Advertisement

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

  • Rodrigo Triana-Del Río
  • Erwin van den Burg
  • Ron Stoop
  • Chloé Hegoburu
Review

Abstract

The extinction of conditioned fear responses entrains the formation of safe new memories to decrease those behavioral responses. The knowledge in neuronal mechanisms of extinction is fundamental in the treatment of anxiety and fear disorders. Interestingly, the use of pharmacological compounds that reduce anxiety and fear has been shown as a potent co-adjuvant in extinction therapy. However, the efficiency and mechanisms by which pharmacological compounds promote extinction of fear memories remains still largely unknown and would benefit from a validation based on functional neuronal circuits, and the neurotransmitters that modulate them. From this perspective, oxytocin receptor signaling, which has been shown in cortical and limbic areas to modulate numerous functions (Eliava et al. Neuron 89(6):1291-1304, 2016), among them fear and anxiety circuits, and to enhance the salience of social stimuli (Stoop Neuron 76(1):142-59, 2012), may offer an interesting perspective. Experiments in animals and humans suggest that oxytocin could be a promising pharmacological agent at adjusting memory consolidation to boost fear extinction. Additionally, it is possible that long-term changes in endogenous oxytocin signaling can also play a role in reducing expression of fear at different brain targets. In this review, we summarize the effects reported for oxytocin in cortico-limbic circuits and on fear behavior that are of relevance for the modulation and potential extinction of fear memories.

Keywords

Fear extinction Fear retrieval Oxytocin Central amygdala Prefrontal cortex 

Abbreviations

ACC

Anterior cingulate cortex

AVP1a-R

Vasopressin receptor

BA

Basal amygdala

BLA

Basolateral amygdala

CBT

Cognitive behavioral therapy

CeA

Central amygdala

CeL

Centro-lateral amygdala

CeM

Centro-medial amygdala

CS

Conditioned stimulus

CSF

Cerebrospinal fluid

dmPFC

Dorso-medial prefrontal cortex

GABA

Gamma amino butyric acid

IL

Infralimbic cortex

ITCd

Intercalated cell masses (dorsal)

ITCv

Intercalated cell masses (ventral)

LA

Lateral amygdala

NMDAR

N-methyl-d-aspartate receptor

Nacc

Nucleus accumbens

OT

Oxytocin

OTR

Oxytocin receptor

PKCδ

Protein kinase delta

PL

Prelimbic cortex

PTSD

Posttraumatic stress disorder

PVN

Paraventricular nucleus of the hypothalamus

US

Unconditioned stimulus

vmPFC

Ventromedial prefrontal cortex

Notes

Funding information

RT is supported by the Synapsis Foundation, CH by a Marie-Heim Vögtlin grant from the Swiss National Science Foundation, and EvdB by a Swiss Federal grant from the Commission of Technology and Innovation.

