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Review
. 2021 Jan;26(1):265-279.
doi: 10.1038/s41380-020-0802-9. Epub 2020 Jun 8.

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry

Valery Grinevich  1 , Inga D Neumann  2
Affiliations
Review

Brain oxytocin: how puzzle stones from animal studies translate into psychiatry

Valery Grinevich et al. Mol Psychiatry. 2021 Jan.

Abstract

The neuropeptide oxytocin has attracted great attention of the general public, basic neuroscience researchers, psychologists, and psychiatrists due to its profound pro-social, anxiolytic, and "anti-stress" behavioral and physiological effects, and its potential application for treatment of mental diseases associated with altered socio-emotional competence. During the last decade, substantial progress has been achieved in understanding the complex neurobiology of the oxytocin system, including oxytocinergic pathways, local release patterns, and oxytocin receptor distribution in the brain, as well as intraneuronal oxytocin receptor signaling. However, the picture of oxytocin actions remains far from being complete, and the central question remains: "How does a single neuropeptide exert such pleotropic actions?" Although this phenomenon, typical for many of about 100 identified neuropeptides, may emerge from the anatomical divergence of oxytocin neurons, their multiple central projections, distinct oxytocin-sensitive cell types in different brain regions, and multiple intraneuronal signaling pathways determining the specific cellular response, further basic studies are required. In conjunction, numerous reports on positive effects of intranasal application of oxytocin on human brain networks controlling socio-emotional behavior in health and disease require harmonic tandems of basic researchers and clinicians. During the COVID-19 crisis in 2020, oxytocin research seems central as question of social isolation-induced inactivation of the oxytocin system, and buffering effects of either activation of the endogenous system or intranasal application of synthetic oxytocin need to be thoroughly investigated.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Overview of the hypothalamic oxytocin nuclei.
Confocal panel shows hypothalamic OXT-ergic SON, PVN, and fornical accessory nucleus (AN) of an adult male rat, stained with antibody against OXT, generously provided by Dr. Harold Gainer (NIH). Images were obtained using a Leica LSM780 confocal microscope at 10× (z-stacks, 30 µm, 1 µm steps) and realigned and merged in Adobe Photoshop. SON supraoptic nucleus, PVN paraventricular nucleus, 3V third ventricle, OC optic chiasm. Arrows point towards the hypothalamic-neurohypophysial tract.
Fig. 2
Fig. 2. Scheme of a sagittal view on a rat brain including OXT neuronal projections, OXT release and OXTR binding within brain target regions.
This scheme summarizes all available data from male and female including lactating rats regarding OXT neuronal projections, sites of OXT release, e.g., during stress exposure, mating, parturition, suckling, and OXT receptors within brain target regions, as outlined in detail in the text. AON anterior olfactory nucleus, OB olfactory bulb, OT olfactory tubercle, Nac nucleus accumbens, OVLT organum vasculosum laminae terminalis, SON supraoptic nucleus, PVN paraventricular nucleus, PP posterior pituitary, PFC prefrontal cortex, CC cingulate cortex, MPOA medial preoptic area, BNST bed nucleus of the stria terminalis, LS lateral septum, CPu caudate putamen, PV periventricular nucleus of the thalamus, CeA central amygdala, MeA medial amygdala, BLA basolateral amygdala, VTA ventral tegmental area, LC locus coeruleus, PBN parabrachial nucleus, DRN dorsal raphe nucleus, PAG periaqueductal gray, SN substantia nigra, HPC hippocampus, HDB nucleus of the horizontal limb of the diagonal band. Adapted with allowance from [1].
Fig. 3
Fig. 3. Scheme of intraneuronal signaling cascades involved in OXT-induced anxiolysis in the hypothalamic paraventricular nucleus.
Activation of the OXT receptor (OXTR) elevates — via the Gβ/γ protein subunit — extracellular Ca2+ influx via incorporation of TRPV2 Ca2+  channels into the cellular membrane and subsequent activation of Ca2+-dependent cascades (PKC, CaMKI, II, IV). OXTR activation via its G-protein αq subunit also leads to transactivation of EGFR and subsequent activation of the MAPK pathway via MEK1/2. The signaling cascades converge on downstream regulation of transcriptions factors, such as MEF2, CREB, and its cofactor CRTC3 and, consequently, modulate neuronal gene expression. Central infusion OXT resulted in 157 up- and 204 downregulated genes identified in rat PVN tissue punches (Affymetrix microarray [131] GEO dataset). Moreover, through activation of PKC and MEK1/2, OXT regulates eEF2 activity to promote protein de novo synthesis, e.g., synthesis of the NPY5R. Ca2+ calcium, TRPV2 transient receptor potential cation channels of vanilloid type 2, EGFR epidermal growth factor receptor, CaMK calcium/calmodulin-dependent kinase, PKC protein kinase C, MAPK mitogen-activated protein kinase pathway, MEK mitogen-activated protein kinase kinase, CRTC cyclic AMP-regulated transcriptional coactivators, CREB cyclic AMP responsive element binding protein, MEF2 myocyte enhancer factor 2, EF2 eukaryotic elongation factor 2, NPY5R neuropeptide Y 5 receptor. Adapted with allowance from [1, 131].
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