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Address correspondence to Valery Grinevich, M.D., Ph.D., German Cancer Research Center and University of Heidelberg, Schaller Research Group on Neuropeptides (V078), CellNetworks Cluster of Excellence, Heidelberg, Germany
Schaller Research Group on Neuropeptides, German Cancer Research Center DKFZ, Heidelberg, GermanyCellNetworks Cluster of Excellence, University of Heidelberg, Heidelberg, Germany
Schaller Research Group on Neuropeptides, German Cancer Research Center DKFZ, Heidelberg, GermanyCellNetworks Cluster of Excellence, University of Heidelberg, Heidelberg, Germany
Schaller Research Group on Neuropeptides, German Cancer Research Center DKFZ, Heidelberg, GermanyCellNetworks Cluster of Excellence, University of Heidelberg, Heidelberg, Germany
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.
), the German anatomist Ernst Scharrer discovered glandule-like giant cells in the hypothalamus of teleost fish. These magnocellular neurons were later shown to produce OT and arginine-vasopressin (AVP) (or their homologs) in two neuron populations found in representatives of all classes of vertebrates. OT and AVP are transported to the posterior pituitary lobe from where they are released into the blood and act on peripheral targets to control water reuptake in the kidney (
). During pregnancy and lactation, OT is important for the delivery of newborns in most of mammals, eggs in fish, amphibians, reptiles, and birds, as well as critical for milk ejection.
In evolution of invertebrates, the OT/AVP-like system was best studied in worms. Neurons expressing the homolog of OT/AVP nematocin (Caenorhabditis elegans) have neuroendocrine and sensory phenotypes.
These neurons have sensory (ciliated) endings and processes, from which nematocin-containing granules might be released into the pseudocoelomic fluid [reviewed in (
)]. In basal vertebrates, neurons expressing OT and AVP homologues are located in one preoptic nucleus of the anterior hypothalamus, which is close to the third ventricle (
Evolutionary basis of the general principle of neuroendocrine regulation. Interaction of peptide and monoamine neurohormones in a dual control mechanism.
in: Bargmann W. Oksche A. Polenov A. Scharrer B. Neurosecretion and Neuroendocrine Activity. Springer,
Berlin, Heidelberg, New York1978: 15-30
Evolutionary basis of the general principle of neuroendocrine regulation. Interaction of peptide and monoamine neurohormones in a dual control mechanism.
in: Bargmann W. Oksche A. Polenov A. Scharrer B. Neurosecretion and Neuroendocrine Activity. Springer,
Berlin, Heidelberg, New York1978: 15-30
Evolutionary basis of the general principle of neuroendocrine regulation. Interaction of peptide and monoamine neurohormones in a dual control mechanism.
in: Bargmann W. Oksche A. Polenov A. Scharrer B. Neurosecretion and Neuroendocrine Activity. Springer,
Berlin, Heidelberg, New York1978: 15-30
) pathway of OT delivery exists in adult mammals as well, although only few dendroventricular contacts can be found rather rarely [studied in rats, see (
)]. A similar relocation of OT neuron precursors occurs during embryogenesis: while at mouse embryonic (E) days E9 to E10.5, precursors of OT neurons are associated with the ependymal layer of the diamond-shaped third ventricle. Starting from ~ E12, they begin to migrate away from the third ventricle in a lateroventral direction to form two main (paraventricular nuclei [PVN] and supraoptic nuclei [SON]) and several accessory nuclei [reviewed in (
Figure 1Schemas of pathways of oxytocin (OT) delivery in evolution and ontogenesis. Left panel represents transformation in the vertebrate evolution of magnocellular nuclei from preoptic nucleus (basal vertebrates) to paraventricular, supraoptic, and accessory nuclei (advanced vertebrates). In parallel, individual magnocellular neurons change morphology and interposition within the wall of the third ventricle. Along evolution, magnocellular neurons form collaterals, which project to extrahypothalamic regions concomitantly with classic projections to the posterior pituitary. Right panel demonstrates ontogenesis of the magnocellular OT system in rodents, which has common features with evolution: magnocellular neurons originate from the one source (the wall of the diamond-shaped third ventricle), migrate in a lateroventral direction, forming a polycentric OT system. Individual neurons undergo the process of maturation and specialization from bipolar neurons in newborns to multipolar neurons carrying rich dendritic trees and bifurcating axons. AN, accessory nuclei; E9 and E12.5, embryonic days 9 and 12.5; NH, neurohypophysis; OCh, optic chiasm; P1 and P21, postnatal days 1 and 21; PON, preoptic nucleus; PP, posterior pituitary lobe; PVN, paraventricular nucleus; SON, supraoptic nucleus; 3V, third ventricle.