References

  1. Abramowitz JS (2013) The practice of exposure therapy: relevance of cognitive-behavioral theory and extinction theory. Behav Ther 44:548–558.  https://doi.org/10.1016/j.beth.2013.03.003 CrossRefPubMedGoogle Scholar
  2. Acheson D, Feifel D, de Wilde S et al (2013) The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology 229:199–208.  https://doi.org/10.1007/s00213-013-3099-4 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alberini CM (ed) (2013) Memory reconsolidation, 1 edition. Academic press, LondonGoogle Scholar
  4. Allsop SA, Wichmann R, Mills F et al (2018) Corticoamygdala transfer of socially derived information gates observational learning. Cell 173:1329–1342.e18.  https://doi.org/10.1016/j.cell.2018.04.004 CrossRefPubMedGoogle Scholar
  5. Amano T, Unal CT, Paré D (2010) Synaptic correlates of fear extinction in the amygdala. Nat Neurosci 13:489–494.  https://doi.org/10.1038/nn.2499 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Amano T, Amir A, Goswami S, Paré D (2012) Morphology, PKCδ expression, and synaptic responsiveness of different types of rat central lateral amygdala neurons. J Neurophysiol 108:3196–3205.  https://doi.org/10.1152/jn.00514.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Amir A, Amano T, Pare D (2011) Physiological identification and infralimbic responsiveness of rat intercalated amygdala neurons. J Neurophysiol 105:3054–3066.  https://doi.org/10.1152/jn.00136.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Anderson DJ, Adolphs R (2014) A framework for studying emotions across species. Cell 157:187–200.  https://doi.org/10.1016/j.cell.2014.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Anderson KC, Insel TR (2006) The promise of extinction research for the prevention and treatment of anxiety disorders. Biol Psychiatry 60:319–321.  https://doi.org/10.1016/j.biopsych.2006.06.022 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Andreescu C, Tudorascu D, Sheu LK et al (2017) Brain structural changes in late-life generalized anxiety disorder. Psychiatry Res 268:15–21.  https://doi.org/10.1016/j.pscychresns.2017.08.004 CrossRefGoogle Scholar
  11. Bentz D, Michael T, de Quervain DJ-F, Wilhelm FH (2010) Enhancing exposure therapy for anxiety disorders with glucocorticoids: from basic mechanisms of emotional learning to clinical applications. J Anxiety Disord 24:223–230.  https://doi.org/10.1016/j.janxdis.2009.10.011 CrossRefPubMedGoogle Scholar
  12. Blanchard DC, Weatherspoon A, Shepherd J et al (1991) “Paradoxical” effects of morphine on antipredator defense reactions in wild and laboratory rats. Pharmacol Biochem Behav 40:819–828CrossRefGoogle Scholar
  13. Blume A, Bosch OJ, Miklos S et al (2008) Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus. Eur J Neurosci 27:1947–1956.  https://doi.org/10.1111/j.1460-9568.2008.06184.x CrossRefPubMedGoogle Scholar
  14. Bosch OJ, Meddle SL, Beiderbeck DI et al (2005) Brain oxytocin correlates with maternal aggression: link to anxiety. J Neurosci 25:6807–6815.  https://doi.org/10.1523/JNEUROSCI.1342-05.2005 CrossRefPubMedGoogle Scholar
  15. Bowers ME, Ressler KJ (2015a) Interaction between the cholecystokinin and endogenous cannabinoid systems in cued fear expression and extinction retention. Neuropsychopharmacology 40:688–700.  https://doi.org/10.1038/npp.2014.225 CrossRefPubMedGoogle Scholar
  16. Bowers ME, Ressler KJ (2015b) An overview of translationally informed treatments for posttraumatic stress disorder: animal models of pavlovian fear conditioning to human clinical trials. Biol Psychiatry 78:E15–E27.  https://doi.org/10.1016/j.biopsych.2015.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Brill-Maoz N, Maroun M (2016) Extinction of fear is facilitated by social presence: synergism with prefrontal oxytocin. Psychoneuroendocrinology 66:75–81.  https://doi.org/10.1016/j.psyneuen.2016.01.003 CrossRefPubMedGoogle Scholar
  18. Bukalo O, Pinard CR, Holmes A (2014) Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders. Br J Pharmacol 171:4690–4718.  https://doi.org/10.1111/bph.12779 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Bukalo O, Pinard CR, Silverstein S, et al (2015) Prefrontal inputs to the amygdala instruct fear extinction memory formation. Sci Adv. 1(6). pii: e1500251Google Scholar
  20. Burghardt NS, Bauer EP (2013) Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits. Neuroscience 247:253–272.  https://doi.org/10.1016/j.neuroscience.2013.05.050 CrossRefPubMedGoogle Scholar
  21. Burgos-Robles A, Kimchi EY, Izadmehr EM et al (2017) Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment. Nat Neurosci 20:824–835.  https://doi.org/10.1038/nn.4553 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Burkett JP, Andari E, Johnson ZV et al (2016) Oxytocin-dependent consolation behavior in rodents. Science 351:375–378.  https://doi.org/10.1126/science.aac4785 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Busti D, Geracitano R, Whittle N et al (2011) Different fear states engage distinct networks within the intercalated cell clusters of the amygdala. J Neurosci 31:5131–5144.  https://doi.org/10.1523/JNEUROSCI.6100-10.2011 CrossRefPubMedGoogle Scholar
  24. Campbell BM, Merchant KM (2003) Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment. Brain Res 993:1–9CrossRefGoogle Scholar
  25. Campbell-Smith EJ, Holmes NM, Lingawi NW et al (2015) Oxytocin signaling in basolateral and central amygdala nuclei differentially regulates the acquisition, expression, and extinction of context-conditioned fear in rats. Learn Mem 22:247–257.  https://doi.org/10.1101/lm.036962.114 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Carpenter JK, Andrews LA, Witcraft SM et al (2018) Cognitive behavioral therapy for anxiety and related disorders: a meta-analysis of randomized placebo-controlled trials. Depress Anxiety 35(6):502–514.  https://doi.org/10.1002/da.22728 CrossRefPubMedGoogle Scholar
  27. Cassell EJ (1999) Diagnosing suffering: a perspective. Ann Intern Med 131:531–534CrossRefGoogle Scholar
  28. Chang SWC, Barter JW, Ebitz RB et al (2012) Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci U S A 109:959–964.  https://doi.org/10.1073/pnas.1114621109 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Chini B, Manning M, Guillon G (2008) Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an “easy guide” to receptor pharmacology. Prog Brain Res 170:513–517.  https://doi.org/10.1016/S0079-6123(08)00438-X CrossRefPubMedGoogle Scholar
