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Cell and Tissue Research

, Volume 375, Issue 1, pp 143–172 | Cite as

Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies—potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST)

  • Michael Janeček
  • Joanna DabrowskaEmail author
Review
First Online:

Abstract

Despite its relatively well-understood role as a reproductive and pro-social peptide, oxytocin (OT) tells a more convoluted story in terms of its modulation of fear and anxiety. This nuanced story has been obscured by a great deal of research into the therapeutic applications of exogenous OT, driving more than 400 ongoing clinical trials. Drawing from animal models and human studies, we review the complex evidence concerning OT’s role in fear learning and anxiety, clarifying the existing confusion about modulation of fear versus anxiety. We discuss animal models and human studies demonstrating the prevailing role of OT in strengthening fear memory to a discrete signal or cue, which allows accurate and rapid threat detection that facilitates survival. We also review ostensibly contrasting behavioral studies that nonetheless provide compelling evidence of OT attenuating sustained contextual fear and anxiety-like behavior, arguing that these OT effects on the modulation of fear vs. anxiety are not mutually exclusive. To disambiguate how endogenous OT modulates fear and anxiety, an understudied area compared to exogenous OT, we survey behavioral studies utilizing OT receptor (OTR) antagonists. Based on emerging evidence about the role of OTR in rat dorsolateral bed nucleus of stria terminalis (BNST) and elsewhere, we postulate that OT plays a critical role in facilitating accurate discrimination between stimuli representing threat and safety. Supported by human studies, we demonstrate that OT uniquely facilitates adaptive fear but reduces maladaptive anxiety. Last, we explore the limited literature on endogenous OT and its interaction with corticotropin-releasing factor (CRF) with a special emphasis on the dorsolateral BNST, which may hold the key to the neurobiology of phasic fear and sustained anxiety.

Keywords

Oxytocin Fear Anxiety Discrimination BNST CRF CRH Rat Human 

Abbreviations

5-HT

Serotonin

ACC

Anterior cingulate cortex

AAV

Adeno-associated viral vector

am

Anteromedial

AN

Accessory nuclei of the hypothalamus

ASR

Acoustic startle response

AVP

Arginine-vasopressin

BBB

Blood-brain barrier

BLA

Basolateral nucleus of the amygdala

BNST

Bed nucleus of the stria terminalis

CeA

Central nucleus of the amygdala

CeL

Lateral central nucleus of the amygdala

CeM

Medial central nucleus of the amygdala

ChR2

Channel Rhodopsin

CNO

Clozapine-N-oxide

CNS

Central nervous system

CORT

Corticosterone (rodents) or cortisol (humans)

CRF

Corticotropin-releasing factor

CRFR

Corticotropin-releasing factor receptor

CS+

Signaled conditioned stimulus (paired)

CS−

Unsignaled conditioned stimulus or unpaired stimulus

CSC

Chronic subordinate colony

dl

Dorsolateral

DI

Discrimination index

DREADD

Designer receptors exclusively activated by designer drugs

EPM

Elevated plus maze

fMRI

Functional magnetic resonance imaging

FPS

Fear-potentiated startle

FST

Forced swim test

GABA

Gamma-aminobutyric acid

GAD

Generalized anxiety disorder

GSAD

Generalized social anxiety disorder

HAB

High-anxiety-related behavior

HPA

Hypothalamic-pituitary-adrenal

HR

Heart rate

ICV

Intracerebroventricular

IN

Intranasal

IP

Intraperitoneal

ITC

Intercalated cell masses of the amygdala

ITI

Inter-trial interval

IU

International unit

IV

Intravenous

LA

Lateral amygdala

LAB

Low-anxiety-related behavior

LDB

Light-dark box

LH

Lateral hypothalamus

LS

Lateral septum

LTP

Long-term potentiation

mPFC

Medial prefrontal cortex

MeA

Medial amygdala

NAc

Nucleus accumbens

NPS

Neuropeptide S

OF

Open field

OT

Oxytocin

OTKO

Oxytocin knockout

OTR

Oxytocin receptor

OTR-A

Oxytocin receptor antagonist

OTRKO

Oxytocin receptor knockout

PAG

Periaqueductal gray

PKCδ

Protein kinase C delta

PLC

Placebo

PND

Post-natal day

PPI

Pre-pulse inhibition

PTSD

Post-traumatic stress disorder

PVN

Paraventricular nucleus of the hypothalamus

RF

Reticular formation

SAD

Social anxiety disorder

SON

Supraoptic nucleus of the hypothalamus

SC

Subcutaneously

STAI

State-Trait Anxiety Inventory

TGOT

(Thr4, Gly7)-oxytocin; potent oxytocin receptor agonist

TMD

Total movement distance

TSST

Trier social stress test

Ucn

Urocortin

US

Unconditioned stimulus

V1AR

Vasopressin V1A receptor

WAY

WAY-267464; oxytocin analog

WNB

White noise burst

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Notes

Acknowledgements

We thank Rachyl Shanker, CMS’20 from the Dabrowska Lab for the image of PKC-STEP double-immunolabeling in the BNSTdl. This manuscript was supported by the grant from the National Institute of Mental Health R01MH113007 to JD, a DePaul-RFUMS seed research grant to JD, as well as start-up funds from the Chicago Medical School, Rosalind Franklin University of Medicine and Science to JD.

