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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

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

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.

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Copyright information

© 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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