  30. Cho J-H, Deisseroth K, Bolshakov VY (2013) Synaptic encoding of fear extinction in mPFC-amygdala circuits. Neuron 80:1491–1507.  https://doi.org/10.1016/j.neuron.2013.09.025 CrossRefPubMedGoogle Scholar
  31. Choleris E, Devidze N, Kavaliers M, Pfaff DW (2008) Steroidal/neuropeptide interactions in hypothalamus and amygdala related to social anxiety. Prog Brain Res 170:291–303.  https://doi.org/10.1016/S0079-6123(08)00424-X CrossRefPubMedGoogle Scholar
  32. Ciocchi S, Herry C, Grenier F et al (2010) Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468:277–282.  https://doi.org/10.1038/nature09559 CrossRefPubMedGoogle Scholar
  33. Cisler JM, Sigel BA, Steele JS, Smitherman S, al e (2016) Changes in functional connectivity of the amygdala during cognitive reappraisal predict symptom reduction during trauma-focused cognitive-behavioral therapy among adolescent girls with post-traumatic stress disorder. Psychol Med 46(14):3013–3023CrossRefGoogle Scholar
  34. Clark RE, Xie H, Brunette MF (2004) Benzodiazepine prescription practices and substance abuse in persons with severe mental illness. J Clin Psychiatry 65:151–155CrossRefGoogle Scholar
  35. Coria-Avila GA, Manzo J, Garcia LI et al (2014) Neurobiology of social attachments. Neurosci Biobehav Rev 43:173–182.  https://doi.org/10.1016/j.neubiorev CrossRefPubMedGoogle Scholar
  36. Courtin J, Chaudun F, Rozeske RR et al (2014) Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505:92–96.  https://doi.org/10.1038/nature12755 CrossRefPubMedGoogle Scholar
  37. Cullen PK, Gilman TL, Winiecki P et al (2015) Activity of the anterior cingulate cortex and ventral hippocampus underlie increases in contextual fear generalization. Neurobiol Learn Mem 124:19–27.  https://doi.org/10.1016/j.nlm.2015.07.001 CrossRefPubMedGoogle Scholar
  38. Dabrowska J, Hazra R, Ahern TH et al (2011) Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: implications for balancing stress and affect. Psychoneuroendocrinology 36:1312–1326.  https://doi.org/10.1016/j.psyneuen.2011.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Dal Monte O, Noble PL, Turchi J et al (2014) CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 9:e103677.  https://doi.org/10.1371/journal.pone.0103677 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Davis M (1992) The role of the amygdala in fear and anxiety. Annu Rev Neurosci 15:353–375.  https://doi.org/10.1146/annurev.ne.15.030192.002033 CrossRefPubMedGoogle Scholar
  41. Davis M, Myers KM, Chhatwal J, Ressler KJ (2006) Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy. NeuroRx 3:82–96.  https://doi.org/10.1016/j.nurx.2005.12.008 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Davis S, Renaudineau S, Poirier R et al (2010) The formation and stability of recognition memory: what happens upon recall? Front Behav Neurosci 4:177.  https://doi.org/10.3389/fnbeh.2010.00177 CrossRefPubMedPubMedCentralGoogle Scholar
  43. de la Mora MP, Pérez-Carrera D, Crespo-Ramírez M et al (2016) Signaling in dopamine D2 receptor-oxytocin receptor heterocomplexes and its relevance for the anxiolytic effects of dopamine and oxytocin interactions in the amygdala of the rat. Biochim Biophys Acta 1862:2075–2085.  https://doi.org/10.1016/j.bbadis.2016.07.004 CrossRefPubMedGoogle Scholar
  44. Debiec J, LeDoux JE (2004) Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience 129:267–272.  https://doi.org/10.1016/j.neuroscience.2004.08.018 CrossRefPubMedGoogle Scholar
  45. Debiec J, LeDoux JE (2006) Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Ann N Y Acad Sci 1071:521–524.  https://doi.org/10.1196/annals.1364.056 CrossRefPubMedGoogle Scholar
  46. Dejean C, Courtin J, Karalis N et al (2016) Prefrontal neuronal assemblies temporally control fear behaviour. Nature 535:420–424.  https://doi.org/10.1038/nature18630 CrossRefPubMedGoogle Scholar
  47. Dilgen J, Tejeda HA, O’Donnell P (2013) Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex. J Neurophysiol 110:221–229.  https://doi.org/10.1152/jn.00531.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Dölen G, Darvishzadeh A, Huang KW, Malenka RC (2013) Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501:179–184.  https://doi.org/10.1038/nature12518 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Domes G, Heinrichs M, Gläscher J et al (2007) Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62:1187–1190.  https://doi.org/10.1016/j.biopsych.2007.03.025 CrossRefPubMedGoogle Scholar
  50. Domes G, Lischke A, Berger C et al (2010) Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 35:83–93.  https://doi.org/10.1016/j.psyneuen.2009.06.016 CrossRefPubMedGoogle Scholar
  51. Do-Monte FH, Manzano-Nieves G, Quiñones-Laracuente K et al (2015) Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci 35:3607–3615.  https://doi.org/10.1523/JNEUROSCI.3137-14.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Donadon MF, Martin-Santos R, Osório F de L (2018) The associations between oxytocin and trauma in humans: a systematic review. Front Pharmacol 9:154.  https://doi.org/10.3389/fphar.2018.00154 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Duke AN, Meng Z, Platt DM et al (2018) Evidence that sedative effects of benzodiazepines involve unexpected GABAA receptor subtypes: quantitative observation studies in rhesus monkeys. J Pharmacol Exp Ther 366:145–157.  https://doi.org/10.1124/jpet.118.249250 CrossRefPubMedGoogle Scholar
  54. Duque-Wilckens N, Steinman MQ, Busnelli M et al (2018) Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice. Biol Psychiatry 83:203–213.  https://doi.org/10.1016/j.biopsych.2017.08.024 CrossRefPubMedGoogle Scholar
  55. Duvarci S, Pare D (2014) Amygdala microcircuits controlling learned fear. Neuron 82:966–980.  https://doi.org/10.1016/j.neuron.2014.04.042 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Duvarci S, Popa D, Paré D (2011) Central amygdala activity during fear conditioning. J Neurosci 31:289–294.  https://doi.org/10.1523/JNEUROSCI.4985-10.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Eckstein M, Becker B, Scheele D et al (2015) Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 78:194–202.  https://doi.org/10.1016/j.biopsych.2014.10.015 CrossRefPubMedGoogle Scholar
  58. Eckstein M, Scheele D, Patin A et al (2016) Oxytocin facilitates Pavlovian fear learning in males. Neuropsychopharmacology 41(4):932–939.  https://doi.org/10.1038/npp.2015.245 CrossRefPubMedGoogle Scholar