References

  1. Abdullahi PR, Eskandarian S, Ghanbari A, Rashidy-Pour A (2018) Oxytocin receptor antagonist atosiban impairs consolidation, but not reconsolidation of contextual fear memory in rats. Brain ResGoogle Scholar
  2. Acheson D, Feifel D, de Wilde S, McKinney R, Lohr J, Risbrough V (2013) The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology 229:199–208Google Scholar
  3. Acheson DT, Feifel D, Kamenski M, McKinney R, Risbrough VB (2015) Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response. Depression and anxiety 32:400–407Google Scholar
  4. Adolphs R, Tranel D, Damasio H, Damasio A (1994) Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 372:669–672Google Scholar
  5. Amico JA, Mantella RC, Vollmer RR, Li X (2004) Anxiety and stress responses in female oxytocin deficient mice. J Neuroendocrinol 16:319–324Google Scholar
  6. Andreatta M, Glotzbach-Schoon E, Muhlberger A, Schulz SM, Wiemer J, Pauli P (2015) Initial and sustained brain responses to contextual conditioned anxiety in humans. Cortex; a journal devoted to the study of the nervous system and behavior 63:352–363Google Scholar
  7. Arima H, Aguilera G (2000) Vasopressin and oxytocin neurones of hypothalamic supraoptic and paraventricular nuclei co-express mRNA for Type-1 and Type-2 corticotropin-releasing hormone receptors. J Neuroendocrinol 12:833–842Google Scholar
  8. Asok A, Schulkin J, Rosen JB (2016) Corticotropin releasing factor type-1 receptor antagonism in the dorsolateral bed nucleus of the stria terminalis disrupts contextually conditioned fear, but not unconditioned fear to a predator odor. Psychoneuroendocrinology 70:17–24Google Scholar
  9. Asok A, Draper A, Hoffman AF, Schulkin J, Lupica CR, Rosen JB (2018) Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear. Mol Psychiatry 23:914–922Google Scholar
  10. Ayers LW, Missig G, Schulkin J, Rosen JB (2011) Oxytocin reduces background anxiety in a fear-potentiated startle paradigm: peripheral vs central administration. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 36:2488–2497Google Scholar
  11. Ayers L, Agostini A, Schulkin J, Rosen JB (2016) Effects of oxytocin on background anxiety in rats with high or low baseline startle. Psychopharmacology 233:2165–2172Google Scholar
  12. Babic S, Pokusa M, Danevova V, Ding ST, Jezova D (2015) Effects of atosiban on stress-related neuroendocrine factors. J Endocrinol 225:9–17Google Scholar
  13. Bale TL, Davis AM, Auger AP, Dorsa DM, McCarthy MM (2001) CNS region-specific oxytocin receptor expression: importance in regulation of anxiety and sex behavior. J Neurosci 21:2546–2552Google Scholar
  14. Bales KL, Pfeifer LA, Carter CS (2004) Sex differences and developmental effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles. Dev Psychobiol 44:123–131Google Scholar
  15. Bangasser DA, Shors TJ (2008) The bed nucleus of the stria terminalis modulates learning after stress in masculinized but not cycling females. J Neurosci 28:6383–6387Google Scholar
  16. Bartels A (2012) Oxytocin and the social brain: beware the complexity. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 37:1795–1796Google Scholar
  17. Blume A, Bosch OJ, Miklos S, Torner L, Wales L, Waldherr M, Neumann ID (2008) Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus. Eur J Neurosci 27:1947–1956Google Scholar
  18. Bosch OJ (2005) Brain oxytocin correlates with maternal aggression: link to anxiety. J Neurosci 25:6807–6815Google Scholar
  19. Bosch OJ, Young LJ (2017) Oxytocin and social relationships: from attachment to bond disruption. Curr Top Behav NeurosciGoogle Scholar
  20. Bosch OJ, Dabrowska J, Modi ME, Johnson ZV, Keebaugh AC, Barrett CE, Ahern TH, Guo J, Grinevich V, Rainnie DG, Neumann ID, Young LJ (2016) Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles. Psychoneuroendocrinology 64:66–78Google Scholar
  21. Bowen MT, Carson DS, Spiro A, Arnold JC, McGregor IS (2011) Adolescent oxytocin exposure causes persistent reductions in anxiety and alcohol consumption and enhances sociability in rats. PLoS One 6:e27237Google Scholar
  22. Bradley R, Greene J, Russ E, Dutra L, Westen D (2005) A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry 162:214–227Google Scholar
  23. Bruhn TO, Sutton SW, Plotsky PM, Vale WW (1986) Central administration of corticotropin-releasing factor modulates oxytocin secretion in the rat. Endocrinology 119:1558–1563Google Scholar
  24. Bulbul M, Babygirija R, Cerjak D, Yoshimoto S, Ludwig K, Takahashi T (2011) Hypothalamic oxytocin attenuates CRF expression via GABA(A) receptors in rats. Brain Res 1387:39–45Google Scholar
  25. Caballero A, Tseng KY (2016) GABAergic function as a limiting factor for prefrontal maturation during adolescence. Trends Neurosci 39:441–448Google Scholar
  26. Caballero A, Granberg R, Tseng KY (2016) Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev 70:4–12Google Scholar
  27. Caldeyro-Barcia R, Poseiro JJ (1959) Oxytocin and contractility of the pregnant human uterus. Ann N Y Acad Sci 75:813–830Google Scholar
  28. Campbell-Smith EJ, Holmes NM, Lingawi NW, Panayi MC, Westbrook RF (2015) Oxytocin signaling in basolateral and central amygdala nuclei differentially regulates the acquisition, expression, and extinction of context-conditioned fear in rats. Learn Mem 22:247–257Google Scholar
  29. Cavalli J, Ruttorf M, Pahi MR, Zidda F, Flor H, Nees F (2017) Oxytocin differentially modulates pavlovian cue and context fear acquisition. Soc Cogn Affect Neurosci 12:976–983Google Scholar
  30. Chalmers DT, Lovenberg TW, De Souza EB (1995) Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci 15:6340–6350Google Scholar
  31. Chen AM, Perrin MH, Digruccio MR, Vaughan JM, Brar BK, Arias CM, Lewis KA, Rivier JE, Sawchenko PE, Vale WW (2005) A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity. Proc Natl Acad Sci U S A 102:2620–2625Google Scholar
  32. Cohen H, Kaplan Z, Kozlovsky N, Gidron Y, Matar MA, Zohar J (2010) Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses. J Neuroendocrinol 22:889–904Google Scholar
  33. Cohen BE, Edmondson D, Kronish IM (2015) State of the art review: depression, stress, anxiety, and cardiovascular disease. Am J Hypertens 28:1295–1302Google Scholar
  34. Cooper MA, Huhman KL (2005) Corticotropin-releasing factor type II (CRF-sub-2) receptors in the bed nucleus of the stria terminalis modulate conditioned defeat in Syrian hamsters (Mesocricetus auratus). Behav Neurosci 119:1042–1051Google Scholar
