receptor–nitric oxide pathway in the medial prefrontal cortex,” Cereb. Cortex, 18, No. 9, 2027–2035 (2008).CrossRefPubMedGoogle Scholar
  18. 18.
    Saulskaya, N. B. and Fofonova, N. V., “Effects of N-methyl-D-aspartate on extracellular citrulline level in the rat nucleus accumbens,” Neurosci. Lett., 407, No. 1, 91–95 (2008).CrossRefGoogle Scholar
  19. 19.
    Saul’skaya, N. B. and Sudorgina, P. V., “A mediolateral gradient in the nitrergic activation of the nucleus accumbens during exploratory behavior,” Ros. Fiziol. Zh., 98, No. 4, 461–468 (2012).Google Scholar
  20. 20.
    Saul’skaya, N. B., Fofonova, N. V., and Sudorgina, P. V., “Activation of the NO-ergic system of the nucleus accumbens of presentation of contextual danger signals,” Ros. Fiziol. Zh., 95, No. 8, 793–800 (2009).Google Scholar
  21. 21.
    Saulskaya, N. B., Fofonova, N. V., Sudorghina, P. V., and Saveliev, S. A., “Dopamine D1 receptor-dependent regulation of extracellular citrulline level in the rat nucleus accumbens during conditioned fear response,” Neurosci. Lett., 440, No. 2, 185–189 (2008).CrossRefPubMedGoogle Scholar
  22. 22.
    Saul’skaya, N. B., Fofonova, N. V., Sudorgina, P. V., and Komarova, A. S., “Sound danger signals activate the nitrergic system of the medial area of the nucleus accumbens,” Zh. Vyssh. Nerv. Deyat., 60, No. 1, 65–73 (2010).Google Scholar
  23. 23.
    Savel’ev, S. A., Repkina, N. S., and Saul’skaya, N. B., “A sensitive method for assay of citrulline for the in vivo monitoring of nitric oxide production in the CNS,” Ros. Fiziol. Zh., 91, No. 5, 587–591 (2005).Google Scholar
  24. 24.
    Sortes-Bayon, F. and Quirk, G. J., “Prefrontal control of fear: more than just extinction,” Curr. Opin. Neurobiol., 20, No. 2, 231–235 (2010).CrossRefGoogle Scholar
  25. 25.
    Xu Wei and Sudhof, T. C., “A neural circuit for memory specificity and generalization,” Science, 339, No. 6125, 1290–1295 (2013).Google Scholar
  26. 26.
    Zelikowsky, M., Bissiere, S., Hast, T. A., et al., “Prefrontal microcircuit underlies contextual learning after hippocampal loss,” Proc. Natl. Acad. Sci. USA, 110, No. 24, 9938–9943 (2013).CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Laboratory for Higher Nervous Activity, Institute of PhysiologyRussian Academy of SciencesSt. PetersburgRussia

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