  59. Eckstein M, Markett S, Kendrick KM et al (2017) Oxytocin differentially alters resting state functional connectivity between amygdala subregions and emotional control networks: inverse correlation with depressive traits. Neuroimage 149:458–467.  https://doi.org/10.1016/j.neuroimage.2017.01.078 CrossRefPubMedGoogle Scholar
  60. Ehrlich I, Humeau Y, Grenier F et al (2009) Amygdala inhibitory circuits and the control of fear memory. Neuron 62:757–771.  https://doi.org/10.1016/j.neuron.2009.05.026 CrossRefPubMedGoogle Scholar
  61. Eliava M, Melchior M, Knobloch-Bollmann HS, Wahis J et al (2016) A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron 89(6):1291–1304.  https://doi.org/10.1016/j.neuron CrossRefPubMedPubMedCentralGoogle Scholar
  62. Fang L-Y, Quan R-D, Kaba H (2008) Oxytocin facilitates the induction of long-term potentiation in the accessory olfactory bulb. Neurosci Lett 438:133–137.  https://doi.org/10.1016/j.neulet.2007.12.070 CrossRefPubMedGoogle Scholar
  63. Fitzgerald PJ, Seemann JR, Maren S (2014) Can fear extinction be enhanced? A review of pharmacological and behavioral findings. Brain Res Bull 105:46–60.  https://doi.org/10.1016/j.brainresbull.2013.12.007 CrossRefPubMedGoogle Scholar
  64. Freeman SM, Young LJ (2016) Comparative perspectives on oxytocin and vasopressin receptor research in rodents and primates: translational implications. J Neuroendocrinol 28.  https://doi.org/10.1111/jne.12382
  65. Freeman SM, Inoue K, Smith AL et al (2014) The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendocrinology 45:128–141.  https://doi.org/10.1016/j.psyneuen.2014.03.023 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Gabbott PLA, Warner TA, Busby SJ (2006) Amygdala input monosynaptically innervates parvalbumin immunoreactive local circuit neurons in rat medial prefrontal cortex. Neuroscience 139:1039–1048.  https://doi.org/10.1016/j.neuroscience.2006.01.026 CrossRefPubMedGoogle Scholar
  67. Gamer M, Zurowski B, Büchel C (2010) Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans. Proc Natl Acad Sci U S A 107:9400–9405.  https://doi.org/10.1073/pnas.1000985107 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Gao S, Becker B, Luo L et al (2016) Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci U S A 113:7650–7654.  https://doi.org/10.1073/pnas.1602620113 CrossRefPubMedPubMedCentralGoogle Scholar
  69. Geracitano R, Kaufmann WA, Szabo G et al (2007) Synaptic heterogeneity between mouse paracapsular intercalated neurons of the amygdala. J Physiol Lond 585:117–134.  https://doi.org/10.1113/jphysiol.2007.142570 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Gillies GE, McArthur S (2010) Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev 62:155–198.  https://doi.org/10.1124/pr.109.002071 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Gimpl G, Wiegand V, Burger K, Fahrenholz F (2002) Cholesterol and steroid hormones: modulators of oxytocin receptor function. Prog Brain Res 139:43–55CrossRefGoogle Scholar
  72. Giustino TF, Maren S (2015) The role of the medial prefrontal cortex in the conditioning and extinction of fear. Front Behav Neurosci 9:298.  https://doi.org/10.3389/fnbeh.2015.00298 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Giustino TF, Fitzgerald PJ, Maren S (2016) Revisiting propranolol and PTSD: memory erasure or extinction enhancement? Neurobiol Learn Mem 130:26–33.  https://doi.org/10.1016/j.nlm.2016.01.009 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Goodman AM, Harnett NG, Knight DC (2018) Pavlovian conditioned diminution of the neurobehavioral response to threat. Neurosci Biobehav Rev 84:218–224.  https://doi.org/10.1016/j.neubiorev.2017.11.021 CrossRefPubMedGoogle Scholar
  75. Grillon C, Krimsky M, Charney DR et al (2013) Oxytocin increases anxiety to unpredictable threat. Mol Psychiatry 18:958–960.  https://doi.org/10.1038/mp.2012.156 CrossRefPubMedGoogle Scholar
  76. Gruene TM, Flick K, Stefano A, et al (2015) Sexually divergent expression of active and passive conditioned fear responses in rats. Elife 4. doi:  https://doi.org/10.7554/eLife.11352
  77. Grund T, Goyon S, Li Y et al (2017) Neuropeptide S activates paraventricular oxytocin neurons to induce anxiolysis. J Neurosci 37:12214–12225.  https://doi.org/10.1523/JNEUROSCI.2161-17.2017 CrossRefPubMedGoogle Scholar
  78. Gur R, Tendler A, Wagner S (2014) Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala. Biol Psychiatry 76:377–386.  https://doi.org/10.1016/j.biopsych.2014.03.022 CrossRefPubMedGoogle Scholar
  79. Hansson AC, Koopmann A, Uhrig S et al (2018) Oxytocin reduces alcohol cue-reactivity in alcohol-dependent rats and humans. Neuropsychopharmacology 43:1235–1246.  https://doi.org/10.1038/npp.2017.257 CrossRefPubMedGoogle Scholar
  80. Haubensak W, Kunwar PS, Cai H et al (2010) Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468:270–276.  https://doi.org/10.1038/nature09553 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Hegoburu C, Shionoya K, Garcia S et al (2011) The RUB cage: respiration-ultrasonic vocalizations-behavior acquisition setup for assessing emotional memory in rats. Front Behav Neurosci 5:25.  https://doi.org/10.3389/fnbeh.2011.00025 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Herry C, Ciocchi S, Senn V et al (2008) Switching on and off fear by distinct neuronal circuits. Nature 454:600–606.  https://doi.org/10.1038/nature07166 CrossRefPubMedGoogle Scholar
  83. Hofmann SG, Otto MW, Pollack MH, Smits JA (2015) D-cycloserine augmentation of cognitive behavioral therapy for anxiety disorders: an update. Curr Psychiatry Rep 17:532.  https://doi.org/10.1007/s11920-014-0532-2 CrossRefPubMedGoogle Scholar
  84. Hoover WB, Vertes RP (2007) Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct 212:149–179.  https://doi.org/10.1007/s00429-007-0150-4 CrossRefPubMedGoogle Scholar
  85. Huber D, Veinante P, Stoop R (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308:245–248.  https://doi.org/10.1126/science.1105636 CrossRefPubMedGoogle Scholar
  86. Ishikawa A, Nakamura S (2003) Convergence and interaction of hippocampal and amygdalar projections within the prefrontal cortex in the rat. J Neurosci 23:9987–9995CrossRefGoogle Scholar
  87. Jiang Y, Platt ML (2018) Oxytocin and vasopressin flatten dominance hierarchy and enhance behavioral synchrony in part via anterior cingulate cortex. Sci Rep 8:8201.  https://doi.org/10.1038/s41598-018-25607-1 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Jiménez A, Young LJ, Triana-Del Río R, LaPrairie JL et al (2015) Neuroanatomical distribution of oxytocin receptor binding in the female rabbit forebrain: variations across the reproductive cycle. Brain Res 1629:329–339.  https://doi.org/10.1016/j.brainres CrossRefPubMedGoogle Scholar