  35. Dabrowska J, Hazra R, Ahern TH, Guo JD, McDonald AJ, Mascagni F, Muller JF, Young LJ, Rainnie DG (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 36:1312–1326Google Scholar
  36. Dabrowska J, Hazra R, Guo JD, Dewitt S, Rainnie DG (2013a) Central CRF neurons are not created equal: phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Front Neurosci 7:156Google Scholar
  37. Dabrowska J, Hazra R, Guo JD, Li C, Dewitt S, Xu J, Lombroso PJ, Rainnie DG (2013b) Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis. Biol Psychiatry 74:817–826Google Scholar
  38. Dabrowska J, Martinon D, Moaddab M, Rainnie DG (2016) Targeting corticotropin-releasing factor (CRF) projections from the oval nucleus of the BNST using cell-type specific neuronal tracing studies in mouse and rat brain. J NeuroendocrinolGoogle Scholar
  39. Daniel SE, Rainnie DG (2016) Stress modulation of opposing circuits in the bed nucleus of the stria terminalis. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 41:103–125Google Scholar
  40. Davis M, Walker DL, Miles L, Grillon C (2010) Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 35:105–135Google Scholar
  41. De Bundel D, Zussy C, Espallergues J, Gerfen CR, Girault JA, Valjent E (2016) Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala. Mol Psychiatry 21:1545–1553Google Scholar
  42. de Oliveira DC, Zuardi AW, Graeff FG, Queiroz RH, Crippa JA (2012) Anxiolytic-like effect of oxytocin in the simulated public speaking test. J Psychopharmacol 26:497–504Google Scholar
  43. Demet EM, Chicz-Demet A, Shaffer E (1990) Influence of protein concentration on platelet 3H-imipramine binding. Prog Neuro-Psychopharmacol Biol Psychiatry 14:553–561Google Scholar
  44. Di Simplicio M, Massey-Chase R, Cowen PJ, Harmer CJ (2009) Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers. J Psychopharmacol 23:241–248Google Scholar
  45. Domes G, Heinrichs M, Glascher J, Buchel C, Braus DF, Herpertz SC (2007) Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62:1187–1190Google Scholar
  46. Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M, Herpertz SC (2010) Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 35:83–93Google Scholar
  47. Donadon MF, Martin-Santos R, Osorio FL (2018) The associations between oxytocin and trauma in humans: a systematic review. Front Pharmacol 9:154Google Scholar
  48. Dong N, Du P, Hao X, He Z, Hou W, Wang L, Yuan W, Yang J, Jia R, Tai F (2017) Involvement of GABA A receptors in the regulation of social preference and emotional behaviors by oxytocin in the central amygdala of female mandarin voles. Neuropeptides 66:8–17Google Scholar
  49. Dos Santos Junior ED, Da Silva AV, Da Silva KR, Haemmerle CA, Batagello DS, Da Silva JM, Lima LB, Da Silva RJ, Diniz GB, Sita LV, Elias CF, Bittencourt JC (2015) The centrally projecting Edinger-Westphal nucleus—I: Efferents in the rat brain. J Chem Neuroanat 68:22–38Google Scholar
  50. Dumais KM, Bredewold R, Mayer TE, Veenema AH (2013) Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex- specific ways. Horm Behav 64:693–701Google Scholar
  51. Dunsmoor JE, Paz R (2015) Fear generalization and anxiety: behavioral and neural mechanisms. Biol Psychiatry 78:336–343Google Scholar
  52. Duque-Wilckens N, Steinman MQ, Busnelli M, Chini B, Yokoyama S, Pham M, Laredo SA, Hao R, Perkeybile AM, Minie VA, Tan PB, Bales KL, Trainor BC (2018) Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice. Biol Psychiatry 83:203–213Google Scholar
  53. Duvarci S, Bauer EP, Pare D (2009) The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear. J Neurosci 29:10357–10361Google Scholar
  54. Eckstein M, Becker B, Scheele D, Scholz C, Preckel K, Schlaepfer TE, Grinevich V, Kendrick KM, Maier W, Hurlemann R (2015) Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 78:194–202Google Scholar
  55. Eckstein M, Scheele D, Patin A, Preckel K, Becker B, Walter A, Domschke K, Grinevich V, Maier W, Hurlemann R (2016) Oxytocin facilitates Pavlovian fear learning in males. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 41:932–939Google Scholar
  56. Eidelman-Rothman M, Goldstein A, Levy J, Weisman O, Schneiderman I, Mankuta D, Zagoory-Sharon O, Feldman R (2015) Oxytocin affects spontaneous neural oscillations in trauma-exposed war veterans. Front Behav Neurosci 9:165Google Scholar
  57. Ellenbogen MA, Linnen AM, Cardoso C, Joober R (2014) Intranasal oxytocin attenuates the human acoustic startle response independent of emotional modulation. Psychophysiology 51:1169–1177Google Scholar
  58. Ermisch A, Ruhle HJ, Landgraf R, Hess J (1985) Blood-brain barrier and peptides. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 5:350–357Google Scholar
  59. Eskandarian S, Vafaei AA, Vaezi GH, Taherian F, Kashefi A, Rashidy-Pour A (2013) Effects of systemic administration of oxytocin on contextual fear extinction in a rat model of post-traumatic stress disorder. Basic and clinical neuroscience 4:315–322Google Scholar
  60. Etkin A, Wager TD (2007) Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. The American journal of psychiatry 164:1476–1488Google Scholar
  61. Feeser M, Fan Y, Weigand A, Hahn A, Gartner M, Aust S, Boker H, Bajbouj M, Grimm S (2014) The beneficial effect of oxytocin on avoidance-related facial emotion recognition depends on early life stress experience. Psychopharmacology 231:4735–4744Google Scholar
  62. Fischer-Shofty M, Shamay-Tsoory SG, Harari H, Levkovitz Y (2010) The effect of intranasal administration of oxytocin on fear recognition. Neuropsychologia 48:179–184Google Scholar
  63. Frijling JL, van Zuiden M, Koch SB, Nawijn L, Veltman DJ, Olff M (2016) Effects of intranasal oxytocin on amygdala reactivity to emotional faces in recently trauma-exposed individuals. Soc Cogn Affect Neurosci 11:327–336Google Scholar
  64. Gale GD, Anagnostaras SG, Godsil BP, Mitchell S, Nozawa T, Sage JR, Wiltgen B, Fanselow MS (2004) Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of rats. J Neurosci 24:3810–3815Google Scholar
  65. Gewirtz JC, McNish KA, Davis M (1998) Lesions of the bed nucleus of the stria terminalis block sensitization of the acoustic startle reflex produced by repeated stress, but not fear-potentiated startle. Prog Neuro-Psychopharmacol Biol Psychiatry 22:625–648Google Scholar
  66. Goode TD, Maren S (2017) Role of the bed nucleus of the stria terminalis in aversive learning and memory. Learn Mem 24:480–491Google Scholar
