Assembling the Puzzle: Pathways of Oxytocin Signaling in the Brain

doi:10.1016/j.biopsych.2015.04.013

Biological Psychiatry

Volume 79, Issue 3, 1 February 2016, Pages 155-164

https://doi.org/10.1016/j.biopsych.2015.04.013 Get rights and content

Abstract

Oxytocin (OT) is a neuropeptide, which can be seen to be one of the molecules of the decade due to its profound prosocial effects in nonvertebrate and vertebrate species, including humans. Although OT can be detected in various physiological fluids (blood, saliva, urine, cerebrospinal fluid) and brain tissue, it is unclear whether peripheral and central OT releases match and synergize. Moreover, the pathways of OT delivery to brain regions involved in specific behaviors are far from clear. Here, we discuss the evolutionarily and ontogenetically determined pathways of OT delivery and OT signaling, which orchestrate activity of the mesolimbic social decision-making network. Furthermore, we speculate that both the alteration in OT delivery and OT receptor expression may cause behavioral abnormalities in patients afflicted with psychosocial diseases.

Section snippets

OT Receptor Trajectories in Evolution

To elicit its actions in the brain, OT must reach and activate its main target, the OT receptor (OTR), whose distribution and level of expression crucially contribute to define its pattern of activity. OT can also bind to and activate, even with a lower efficacy, the related AVP receptor subtypes (V1a, V1b, and V2), which may thus constitute alternative targets, at least in some particular conditions (i.e., at high local OT concentration and/or in regions with no OTR expression).²

Mismatch Between OTR and OT Axons?

The detection of OT immunosignal in a few brain regions, compared with a more widespread expression of OTR, led to a common assumption that has prevailed for the last 20 years about a profound mismatch between OT fibers and OTR within many brain areas. Furthermore, this mismatch was considered to be an argument for diffusion of OT through the adult brain after an event of somatodendritic release from hypothalamic nuclei (45). However, in our previous work employing viral vector-based techniques

OTR Activation by Diffusion

Few considerations should be made concerning the amount of OT that, within the brain, can diffuse to activate OTRs. In basal conditions, microdialysis studies [reviewed in (54)] reported a quantity of OT around 4 pg/sample in 30-minute dialysates from the SON and 2 pg/sample in dialysates from PVN (55, 56). In other discrete brain regions a few millimeters away from the SON and PVN [i.e., the lateral septum, amygdala, and dorsal hippocampus (55, 57, 58, 59)], OT concentrations were only twofold

As a Conclusion: OT Signaling and Psychosocial Alterations

Despite weekly published articles reporting effects of externally applied OT on a number of social behaviors in humans, primates, and rodents, there is still no evidence for consistent and reproducible ameliorating effects of exogenous OT administration on social dysfunction in patients affected by psychiatric or neurodevelopmental disorders (73).

Nevertheless, in preclinical animal models characterized by autistic-like symptoms, OT administration has been reported to rescue social deficits when

Acknowledgments and Disclosures

The preparation of this review was funded by the Chica and Heinz Schaller Research Foundation, the German Research Foundation Grant No. GR 3619/4-1, the German Research Foundation within the Collaborative Research Center “Functional Ensembles” SFB-1134, Royal Society Edinburgh Award, German Academic Exchange Service program for partnership between German and Japanese Universities, Partenariat Hubert Curien PROCOPE program (German Academic Exchange Service and Campus France), and Human Frontiers

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ReviewAssembling the Puzzle: Pathways of Oxytocin Signaling in the Brain

Abstract

Section snippets

OT Receptor Trajectories in Evolution

Mismatch Between OTR and OT Axons?

OTR Activation by Diffusion

As a Conclusion: OT Signaling and Psychosocial Alterations

Acknowledgments and Disclosures

Neuroscience

J Chem Neuroanat

Brain Res

Neuroscience

Neuron

Prog Brain Res

Mol Phylogenet Evol

Gen Comp Endocrinol

Trends Cogn Sci

Psychoneuroendocrinology

Horm Behav

Neurosci Lett

Neuroscience

Brain Res

Horm Behav

Horm Behav

Prog Brain Res

Psychoneuroendocrinology

Neurosci Res

Physiol Behav

Pharmacol Biochem Behav

Neuroscience

Front Neuroendocrinol

Prog Neurobiol

Brain Res

J Biol Chem

Biol Psychiatry

Curr Opin Neurobiol

Neurosci Biobehav Rev

Trends Neurosci

Cell Rep

J Chem Neuroanat

Horm Behav

Oxytocin: Synthesis

J Am Chem Soc

Oxytocin produces natriuresis in rats at physiological plasma concentrations

Endocrinology

Nonsocial functions of hypothalamic oxytocin

ISRN Neurosci

Ancient neuromodulation by vasopressin/oxytocin-related peptides

Worm

[The evolution of the nonapeptidergic neurosecretory formations of the hypothalamus in vertebrate animals]

Zh Evol Biokhim Fiziol

Evolution of oxytocin pathways in the brain of vertebrates

Front Behav Neurosci

Evolutionary basis of the general principle of neuroendocrine regulation. Interaction of peptide and monoamine neurohormones in a dual control mechanism

The central oxytocin pathways in mammalian ontogenesis: The late maturation and psychosocial diseases

Front Neuroanat

Neurotransmitters and peptides: Whispered secrets and public announcements

J Physiol

Mesotocin and vasotocin in the brain of the lizard Gekko gecko. An immunocytochemical study

Cell Tissue Res

Projections from vasopressin, oxytocin, and neurophysin neurons to neural targets in the rat and human

J Histochem Cytochem

Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin

Nature

Review
Assembling the Puzzle: Pathways of Oxytocin Signaling in the Brain