  89. Jurek B, Slattery DA, Maloumby R et al (2012) Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats. PLoS One 7:e37060.  https://doi.org/10.1371/journal.pone.0037060 CrossRefPubMedPubMedCentralGoogle Scholar
  90. Kaoru T, Liu F-C, Ishida M et al (2010) Molecular characterization of the intercalated cell masses of the amygdala: implications for the relationship with the striatum. Neuroscience 166:220–230.  https://doi.org/10.1016/j.neuroscience.2009.12.004 CrossRefPubMedGoogle Scholar
  91. Karalis N, Dejean C, Chaudun F et al (2016) 4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior. Nat Neurosci 19:605–612.  https://doi.org/10.1038/nn.4251 CrossRefPubMedPubMedCentralGoogle Scholar
  92. Kessler RC, Aguilar-Gaxiola S, Alonso J et al (2017) The associations of earlier trauma exposures and history of mental disorders with PTSD after subsequent traumas. Mol Psychiatry.  https://doi.org/10.1038/mp.2017.194
  93. Kim JH, Richardson R (2010) New findings on extinction of conditioned fear early in development: theoretical and clinical implications. Biol Psychiatry 67:297–303.  https://doi.org/10.1016/j.biopsych.2009.09.003 CrossRefPubMedGoogle Scholar
  94. Kirsch P, Esslinger C, Chen Q et al (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489–11493.  https://doi.org/10.1523/JNEUROSCI.3984-05.2005 CrossRefPubMedGoogle Scholar
  95. Klumpp H, Fitzgerald JM, Kinney KL et al (2017) Predicting cognitive behavioral therapy response in social anxiety disorder with anterior cingulate cortex and amygdala during emotion regulation. Neuroimage Clin 15:25–34.  https://doi.org/10.1016/j.nicl.2017.04.006 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Knobloch HS, Charlet A, Hoffmann LC et al (2012) Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73:553–566.  https://doi.org/10.1016/j.neuron.2011.11.030 CrossRefPubMedGoogle Scholar
  97. Knoflach F, Hernandez M-C, Bertrand D (2016) GABAA receptor-mediated neurotransmission: not so simple after all. Biochem Pharmacol 115:10–17.  https://doi.org/10.1016/j.bcp.2016.03.014 CrossRefPubMedGoogle Scholar
  98. Krettek JE, Price JL (1978) Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J Comp Neurol 178:225–254.  https://doi.org/10.1002/cne.901780204 CrossRefPubMedGoogle Scholar
  99. Kroes MCW, Schiller D, LeDoux JE, Phelps EA (2016) Translational approaches targeting reconsolidation. Curr Top Behav Neurosci 28:197–230.  https://doi.org/10.1007/7854_2015_5008 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Labuschagne I, Phan KL, Wood A et al (2010) Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology 35:2403–2413.  https://doi.org/10.1038/npp.2010.123 CrossRefPubMedPubMedCentralGoogle Scholar
  101. Lahoud N, Maroun M (2013) Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction. Psychoneuroendocrinology 38:2184–2195.  https://doi.org/10.1016/j.psyneuen.2013.04.006 CrossRefPubMedGoogle Scholar
  102. Ledgerwood L, Richardson R, Cranney J (2005) D-cycloserine facilitates extinction of learned fear: effects on reacquisition and generalized extinction. Biol Psychiatry 57:841–847.  https://doi.org/10.1016/j.biopsych.2005.01.023 CrossRefPubMedGoogle Scholar
  103. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184.  https://doi.org/10.1146/annurev.neuro.23.1.155 CrossRefPubMedGoogle Scholar
  104. LeDoux JE (2014) Coming to terms with fear. Proc Natl Acad Sci U S A 111:2871–2878.  https://doi.org/10.1073/pnas.1400335111 CrossRefPubMedPubMedCentralGoogle Scholar
  105. LeDoux JE, Iwata J, Cicchetti P, Reis DJ (1988) Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci 8:2517–2529CrossRefGoogle Scholar
  106. Leng G, Ludwig M (2016) Intranasal oxytocin: myths and delusions. Biol Psychiatry 79:243–250.  https://doi.org/10.1016/j.biopsych.2015.05.003 CrossRefPubMedGoogle Scholar
  107. Levar N, van Leeuwen JMC, Denys D, van Wingen GA (2017a) Divergent influences of anterior cingulate cortex GABA concentrations on the emotion circuitry. Neuroimage 158:136–144.  https://doi.org/10.1016/j.neuroimage.2017.06.055 CrossRefPubMedGoogle Scholar
  108. Levar N, van Leeuwen JMC, Puts NAJ et al (2017b) GABA concentrations in the anterior cingulate cortex are associated with fear network function and fear recovery in humans. Front Hum Neurosci 11:202.  https://doi.org/10.3389/fnhum.2017.00202 CrossRefPubMedPubMedCentralGoogle Scholar
  109. Li H, Penzo MA, Taniguchi H, Kopec CD, Huang ZJ, Li B (2013a) Experience-dependent modification of a central amygdala fear circuit. Nat Neurosci 16(3):332–339.  https://doi.org/10.1038/nn.3322 CrossRefPubMedPubMedCentralGoogle Scholar
  110. Li Y, Meloni EG, Carlezon WA et al (2013b) Learning and reconsolidation implicate different synaptic mechanisms. Proc Natl Acad Sci U S A 110:4798–4803.  https://doi.org/10.1073/pnas.1217878110 CrossRefPubMedPubMedCentralGoogle Scholar
  111. Li K, Nakajima M, Ibañez-Tallon I, Heintz N (2016) A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167:60–72.e11.  https://doi.org/10.1016/j.cell.2016.08.067 CrossRefPubMedPubMedCentralGoogle Scholar
  112. Likhtik E, Stujenske JM, Topiwala MA et al (2014) Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat Neurosci 17:106–113.  https://doi.org/10.1038/nn.3582 CrossRefPubMedGoogle Scholar
  113. Lischke A, Berger C, Prehn K et al (2012) Intranasal oxytocin enhances emotion recognition from dynamic facial expressions and leaves eye-gaze unaffected. Psychoneuroendocrinology 37:475–481.  https://doi.org/10.1016/j.psyneuen.2011.07.015 CrossRefPubMedGoogle Scholar
  114. Little JP, Carter AG (2013) Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala. J Neurosci 33:15333–15342.  https://doi.org/10.1523/JNEUROSCI.2385-13.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  115. Litvin Y, Turner CA, Rios MB et al (2016) Fibroblast growth factor 2 alters the oxytocin receptor in a developmental model of anxiety-like behavior in male rat pups. Horm Behav 86:64–70.  https://doi.org/10.1016/j.yhbeh CrossRefPubMedPubMedCentralGoogle Scholar
  116. Loyens E, Vermoesen K, Schallier A et al (2012) Proconvulsive effects of oxytocin in the generalized pentylenetetrazol mouse model are mediated by vasopressin 1a receptors. Brain Res 1436:43–50.  https://doi.org/10.1016/j.brainres.2011.11.059 CrossRefPubMedGoogle Scholar
  117. Luo L, Becker B, Geng Y et al (2017) Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces. Neuroimage 162:127–137.  https://doi.org/10.1016/j.neuroimage.2017.08.079 CrossRefPubMedGoogle Scholar