  67. Goode TD, Kim JJ, Maren S (2015) Reversible inactivation of the bed nucleus of the stria terminalis prevents reinstatement but not renewal of extinguished fear. eNeuro 2Google Scholar
  68. Gorka SM, Fitzgerald DA, Labuschagne I, Hosanagar A, Wood AG, Nathan PJ, Phan KL (2015) Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 40:278–286Google Scholar
  69. Grillon C, Pine DS, Lissek S, Rabin S, Bonne O, Vythilingam M (2009) Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol Psychiatry 66:47–53Google Scholar
  70. Grillon C, Krimsky M, Charney DR, Vytal K, Ernst M, Cornwell B (2013) Oxytocin increases anxiety to unpredictable threat. Mol Psychiatry 18:958–960Google Scholar
  71. Grillon C, Hale E, Lieberman L, Davis A, Pine DS, Ernst M (2015) The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 40:1064–1071Google Scholar
  72. Grippo AJ, Gerena D, Huang J, Kumar N, Shah M, Ughreja R, Carter CS (2007) Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles. Psychoneuroendocrinology 32:966–980Google Scholar
  73. Grippo AJ, Trahanas DM, Zimmerman RR 2nd, Porges SW, Carter CS (2009) Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation. Psychoneuroendocrinology 34:1542–1553Google Scholar
  74. Grippo AJ, Pournajafi-Nazarloo H, Sanzenbacher L, Trahanas DM, McNeal N, Clarke DA, Porges SW, Sue Carter C (2012) Peripheral oxytocin administration buffers autonomic but not behavioral responses to environmental stressors in isolated prairie voles. Stress 15:149–161Google Scholar
  75. Grund T, Goyon S, Li Y, Eliava M, Liu H, Charlet A, Grinevich V, Neumann ID (2017) Neuropeptide S activates paraventricular oxytocin neurons to induce anxiolysis. J Neurosci 37:12214–12225Google Scholar
  76. Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS (2009) A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 34:917–923Google Scholar
  77. Gungor NZ, Pare D (2016) Functional heterogeneity in the bed nucleus of the stria terminalis. J Neurosci 36:8038–8049Google Scholar
  78. Gungor NZ, Yamamoto R, Pare D (2015) Optogenetic study of the projections from the bed nucleus of the stria terminalis to the central amygdala. J Neurophysiol 114:2903–2911Google Scholar
  79. Guzman YF, Tronson NC, Jovasevic V, Sato K, Guedea AL, Mizukami H, Nishimori K, Radulovic J (2013) Fear-enhancing effects of septal oxytocin receptors. Nat Neurosci 16:1185–1187Google Scholar
  80. Hammack SE, Richey KJ, Watkins LR, Maier SF (2004) Chemical lesion of the bed nucleus of the stria terminalis blocks the behavioral consequences of uncontrollable stress. Behav Neurosci 118:443–448Google Scholar
  81. Hammack SE, Guo JD, Hazra R, Dabrowska J, Myers KM, Rainnie DG (2009) The response of neurons in the bed nucleus of the stria terminalis to serotonin: implications for anxiety. Prog Neuro-Psychopharmacol Biol PsychiatryGoogle Scholar
  82. Han JS, Maeda Y, Knepper MA (1993) Dual actions of vasopressin and oxytocin in regulation of water permeability in terminal collecting duct. Am J Phys 265:F26–F34Google Scholar
  83. Harden SW, Frazier CJ (2016) Oxytocin depolarizes fast-spiking hilar interneurons and induces GABA release onto mossy cells of the rat dentate gyrus. HippocampusGoogle Scholar
  84. Haubensak W, Kunwar PS, Cai H, Ciocchi S, Wall NR, Ponnusamy R, Biag J, Dong HW, Deisseroth K, Callaway EM, Fanselow MS, Luthi A, Anderson DJ (2010) Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468:270–276Google Scholar
  85. Haufler D, Nagy FZ, Pare D (2013) Neuronal correlates of fear conditioning in the bed nucleus of the stria terminalis. Learn Mem (Cold Spring Harbor, NY) 20:633–641Google Scholar
  86. Hauger RL, Olivares-Reyes JA, Braun S, Catt KJ, Dautzenberg FM (2003a) Mediation of corticotropin releasing factor type 1 receptor phosphorylation and desensitization by protein kinase C: a possible role in stress adaptation. J Pharmacol Exp Ther 306:794–803Google Scholar
  87. Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM (2003b) International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. Pharmacol Rev 55:21–26Google Scholar
  88. Havranek T, Zatkova M, Lestanova Z, Bacova Z, Mravec B, Hodosy J, Strbak V, Bakos J (2015) Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I. J Neurosci Res 93:893–901Google Scholar
  89. Henckens M, Printz Y, Shamgar U, Dine J, Lebow M, Drori Y, Kuehne C, Kolarz A, Eder M, Deussing JM, Justice NJ, Yizhar O, Chen A (2017) CRF receptor type 2 neurons in the posterior bed nucleus of the stria terminalis critically contribute to stress recovery. Mol Psychiatry 22:1691–1700Google Scholar
  90. Herrmann MJ, Boehme S, Becker MP, Tupak SV, Guhn A, Schmidt B, Brinkmann L, Straube T (2016) Phasic and sustained brain responses in the amygdala and the bed nucleus of the stria terminalis during threat anticipation. Hum Brain Mapp 37:1091–1102Google Scholar
  91. Hicks C, Jorgensen W, Brown C, Fardell J, Koehbach J, Gruber CW, Kassiou M, Hunt GE, McGregor IS (2012) The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats. J Neuroendocrinol 24:1012–1029Google Scholar
  92. Hitchcock JM, Davis M (1991) Efferent pathway of the amygdala involved in conditioned fear as measured with the fear-potentiated startle paradigm. Behav Neurosci 105:826–842Google Scholar
  93. Huber D, Veinante P, Stoop R (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science (New York NY) 308:245–248Google Scholar
  94. Hurlemann R, Patin A, Onur OA, Cohen MX, Baumgartner T, Metzler S, Dziobek I, Gallinat J, Wagner M, Maier W, Kendrick KM (2010) Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans. J Neurosci 30:4999–5007Google Scholar
  95. Ingram CD, Cutler KL, Wakerley JB (1990) Oxytocin excites neurones in the bed nucleus of the stria terminalis of the lactating rat in vitro. Brain Res 527:167–170Google Scholar
  96. Jaferi A, Pickel VM (2009) Mu-opioid and corticotropin-releasing-factor receptors show largely postsynaptic co-expression, and separate presynaptic distributions, in the mouse central amygdala and bed nucleus of the stria terminalis. Neuroscience 159:526–539Google Scholar
  97. Jamieson BB, Nair BB, Iremonger KJ (2017) Regulation of hypothalamic CRH neuron excitability by oxytocin. J NeuroendocrinolGoogle Scholar
  98. Jovanovic T, Ressler KJ (2010) How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am J Psychiatry 167:648–662Google Scholar
