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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)

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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.

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Fig. 1: Effects of brain-specific exogenous OT or OTR antagonist infusion on fear learning in animal models.
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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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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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  1. Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA

    Michael Janeček & Joanna Dabrowska

  2. Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA

    Joanna Dabrowska

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  1. Michael Janeček
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Correspondence to Joanna Dabrowska.

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Janeček, M., Dabrowska, J. 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). Cell Tissue Res 375, 143–172 (2019). https://doi.org/10.1007/s00441-018-2889-8

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