  118. MacDonald K, MacDonald TM, Brüne M et al (2013) Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology 38:2831–2843.  https://doi.org/10.1016/j.psyneuen.2013.05.014 CrossRefPubMedGoogle Scholar
  119. Maren S (2001) Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 24:897–931.  https://doi.org/10.1146/annurev.neuro.24.1.897 CrossRefGoogle Scholar
  120. Marlin BJ, Mitre M, D’amour JA et al (2015) Oxytocin enables maternal behaviour by balancing cortical inhibition. Nature 520:499–504.  https://doi.org/10.1038/nature14402 CrossRefPubMedPubMedCentralGoogle Scholar
  121. Martinon D, Dabrowska J (2018) Corticotropin-releasing factor receptors modulate oxytocin release in the dorsolateral bed nucleus of the stria terminalis (BNST) in male rats. Front Neurosci 12:183.  https://doi.org/10.3389/fnins.2018.00183 CrossRefPubMedPubMedCentralGoogle Scholar
  122. Mataix-Cols D, Fernández de la Cruz L, Monzani B et al (2017) D-Cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data. JAMA Psychiatry 74:501–510.  https://doi.org/10.1001/jamapsychiatry.2016.3955 CrossRefPubMedGoogle Scholar
  123. McGarry LM, Carter AG (2017) Prefrontal cortex drives distinct projection neurons in the basolateral amygdala. Cell Rep 21:1426–1433.  https://doi.org/10.1016/j.celrep.2017.10.046 CrossRefPubMedPubMedCentralGoogle Scholar
  124. Meins M, Herry C, Müller C et al (2010) Impaired fear extinction in mice lacking protease nexin-1. Eur J Neurosci 31:2033–2042.  https://doi.org/10.1111/j.1460-9568.2010.07221.x CrossRefPubMedGoogle Scholar
  125. Menon R, Grund T, Zoicas I et al (2018) Oxytocin signaling in the lateral septum prevents social fear during lactation. Curr Biol 28:1066–1078.e6.  https://doi.org/10.1016/j.cub.2018.02.044 CrossRefPubMedGoogle Scholar
  126. Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74.  https://doi.org/10.1038/nature01138 CrossRefPubMedGoogle Scholar
  127. Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129–151.  https://doi.org/10.1146/annurev.psych.121208.131631 CrossRefPubMedPubMedCentralGoogle Scholar
  128. Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61–71.  https://doi.org/10.1016/j.biopsycho.2006.01.008 CrossRefPubMedGoogle Scholar
  129. Milad MR, Pitman RK, Ellis CB et al (2009) Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 66:1075–1082.  https://doi.org/10.1016/j.biopsych.2009.06.026 CrossRefPubMedPubMedCentralGoogle Scholar
  130. Mitre M, Marlin BJ, Schiavo JK et al (2016) A distributed network for social cognition enriched for oxytocin receptors. J Neurosci 36:2517–2535.  https://doi.org/10.1523/JNEUROSCI.2409-15.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  131. Moaddab M, Dabrowska J (2017) Oxytocin receptor neurotransmission in the dorsolateral bed nucleus of the stria terminalis facilitates the acquisition of cued fear in the fear-potentiated startle paradigm in rats. Neuropharmacology 121:130–139.  https://doi.org/10.1016/j.neuropharm CrossRefPubMedPubMedCentralGoogle Scholar
  132. Modi ME, Connor-Stroud F, Landgraf R et al (2014) Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 45:49–57.  https://doi.org/10.1016/j.psyneuen.2014.02.011 CrossRefPubMedPubMedCentralGoogle Scholar
  133. Modi ME, Inoue K, Barrett CE, Kittelberger KA et al (2015) Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole. Neuropsychopharmacology 40(8):1856–1865.  https://doi.org/10.1038/npp CrossRefPubMedPubMedCentralGoogle Scholar
  134. Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150.  https://doi.org/10.1038/sj.mp.4001939 CrossRefGoogle Scholar
  135. Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726.  https://doi.org/10.1038/35021052 CrossRefPubMedGoogle Scholar
  136. Nagai T, Kimura H, Maeda T et al (1982) Cholinergic projections from the basal forebrain of rat to the amygdala. J Neurosci 2:513–520CrossRefGoogle Scholar
  137. Nakajima M, Görlich A, Heintz N (2014) Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159:295–305.  https://doi.org/10.1016/j.cell.2014.09.020 CrossRefPubMedPubMedCentralGoogle Scholar
  138. Neumann ID, Maloumby R, Beiderbeck DI et al (2013) Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 38:1985–1993.  https://doi.org/10.1016/j.psyneuen.2013.03.003 CrossRefPubMedGoogle Scholar
  139. Orsini CA, Maren S (2012) Neural and cellular mechanisms of fear and extinction memory formation. Neurosci Biobehav Rev 36:1773–1802.  https://doi.org/10.1016/j.neubiorev.2011.12.014 CrossRefPubMedPubMedCentralGoogle Scholar
  140. Otto MW, Bruce SE, Deckersbach T (2005) Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need. J Clin Psychiatry 66(Suppl 2):34–38PubMedGoogle Scholar
  141. Owen SF, Tuncdemir SN, Bader PL et al (2013) Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500:458–462.  https://doi.org/10.1038/nature12330 CrossRefPubMedPubMedCentralGoogle Scholar
  142. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322Google Scholar
  143. Paloyelis Y, Krahé C, Maltezos S, et al (2016) The analgesic effect of oxytocin in humans: a double-blind, placebo-controlled cross-over study using laser-evoked potentials. J Neuroendocrinol 28. doi:  https://doi.org/10.1111/jne.12347
  144. Pape H-C, Paré D (2010) Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev 90:419–463.  https://doi.org/10.1152/physrev.00037.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  145. Paré D, Quirk GJ, Ledoux JE (2004) New vistas on amygdala networks in conditioned fear. J Neurophysiol 92:1–9.  https://doi.org/10.1152/jn.00153.2004 CrossRefPubMedGoogle Scholar
  146. Pavlov IP (1927) Conditioned reflexes. Oxford University PressGoogle Scholar
  147. Pisansky MT, Hanson LR, Gottesman II, Gewirtz JC (2017) Oxytocin enhances observational fear in mice. Nat Commun 8:2102.  https://doi.org/10.1038/s41467-017-02279-5 CrossRefPubMedPubMedCentralGoogle Scholar
  148. Power AE, Vazdarjanova A, McGaugh JL (2003) Muscarinic cholinergic influences in memory consolidation. Neurobiol Learn Mem 80:178–193CrossRefGoogle Scholar
  149. Quirk GJ, Milad MR (2010) Neuroscience: editing out fear. Nature 463:36–37.  https://doi.org/10.1038/463036a CrossRefPubMedGoogle Scholar
  150. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72.  https://doi.org/10.1038/sj.npp.1301555 CrossRefPubMedGoogle Scholar
  151. Quirk GJ, Likhtik E, Pelletier JG, Paré D (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci 23:8800–8807CrossRefGoogle Scholar
  152. Quirk GJ, Garcia R, González-Lima F (2006) Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 60:337–343.  https://doi.org/10.1016/j.biopsych.2006.03.010 CrossRefPubMedGoogle Scholar