  99. Jovanovic T, Norrholm SD, Fennell JE, Keyes M, Fiallos AM, Myers KM, Davis M, Duncan EJ (2009) Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity. Psychiatry Res 167:151–160Google Scholar
  100. Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G, Neumann ID, van den Burg EH (2015) Oxytocin regulates stress-induced Crf gene transcription through CREB-regulated transcription coactivator 3. J Neurosci 35:12248–12260Google Scholar
  101. Kash TL, Winder DG (2006) Neuropeptide Y and corticotropin-releasing factor bi-directionally modulate inhibitory synaptic transmission in the bed nucleus of the stria terminalis. Neuropharmacology 51:1013–1022Google Scholar
  102. Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science (New York, NY) 256:675–677Google Scholar
  103. Kim SJ, Park SH, Choi SH, Moon BH, Lee KJ, Kang SW, Lee MS, Choi SH, Chun BG, Shin KH (2006) Effects of repeated tianeptine treatment on CRF mRNA expression in non-stressed and chronic mild stress-exposed rats. Neuropharmacology 50:824–833Google Scholar
  104. King MG, Brown R, Kusnecov A (1985) An increase in startle response in rats administered oxytocin. Peptides 6:567–568Google Scholar
  105. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489–11493Google Scholar
  106. Klampfl SM, Schramm MM, Gassner BM, Hubner K, Seasholtz AF, Brunton PJ, Bayerl DS, Bosch OJ (2018) Maternal stress and the MPOA: activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats. Neuropharmacology 133:440–450Google Scholar
  107. Klenerova V, Krejci I, Sida P, Hlinak Z, Hynie S (2009) Oxytocin and carbetocin effects on spontaneous behavior of male rats: modulation by oxytocin receptor antagonists. Neuro endocrinology letters 30:335–342Google Scholar
  108. Klenerova V, Krejci I, Sida P, Hlinak Z, Hynie S (2010) Oxytocin and carbetocin ameliorating effects on restraint stress-induced short- and long-term behavioral changes in rats. Neuro endocrinology letters 31:622–630Google Scholar
  109. Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, Osten P, Schwarz MK, Seeburg PH, Stoop R, Grinevich V (2012) Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73:553–566Google Scholar
  110. Koch SB, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M (2014) Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes. Psychoneuroendocrinology 40:242–256Google Scholar
  111. Koch SB, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M (2016) Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 41:2041–2051Google Scholar
  112. Kovacs GL, Bohus B, Versteeg DH, de Kloet ER, de Wied D (1979) Effect of oxytocin and vasopressin on memory consolidation: sites of action and catecholaminergic correlates after local microinjection into limbic-midbrain structures. Brain Res 175:303–314Google Scholar
  113. Kritman M, Lahoud N, Maroun M (2017) Oxytocin in the amygdala and not the prefrontal cortex enhances fear and impairs extinction in the juvenile rat. Neurobiol Learn Mem 141:179–188Google Scholar
  114. Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M, Stout JC, Nathan PJ (2010) Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 35:2403–2413Google Scholar
  115. Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M, Stout JC, Nathan PJ (2012) Medial frontal hyperactivity to sad faces in generalized social anxiety disorder and modulation by oxytocin. Int J Neuropsychopharmacol 15:883–896Google Scholar
  116. Lahoud N, Maroun M (2013) Oxytocinergic manipulations in corticolimbic circuit differentially affect fear acquisition and extinction. Psychoneuroendocrinology 38:2184–2195Google Scholar
  117. Landgraf R, Wigger A (2002) High vs low anxiety-related behavior rats: an animal model of extremes in trait anxiety. Behav Genet 32:301–314Google Scholar
  118. Lange MD, Daldrup T, Remmers F, Szkudlarek HJ, Lesting J, Guggenhuber S, Ruehle S, Jungling K, Seidenbecher T, Lutz B, Pape HC (2017) Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat. Mol Psychiatry 22:1422–1430Google Scholar
  119. Lebow MA, Chen A (2016) Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol Psychiatry 21:450–463Google Scholar
  120. LeDoux J (1998) Fear and the brain: where have we been, and where are we going? Biol Psychiatry 44:1229–1238Google Scholar
  121. 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 8:2517–2529Google Scholar
  122. Lee Y, Davis M (1997) Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. J Neurosci 17:6434–6446Google Scholar
  123. Lee Y, Fitz S, Johnson PL, Shekhar A (2008) Repeated stimulation of CRF receptors in the BNST of rats selectively induces social but not panic-like anxiety. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 33:2586–2594Google Scholar
  124. Leng G, Ludwig M (2016) Intranasal oxytocin: myths and delusions. Biol Psychiatry 79:243–250Google Scholar
  125. Lever C, Burton S, O'Keefe J (2006) Rearing on hind legs, environmental novelty, and the hippocampal formation. Rev Neurosci 17:111–133Google Scholar
  126. Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW (2001) Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci U S A 98:7570–7575Google Scholar
  127. Liddell BJ, Brown KJ, Kemp AH, Barton MJ, Das P, Peduto A, Gordon E, Williams LM (2005) A direct brainstem-amygdala-cortical 'alarm' system for subliminal signals of fear. NeuroImage 24:235–243Google Scholar
  128. Lissek S, Kaczkurkin AN, Rabin S, Geraci M, Pine DS, Grillon C (2014) Generalized anxiety disorder is associated with overgeneralization of classically conditioned fear. Biol Psychiatry 75:909–915Google Scholar
  129. LoBue V (2009) More than just another face in the crowd: superior detection of threatening facial expressions in children and adults. Dev Sci 12:305–313Google Scholar
  130. Lobue V, DeLoache JS (2008) Detecting the snake in the grass: attention to fear-relevant stimuli by adults and young children. Psychol Sci 19:284–289Google Scholar
  131. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB, Oltersdorf T (1995) Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc Natl Acad Sci U S A 92:836–840Google Scholar
  132. Lukas M, Toth I, Veenema AH, Neumann ID (2013) Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics. Psychoneuroendocrinology 38:916–926Google Scholar
  133. Luyck K, Nuttin B, Luyten L (2017) Electrolytic post-training lesions of the bed nucleus of the stria terminalis block startle potentiation in a cued fear conditioning procedure. Brain Struct FunctGoogle Scholar
  134. Mak P, Broussard C, Vacy K, Broadbear JH (2012) Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat. J Psychopharmacol 26:532–542Google Scholar
  135. Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, Durroux T, Mouillac B, Corbani M, Guillon G (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol 24:609–628Google Scholar
  136. Mantella RC, Vollmer RR, Li X, Amico JA (2003) Female oxytocin-deficient mice display enhanced anxiety-related behavior. Endocrinology 144:2291–2296Google Scholar
  137. Marcinkiewcz CA, Mazzone CM, D'Agostino G, Halladay LR, Hardaway JA, DiBerto JF, Navarro M, Burnham N, Cristiano C, Dorrier CE, Tipton GJ, Ramakrishnan C, Kozicz T, Deisseroth K, Thiele TE, McElligott ZA, Holmes A, Heisler LK, Kash TL (2016) Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature 537:97–101Google Scholar
  138. 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 12:183Google Scholar
  139. Matus-Amat P, Higgins EA, Sprunger D, Wright-Hardesty K, Rudy JW (2007) The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories. Behav Neurosci 121:721–731Google Scholar
  140. McCarthy MM, McDonald CH, Brooks PJ, Goldman D (1996) An anxiolytic action of oxytocin is enhanced by estrogen in the mouse. Physiol Behav 60:1209–1215Google Scholar
  141. Meloni EG, Jackson A, Gerety LP, Cohen BM, Carlezon WA Jr (2006) Role of the bed nucleus of the stria terminalis (BST) in the expression of conditioned fear. Ann N Y Acad Sci 1071:538–541Google Scholar
  142. Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61–71Google Scholar
  143. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK (2008) Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res 42:515–520Google Scholar
  144. Missig G, Ayers LW, Schulkin J, Rosen JB (2010) Oxytocin reduces background anxiety in a fear-potentiated startle paradigm. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 35:2607–2616Google Scholar
  145. Miyata I, Shiota C, Ikeda Y, Oshida Y, Chaki S, Okuyama S, Inagami T (1999) Cloning and characterization of a short variant of the corticotropin-releasing factor receptor subtype from rat amygdala. Biochem Biophys Res Commun 256:692–696Google Scholar
  146. Miyata I, Shiota C, Chaki S, Okuyama S, Inagami T (2001) Localization and characterization of a short isoform of the corticotropin-releasing factor receptor type 2alpha (CRF(2)alpha-tr) in the rat brain. Biochem Biophys Res Commun 280:553–557Google Scholar
  147. 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 121:130–139Google Scholar
  148. Modi ME, Majchrzak MJ, Fonseca KR, Doran A, Osgood S, Vanase-Frawley M, Feyfant E, McInnes H, Darvari R, Buhl DL, Kablaoui NM (2016) Peripheral administration of a long-acting peptide oxytocin receptor agonist inhibits fear-induced freezing. J Pharmacol Exp Ther 358:164–172Google Scholar
  149. Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, Dolan RJ (1996) A differential neural response in the human amygdala to fearful and happy facial expressions. Nature 383:812–815Google Scholar
  150. Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150Google Scholar
  151. Nakajima M, Gorlich A, Heintz N (2014) Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159:295–305Google Scholar
  152. Neumann ID, Slattery DA (2016) Oxytocin in general anxiety and social fear: a translational approach. Biol Psychiatry 79:213–221Google Scholar
  153. Neumann ID, Torner L, Wigger A (1999) Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 95:567–575Google Scholar
  154. Nickerson K, Bonsness RW, Douglas RG, Condliffe P, Du Vigneaud V (1954) Oxytocin and milk ejection. Am J Obstet Gynecol 67:1028–1034Google Scholar
  155. Nomura M, Saito J, Ueta Y, Muglia LJ, Pfaff DW, Ogawa S (2003) Enhanced up-regulation of corticotropin-releasing hormone gene expression in response to restraint stress in the hypothalamic paraventricular nucleus of oxytocin gene-deficient male mice. J Neuroendocrinol 15:1054–1061Google Scholar
  156. Norrholm SD, Jovanovic T, Olin IW, Sands LA, Karapanou I, Bradley B, Ressler KJ (2011) Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity. Biol Psychiatry 69:556–563Google Scholar
  157. Nyuyki KD, Waldherr M, Baeuml S, Neumann ID (2011) Yes, I am ready now: differential effects of paced versus unpaced mating on anxiety and central oxytocin release in female rats. PLoS One 6:e23599Google Scholar
  158. Olff M, Langeland W, Draijer N, Gersons BP (2007) Gender differences in posttraumatic stress disorder. Psychol Bull 133:183–204Google Scholar
  159. Olff M, Langeland W, Witteveen A, Denys D (2010) A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder. CNS spectrums 15:522–530Google Scholar
  160. Owen SF, Tuncdemir SN, Bader PL, Tirko NN, Fishell G, Tsien RW (2013) Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500:458–462Google Scholar
  161. Pagani JH, Lee HJ, Young WS 3rd (2011) Postweaning, forebrain-specific perturbation of the oxytocin system impairs fear conditioning. Genes Brain Behav 10:710–719Google Scholar
  162. Pagani JH, Williams Avram SK, Cui Z, Song J, Mezey E, Senerth JM, Baumann MH, Young WS (2015) Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only. Genes Brain Behav 14:167–176Google Scholar
  163. Pare D, Quirk GJ, Ledoux JE (2004) New vistas on amygdala networks in conditioned fear. J Neurophysiol 92:1–9Google Scholar
  164. Pedersen CA, Caldwell JD, Peterson G, Walker CH, Mason GA (1992) Oxytocin activation of maternal behavior in the rat. Ann N Y Acad Sci 652:58–69Google Scholar
  165. Pelrine E, Pasik SD, Bayat L, Goldschmiedt D, Bauer EP (2016) 5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors. Neurobiol Learn Mem 136:189–195Google Scholar
  166. Peters S, Slattery DA, Uschold-Schmidt N, Reber SO, Neumann ID (2014) Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 42:225–236Google Scholar
  167. Petrovic P, Kalisch R, Singer T, Dolan RJ (2008) Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J Neurosci 28:6607–6615Google Scholar
  168. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285Google Scholar
  169. Phillips ML, Young AW, Scott SK, Calder AJ, Andrew C, Giampietro V, Williams SC, Bullmore ET, Brammer M, Gray JA (1998) Neural responses to facial and vocal expressions of fear and disgust. Proceedings Biological sciences 265:1809–1817Google Scholar