  153. Ramikie TS, Ressler KJ (2018) Mechanisms of sex differences in fear and posttraumatic stress disorder. Biol Psychiatry 83:876–885.  https://doi.org/10.1016/j.biopsych.2017.11.016 CrossRefPubMedGoogle Scholar
  154. Rashid AJ, Yan C, Mercaldo V et al (2016) Competition between engrams influences fear memory formation and recall. Science 353:383–387.  https://doi.org/10.1126/science.aaf0594 CrossRefPubMedGoogle Scholar
  155. Rescorla RA (2004) Spontaneous recovery varies inversely with the training-extinction interval. Learn Behav 32:401–408CrossRefGoogle Scholar
  156. Rickenbacher E, Perry RE, Sullivan RM, Moita MA (2017) Freezing suppression by oxytocin in central amygdala allows alternate defensive behaviours and mother-pup interactions. Elife 6. doi:  https://doi.org/10.7554/eLife.24080
  157. Rilling JK, Demarco AC, Hackett PD et al (2014) Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 39:237–248.  https://doi.org/10.1016/j.psyneuen.2013.09.022 CrossRefPubMedGoogle Scholar
  158. Rogers CN, Ross AP, Sahu SP, et al (2018) Oxytocin- and arginine vasopressin-containing fibers in the cortex of humans, chimpanzees, and rhesus macaques. Am J Primatol e22875. doi:  https://doi.org/10.1002/ajp.22875
  159. Royer S, Martina M, Paré D (1999) An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J Neurosci 19:10575–10583CrossRefGoogle Scholar
  160. Sabihi S, Dong SM, Durosko NE, Leuner B (2014) Oxytocin in the medial prefrontal cortex regulates maternal care, maternal aggression and anxiety during the postpartum period. Front Behav Neurosci 8:258.  https://doi.org/10.3389/fnbeh.2014.00258 CrossRefPubMedPubMedCentralGoogle Scholar
  161. Sabihi S, Dong SM, Maurer SD et al (2017) Oxytocin in the medial prefrontal cortex attenuates anxiety: anatomical and receptor specificity and mechanism of action. Neuropharmacology 125:1–12.  https://doi.org/10.1016/j.neuropharm.2017.06.024 CrossRefPubMedPubMedCentralGoogle Scholar
  162. Sack M, Spieler D, Wizelman L et al (2017) Intranasal oxytocin reduces provoked symptoms in female patients with posttraumatic stress disorder despite exerting sympathomimetic and positive chronotropic effects in a randomized controlled trial. BMC Med 15:40.  https://doi.org/10.1186/s12916-017-0801-0 CrossRefPubMedPubMedCentralGoogle Scholar
  163. Saffari R, Teng Z, Zhang M et al (2016) NPY+-, but not PV+- GABAergic neurons mediated long-range inhibition from infra- to prelimbic cortex. Transl Psychiatry 6:e736.  https://doi.org/10.1038/tp.2016.7 CrossRefPubMedPubMedCentralGoogle Scholar
  164. Salchner P, Singewald N (2006) 5-HT receptor subtypes involved in the anxiogenic-like action and associated Fos response of acute fluoxetine treatment in rats. Psychopharmacology 185:282–288.  https://doi.org/10.1007/s00213-005-0247-5 CrossRefPubMedGoogle Scholar
  165. Schiller D, Kanen JW, LeDoux JE et al (2013) Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement. Proc Natl Acad Sci U S A 110:20040–20045.  https://doi.org/10.1073/pnas.1320322110 CrossRefPubMedPubMedCentralGoogle Scholar
  166. Senn V, Wolff SBE, Herry C et al (2014) Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81:428–437.  https://doi.org/10.1016/j.neuron.2013.11.006 CrossRefPubMedGoogle Scholar
  167. Shansky RM, Hamo C, Hof PR et al (2010) Estrogen promotes stress sensitivity in a prefrontal cortex-amygdala pathway. Cereb Cortex 20:2560–2567.  https://doi.org/10.1093/cercor/bhq003 CrossRefPubMedPubMedCentralGoogle Scholar
  168. Shvil E, Sullivan GM, Schafer S et al (2014) Sex differences in extinction recall in posttraumatic stress disorder: a pilot fMRI study. Neurobiol Learn Mem 113:101–108.  https://doi.org/10.1016/j.nlm.2014.02.003 CrossRefPubMedPubMedCentralGoogle Scholar
  169. Sierra RO, Pedraza LK, Zanona QK et al (2017) Reconsolidation-induced rescue of a remote fear memory blocked by an early cortical inhibition: involvement of the anterior cingulate cortex and the mediation by the thalamic nucleus reuniens. Hippocampus 27:596–607.  https://doi.org/10.1002/hipo.22715 CrossRefPubMedGoogle Scholar
  170. Singewald N, Schmuckermair C, Whittle N et al (2015) Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther 149:150–190.  https://doi.org/10.1016/j.pharmthera.2014.12.004 CrossRefPubMedGoogle Scholar
  171. Smith AL, Freeman SM, Barnhart TE, Abbott DH, Ahlers EO, Kukis DL, Bales KL, Goodman MM, Young LJ (2016a) Initial investigation of three selective and potent small molecule oxytocin receptor PET ligands in New World monkeys. Bioorg Med Chem Lett 26(14):3370–3375.  https://doi.org/10.1016/j.bmcl CrossRefPubMedPubMedCentralGoogle Scholar
  172. Smith AS, Tabbaa M, Lei K et al (2016b) Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. Psychoneuroendocrinology 63:50–58.  https://doi.org/10.1016/j.psyneuen.2015.09.017 CrossRefGoogle Scholar
  173. Sotres-Bayon F, Sierra-Mercado D, Pardilla-Delgado E, Quirk GJ (2012) Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76:804–812.  https://doi.org/10.1016/j.neuron.2012.09.028 CrossRefPubMedPubMedCentralGoogle Scholar
  174. Stamatakis A, Manatos V, Kalpachidou T, Stylianopoulou F (2016) Exposure to a mildly aversive early life experience leads to prefrontal cortex deficits in the rat. Brain Struct Funct 221:4141–4157.  https://doi.org/10.1007/s00429-015-1154-0 CrossRefPubMedGoogle Scholar
  175. Steenen SA, van Wijk AJ, van der Heijden GJMG et al (2016) Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis. J Psychopharmacol (Oxford) 30:128–139.  https://doi.org/10.1177/0269881115612236 CrossRefGoogle Scholar
  176. Stewart RE, Chambless DL (2009) Cognitive-behavioral therapy for adult anxiety disorders in clinical practice: a meta-analysis of effectiveness studies. J Consult Clin Psychol 77:595–606.  https://doi.org/10.1037/a0016032 CrossRefPubMedGoogle Scholar
  177. Stoop R (2012) Neuromodulation by oxytocin and vasopressin. Neuron 76(1):142–159.  https://doi.org/10.1016/j.neuron2012.09.025 CrossRefPubMedGoogle Scholar
  178. Stoop R, Hegoburu C, van den Burg E (2015) New opportunities in vasopressin and oxytocin research: a perspective from the amygdala. Annu Rev Neurosci 38:369–388.  https://doi.org/10.1146/annurev-neuro-071714-033904 CrossRefPubMedGoogle Scholar
  179. Straub J, Metzger CD, Plener PL et al (2017) Successful group psychotherapy of depression in adolescents alters fronto-limbic resting-state connectivity. J Affect Disord 209:135–139.  https://doi.org/10.1016/j.jad CrossRefPubMedGoogle Scholar