  170. Pisansky MT, Hanson LR, Gottesman II, Gewirtz JC (2017) Oxytocin enhances observational fear in mice. Nat Commun 8:2102Google Scholar
  171. Pitman RK, Orr SP, Lasko NB (1993) Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res 48:107–117Google Scholar
  172. Pitzalis MV, Iacoviello M, Todarello O, Fioretti A, Guida P, Massari F, Mastropasqua F, Russo GD, Rizzon P (2001) Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am Heart J 141:765–771Google Scholar
  173. Pomrenze MB, Millan EZ, Hopf FW, Keiflin R, Maiya R, Blasio A, Dadgar J, Kharazia V, De Guglielmo G, Crawford E, Janak PH, George O, Rice KC, Messing RO (2015) A transgenic rat for investigating the anatomy and function of corticotrophin releasing factor circuits. Front Neurosci 9:487Google Scholar
  174. Preckel K, Scheele D, Kendrick KM, Maier W, Hurlemann R (2014) Oxytocin facilitates social approach behavior in women. Front Behav Neurosci 8:191Google Scholar
  175. Quintana DS, Westlye LT, Alnaes D, Rustan OG, Kaufmann T, Smerud KT, Mahmoud RA, Djupesland PG, Andreassen OA (2016) Low dose intranasal oxytocin delivered with breath powered device dampens amygdala response to emotional stimuli: a peripheral effect-controlled within-subjects randomized dose-response fMRI trial. Psychoneuroendocrinology 69:180–188Google Scholar
  176. Ragen BJ, Seidel J, Chollak C, Pietrzak RH, Neumeister A (2015) Investigational drugs under development for the treatment of PTSD. Expert Opin Investig Drugs 24:659–672Google Scholar
  177. Rauch SA, Grunfeld TE, Yadin E, Cahill SP, Hembree E, Foa EB (2009) Changes in reported physical health symptoms and social function with prolonged exposure therapy for chronic posttraumatic stress disorder. Depression and anxiety 26:732–738Google Scholar
  178. Ravinder S, Burghardt NS, Brodsky R, Bauer EP, Chattarji S (2013) A role for the extended amygdala in the fear-enhancing effects of acute selective serotonin reuptake inhibitor treatment. Transl Psychiatry 3:e209Google Scholar
  179. Regev L, Neufeld-Cohen A, Tsoory M, Kuperman Y, Getselter D, Gil S, Chen A (2011) Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation. Mol Psychiatry 16:714–728Google Scholar
  180. Reinders AA, Glascher J, de Jong JR, Willemsen AT, den Boer JA, Buchel C (2006) Detecting fearful and neutral faces: BOLD latency differences in amygdala-hippocampal junction. NeuroImage 33:805–814Google Scholar
  181. Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S, Rahman Z, Rosenzweig-Lipson S (2006) Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology 185:218–225Google Scholar
  182. Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z, Sukoff Rizzo SJ, Luo B, Beyer CE, Logue SF, Marquis KL, Hughes ZA, Rosenzweig-Lipson S (2010) Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 58:69–77Google Scholar
  183. Roman AN, Martinon D, Dabrowska J (2017) Corticotropin-releasing factor (CRF) neurons in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) modulate fear and anxiety in rats. Society for Neuroscience Annual Meeting Washington DC 513:510Google Scholar
  184. Roozendaal B, Schoorlemmer GH, Wiersma A, Sluyter S, Driscoll P, Koolhaas JM, Bohus B (1992) Opposite effects of central amygdaloid vasopressin and oxytocin on the regulation of conditioned stress responses in male rats. Ann N Y Acad Sci 652:460–461Google Scholar
  185. Rothbaum BO, Davis M (2003) Applying learning principles to the treatment of post-trauma reactions. Ann N Y Acad Sci 1008:112–121Google Scholar
  186. Rupp HA, James TW, Ketterson ED, Sengelaub DR, Ditzen B, Heiman JR (2014) Amygdala response to negative images in postpartum vs nulliparous women and intranasal oxytocin. Soc Cogn Affect Neurosci 9:48–54Google Scholar
  187. Sabihi S, Durosko NE, Dong SM, Leuner B (2014a) Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats. Psychoneuroendocrinology 45:31–42Google Scholar
  188. Sabihi S, Dong SM, Durosko NE, Leuner B (2014b) Oxytocin in the medial prefrontal cortex regulates maternal care, maternal aggression and anxiety during the postpartum period. Front Behav Neurosci 8:258Google Scholar
  189. Sack M, Spieler D, Wizelman L, Epple G, Stich J, Zaba M, Schmidt U (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 15:40Google Scholar
  190. Sahuque LL, Kullberg EF, McGeehan AJ, Kinder JR, Hicks MP, Blanton MG, Janak PH, Olive MF (2006) Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacology 186:122–132Google Scholar
  191. Sanford CA, Soden ME, Baird MA, Miller SM, Schulkin J, Palmiter RD, Clark M, Zweifel LS (2017) A central amygdala CRF circuit facilitates learning about weak threats. Neuron 93:164–178Google Scholar
  192. Schumacher S, Oe M, Wilhelm FH, Rufer M, Heinrichs M, Weidt S, Moergeli H, Martin-Soelch C (2018) Does trait anxiety influence effects of oxytocin on eye-blink startle reactivity? A randomized, double-blind, placebo-controlled crossover study. PLoS One 13:e0190809Google Scholar
  193. Selden NR, Everitt BJ, Jarrard LE, Robbins TW (1991) Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience 42:335–350Google Scholar
  194. Shackman AJ, Fox AS (2016) Contributions of the central extended amygdala to fear and anxiety. J Neurosci 36:8050–8063Google Scholar
  195. Shahrestani S, Kemp AH, Guastella AJ (2013) The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 38:1929–1936Google Scholar
  196. Sink KS, Walker DL, Freeman SM, Flandreau EI, Ressler KJ, Davis M (2013) Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol Psychiatry 18:308–319Google Scholar
  197. Slattery DA, Neumann ID (2010) Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats. Neuropharmacology 58:56–61Google Scholar
  198. Smith AS, Tabbaa M, Lei K, Eastham P, Butler MJ, Linton L, Altshuler R, Liu Y, Wang Z (2016) Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. Psychoneuroendocrinology 63:50–58Google Scholar
  199. Sofroniew MV (1983) Morphology of vasopressin and oxytocin neurones and their central and vascular projections. Prog Brain Res 60:101–114Google Scholar
  200. Somerville LH, Whalen PJ, Kelley WM (2010) Human bed nucleus of the stria terminalis indexes hypervigilant threat monitoring. Biol Psychiatry 68:416–424Google Scholar
  201. Sparta DR, Jennings JH, Ung RL, Stuber GD (2013) Optogenetic strategies to investigate neural circuitry engaged by stress. Behav Brain Res 255:19–25Google Scholar
  202. Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG (2013) Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 16:255–260Google Scholar
  203. Straube T, Mentzel HJ, Miltner WH (2007) Waiting for spiders: brain activation during anticipatory anxiety in spider phobics. NeuroImage 37:1427–1436Google Scholar
  204. Striepens N, Scheele D, Kendrick KM, Becker B, Schafer L, Schwalba K, Reul J, Maier W, Hurlemann R (2012) Oxytocin facilitates protective responses to aversive social stimuli in males. Proc Natl Acad Sci U S A 109:18144–18149Google Scholar
  205. Suda T, Kageyama K, Sakihara S, Nigawara T (2004) Physiological roles of urocortins, human homologues of fish urotensin I, and their receptors. Peptides 25:1689–1701Google Scholar
  206. Sullivan GM, Apergis J, Bush DE, Johnson LR, Hou M, Ledoux JE (2004) Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus. Neuroscience 128:7–14Google Scholar
  207. Sun N, Cassell MD (1993) Intrinsic GABAergic neurons in the rat central extended amygdala. J Comp Neurol 330:381–404Google Scholar
  208. Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6:269–324Google Scholar
  209. Tian JB, Shan X, Bishop GA, King JS (2006) Presynaptic localization of a truncated isoform of the type 2 corticotropin releasing factor receptor in the cerebellum. Neuroscience 138:691–702Google Scholar
  210. Toth I, Neumann ID, Slattery DA (2012) Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner. Psychopharmacology 223:149–158Google Scholar
  211. Tribollet E, Dubois-Dauphin M, Dreifuss JJ, Barberis C, Jard S (1992) Oxytocin receptors in the central nervous system. Distribution, development, and species differences. Ann N Y Acad Sci 652:29–38Google Scholar
  212. Uvnas-Moberg K, Alster P, Hillegaart V, Ahlenius S (1992) Oxytocin reduces exploratory motor behaviour and shifts the activity towards the centre of the arena in male rats. Acta Physiol Scand 145:429–430Google Scholar
  213. Uvnas-Moberg K, Ahlenius S, Hillegaart V, Alster P (1994) High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats. Pharmacol Biochem Behav 49:101–106Google Scholar
  214. van Zuiden M, Frijling JL, Nawijn L, Koch SBJ, Goslings JC, Luitse JS, Biesheuvel TH, Honig A, Veltman DJ, Olff M (2017) Intranasal oxytocin to prevent posttraumatic stress disorder symptoms: a randomized controlled trial in emergency department patients. Biol Psychiatry 81:1030–1040Google Scholar
  215. Veinante P, Freund-Mercier MJ (1997) Distribution of oxytocin- and vasopressin-binding sites in the rat extended amygdala: a histoautoradiographic study. J Comp Neurol 383:305–325Google Scholar
  216. Ventura-Silva AP, Pego JM, Sousa JC, Marques AR, Rodrigues AJ, Marques F, Cerqueira JJ, Almeida OF, Sousa N (2012) Stress shifts the response of the bed nucleus of the stria terminalis to an anxiogenic mode. Eur J Neurosci 36:3396–3406Google Scholar
  217. Verbalis JG, Blackburn RE, Olson BR, Stricker EM (1993) Central oxytocin inhibition of food and salt ingestion: a mechanism for intake regulation of solute homeostasis. Regul Pept 45:149–154Google Scholar
  218. Viviani D, Charlet A, van den Burg E, Robinet C, Hurni N, Abatis M, Magara F, Stoop R (2011) Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333:104–107Google Scholar
  219. Waldherr M, Neumann ID (2007) Centrally released oxytocin mediates mating-induced anxiolysis in male rats. Proc Natl Acad Sci U S A 104:16681–16684Google Scholar
  220. Walker DL, Davis M (1997) Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. J Neurosci 17:9375–9383Google Scholar
  221. Walker D, Yang Y, Ratti E, Corsi M, Trist D, Davis M (2009a) Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-enhanced startle suggest preferential involvement in sustained vs phasic threat responses. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 34:1533–1542Google Scholar
  222. Walker DL, Miles LA, Davis M (2009b) Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuro-Psychopharmacol Biol Psychiatry 33:1291–1308Google Scholar
  223. Wang T, Shi C, Li X, Zhang P, Liu B, Wang H, Wang Y, Yang Y, Wu Y, Li H, Xu ZD (2018) Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model. Behav Brain Res 336:236–243Google Scholar
  224. Weathers FW, Bovin MJ, Lee DJ, Sloan DM, Schnurr PP, Kaloupek DG, Keane TM, Marx BP (2018) The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychol Assess 30:383–395Google Scholar
  225. Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA (1998) Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J Neurosci 18:411–418Google Scholar
  226. Wilensky AE, Schafe GE, Kristensen MP, LeDoux JE (2006) Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J Neurosci 26:12387–12396Google Scholar
  227. Windle RJ, Shanks N, Lightman SL, Ingram CD (1997) Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology 138:2829–2834Google Scholar
  228. Winslow JT, Noble PL, Davis M (2008) AX+/BX- discrimination learning in the fear-potentiated startle paradigm in monkeys. Learn Mem 15:63–66Google Scholar
  229. Wood RI, Knoll AT, Levitt P (2015) Social housing conditions and oxytocin and vasopressin receptors contribute to ethanol conditioned social preference in female mice. Physiol Behav 151:469–477Google Scholar
  230. Yassa MA, Hazlett RL, Stark CE, Hoehn-Saric R (2012) Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder. J Psychiatr Res 46:1045–1052Google Scholar
  231. Yoshida M, Takayanagi Y, Inoue K, Kimura T, Young LJ, Onaka T, Nishimori K (2009) Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci 29:2259–2271Google Scholar
  232. Yu CJ, Zhang SW, Tai FD (2016) Effects of nucleus accumbens oxytocin and its antagonist on social approach behavior. Behav Pharmacol 27:672–680Google Scholar
  233. Zaninetti M, Raggenbass M (2000) Oxytocin receptor agonists enhance inhibitory synaptic transmission in the rat hippocampus by activating interneurons in stratum pyramidale. Eur J Neurosci 12:3975–3984Google Scholar
  234. Zoicas I, Slattery DA, Neumann ID (2014) Brain oxytocin in social fear conditioning and its extinction: involvement of the lateral septum. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 39:3027–3035Google Scholar

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

Authors and Affiliations

  1. 1.Department of Cellular and Molecular Pharmacology, Chicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA
  2. 2.Department of Neuroscience, Chicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA

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