  180. Striepens N, Scheele D, Kendrick KM et al (2012) Oxytocin facilitates protective responses to aversive social stimuli in males. Proc Natl Acad Sci U S A 109:18144–18149.  https://doi.org/10.1073/pnas.1208852109 CrossRefPubMedPubMedCentralGoogle Scholar
  181. Striepens N, Kendrick KM, Hanking V et al (2013) Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 3:3440.  https://doi.org/10.1038/srep03440 CrossRefPubMedPubMedCentralGoogle Scholar
  182. Sun N, Laviolette SR (2012) Inactivation of the basolateral amygdala during opiate reward learning disinhibits prelimbic cortical neurons and modulates associative memory extinction. Psychopharmacology 222:645–661.  https://doi.org/10.1007/s00213-012-2665-5 CrossRefPubMedGoogle Scholar
  183. Terashima Y, Kondo K, Oiso Y (1999) Administration of oxytocin affects vasopressin V2 receptor and aquaporin-2 gene expression in the rat. Life Sci 64:1447–1453CrossRefGoogle Scholar
  184. Tomizawa K, Iga N, Lu Y-F et al (2003) Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade. Nat Neurosci 6:384–390.  https://doi.org/10.1038/nn1023 CrossRefPubMedGoogle Scholar
  185. Tonegawa S, Pignatelli M, Roy DS, Ryan TJ (2015) Memory engram storage and retrieval. Curr Opin Neurobiol 35:101–109.  https://doi.org/10.1016/j.conb.2015.07.009 CrossRefPubMedGoogle Scholar
  186. Tovote P, Fadok JP, Lüthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331.  https://doi.org/10.1038/nrn3945 CrossRefPubMedGoogle Scholar
  187. Triana-Del Rio R, Tecamachaltzi-Silvarán MB, Díaz-Estrada VX et al (2015) Conditioned same-sex partner preference in male rats is facilitated by oxytocin and dopamine: effect on sexually dimorphic brain nuclei. Behav Brain Res 283:69–77.  https://doi.org/10.1016/j.bbr CrossRefPubMedGoogle Scholar
  188. Tye KM, Deisseroth K (2012) Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci 13:251–266.  https://doi.org/10.1038/nrn3171 CrossRefPubMedGoogle Scholar
  189. Tye KM, Prakash R, Kim S-Y et al (2011) Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471:358–362.  https://doi.org/10.1038/nature09820 CrossRefPubMedPubMedCentralGoogle Scholar
  190. Uhrig S, Hirth N, Broccoli L et al (2016) Reduced oxytocin receptor gene expression and binding sites in different brain regions in schizophrenia: a post-mortem study. Schizophr Res 177:59–66.  https://doi.org/10.1016/j.schres.2016.04.019 CrossRefPubMedGoogle Scholar
  191. Van den Burg EH, Stindl J, Grund T et al (2015) Oxytocin stimulates extracellular Ca2+ influx through TRPV2 channels in hypothalamic neurons to exert its anxiolytic effects. Neuropsychopharmacology 40:2938–2947.  https://doi.org/10.1038/npp.2015.147 CrossRefPubMedPubMedCentralGoogle Scholar
  192. Veening JG, Swanson LW, Sawchenko PE (1984) The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res 303:337–357CrossRefGoogle Scholar
  193. Vertes RP (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51:32–58.  https://doi.org/10.1002/syn.10279 CrossRefPubMedGoogle Scholar
  194. Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL, Quirk GJ (2006) Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn Mem 13:728–733.  https://doi.org/10.1101/lm.306106 CrossRefPubMedPubMedCentralGoogle Scholar
  195. Viviani D, Charlet A, van den Burg E et al (2011) Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333:104–107.  https://doi.org/10.1126/science.1201043 CrossRefPubMedGoogle Scholar
  196. Vogel E, Krabbe S, Gründemann J, Wamsteeker Cusulin JI, Lüthi A (2016) Projection-specific dynamic regulation of inhibition in amygdala micro-circuits. Neuron 91(3):644–651.  https://doi.org/10.1016/j.neuron CrossRefPubMedGoogle Scholar
  197. Volkow ND, Wang G-J, Fowler JS, Ding Y-S (2005) Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1410–1415.  https://doi.org/10.1016/j.biopsych.2004.11.006 CrossRefPubMedGoogle Scholar
  198. Walum H, Waldman ID, Young LJ (2016) Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatry 79:251–257.  https://doi.org/10.1016/j.biopsych.2015.06.016 CrossRefPubMedGoogle Scholar
  199. Webb WM, Sanchez RG, Perez G et al (2017) Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory. Neurobiol Learn Mem 142:66–78.  https://doi.org/10.1016/j.nlm.2017.02.010 CrossRefPubMedGoogle Scholar
  200. WHO (2016) Investing in treatment for depression and anxiety leads to fourfold return. In: WHO. http://www.who.int/mediacentre/news/releases/2016/depression-anxiety-treatment/en/. Accessed 5 Apr 2018
  201. Wöhr M, Schwarting RKW (2013) Affective communication in rodents: ultrasonic vocalizations as a tool for research on emotion and motivation. Cell Tissue Res 354:81–97.  https://doi.org/10.1007/s00441-013-1607-9 CrossRefPubMedGoogle Scholar
  202. Woods AM, Bouton ME (2006) D-cycloserine facilitates extinction but does not eliminate renewal of the conditioned emotional response. Behav Neurosci 120:1159–1162.  https://doi.org/10.1037/0735-7044.120.5.1159 CrossRefPubMedGoogle Scholar
  203. Woolf NJ, Butcher LL (1982) Cholinergic projections to the basolateral amygdala: a combined Evans Blue and acetylcholinesterase analysis. Brain Res Bull 8:751–763CrossRefGoogle Scholar
  204. Yang C-H, Shi H-S, Zhu W-L et al (2012) Venlafaxine facilitates between-session extinction and prevents reinstatement of auditory-cue conditioned fear. Behav Brain Res 230:268–273.  https://doi.org/10.1016/j.bbr.2012.02.023 CrossRefPubMedGoogle Scholar
  205. Yin S, Liu Y, Petro NM, et al (2018) Amygdala adaptation and temporal dynamics of the salience network in conditioned fear: a single-trial fMRI study. eNeuro 5. doi:  https://doi.org/10.1523/ENEURO.0445-17.2018 CrossRefGoogle Scholar
  206. Yoon S, Kim JE, Hwang J et al (2017) Recovery from posttraumatic stress requires dynamic and sequential shifts in amygdalar connectivities. Neuropsychopharmacology 42:454–461.  https://doi.org/10.1038/npp.2016.136 CrossRefPubMedGoogle Scholar
  207. Young LJ, Flanagan-Cato LM (2012) Editorial comment: oxytocin, vasopressin and social behavior. Horm Behav 61:227–229.  https://doi.org/10.1016/j.yhbeh.2012.02.019 CrossRefPubMedPubMedCentralGoogle Scholar
  208. Zeidan MA, Igoe SA, Linnman C et al (2011) Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol Psychiatry 70:920–927.  https://doi.org/10.1016/j.biopsych.2011.05.016 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Rodrigo Triana-Del Río
    • 1
  • Erwin van den Burg
    • 1
  • Ron Stoop
    • 1
  • Chloé Hegoburu
    • 1
  1. 1.Laboratory of Neurobiology of emotions, Center of Psychiatric NeuroscienceCHUVLausanneSwitzerland

Personalised recommendations