Individual OT neurons have been transformed along the evolution from primitive unipolar and bipolar glandule-like neurons to multipolar neurons carrying extensive dendritic trees (Figure 1). The later achievement allowed the efficient release of OT from dendrites in a paracrine manner (
). Thus, OT modulates local activity of hypothalamic neurons and can also reach the third ventricle, contributing to transventricular pathway of OT delivery.
The most fascinating evolutionary-determined feature of the OT neuron is the long-range axonal projections in the forebrain (Figure 1), which have been convincingly demonstrated only in advanced vertebrates: reptiles (
). Accordingly, during embryogenesis and the early postnatal period, no central axonal OT projections have been reported in mammals; they appear only later in mature animals. Increasing knowledge about the evolution and ontogenesis of the OT system allows us to speculate that central OT projections appeared at later steps in evolution and in postnatal life in mammals, allowing addressed OT release to modulate specific functions. In fact, the majority of OT neurons located in the PVN and accessory nuclei morphologically represent projecting neurons, which can also be observed elsewhere in the forebrain (
). Such extensive branching and three-dimensional orientation of OT axons (Figure 2) add a new level of complexity to the central OT system, which will require further research to dissect which subset(s) of OT neurons project to which brain region(s) to sustain region-specific behaviors.
Figure 2Three-dimensional reconstruction of projections of three individual oxytocin (OT) neurons using light-sheet microscopy. The cleared rat brain (female) contains virally mediated Venus labeling unilaterally in OT neurons of the paraventricular nucleus (PVN). (A) Depicted is a horizontal light sheet at the level of the PVN in the ventral brain showing the unilateral Venus labeling of OT neurons. Anterior (a) and posterior (p) are indicated. (B) Magnocellular OT cells at the edge of the caudal PVN were chosen for tracing of single cells in horizontal view by focusing along z. Color code of tracing skeletons indicate fibers emanating from different cell somata (g, green; b, blue; r, red cell). Somata indicated by circles. (C) Fibers of three neurons were traced until the Venus signal became too faint to follow further. The tracing revealed four to five fibers emanating from the soma (g = 4; b = 4; r = 5 main fibers) and if further branched, bifurcate one to four times along the fiber (g = 8/0; b = 3/2; r = 1 total # of subbranches/4 unbranched fibers). Venus fluorescence was recorded from the uncut translucent brain on a custom-built light-sheet microscope controlled by custom acquisition software based on Labview 8.6 (
) in cooperation with Dr. Günter Giese, Max Planck Institute for Medical Research, Heidelberg, Germany. Scale bars represent 1 µm (A) and 350 μm (C). Somata indicated by circles. cp, cerebral peduncle; d, dorsal; H, hippocampus; SNR, substantia nigra, reticular part; 3V, third ventricle; v, ventral.
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).
Due to the high conservation in both peptides and receptors, it is presumable that all OT/AVP-related peptides interact with the different receptors in a common way, as confirmed by structure-function studies indicating that these receptors share a common peptide-binding pocket. By consequence, specific and selective ligands have been difficult to obtain (
) and it should be noted here that these structurally related analogues often do not possess an absolute receptor subtype selectivity but that their receptor subtype selectivity is always relative, i.e. concentration dependent. The working doses at which OT/AVP agonists and antagonists are used should thus be carefully assayed to avoid cross-reactivity on the different OT/AVP receptor subtypes. Finally, due to subtle species-specific differences in both the peptides and the receptors, it is extremely difficult to extrapolate data from one species to another. Selective agonist/antagonist concentrations should always be experimentally determined by setting up appropriate dose-response curves, as detailed in Chini et al. (
This cross-activation is due to the high structural homology of OT/AVP peptides and receptors, which roots back to their long evolutionary history. OT and AVP vertebrate genes likely originated from the duplication of a common vasotocin precursor gene more than 500 million years ago (MYA) (Figure 3); similarly, all of the OT/AVP receptor subtypes are believed to have originated from a single vasotocin receptor ancestor gene whose prototype is found in lamprey. Around 400 MYA, one of the duplicated vasotocin peptides mutated into mesotocin, the OT precursor, and at the same time, tandem duplications of the vasotocin receptor gene gave rise to four vasotocin receptors, one of which evolved into the isotocin/mesotocin receptor found in teleost fishes, birds, and amphibians. Around 200 to 250 MYA, vasotocin mutated into AVP and finally, around 100 MYA, OT was established from mesotocin. At the same time, the three vasotocin receptors progressively acquired the molecular features of the V1a, V1b, and V2 AVP receptors, while the mesotocin receptor evolved into the mammalian OTR (
Molecular evolution of the neurohypophysial hormone precursors in mammals: Comparative genomics reveals novel mammalian oxytocin and vasopressin analogues.
Molecular evolution of the neurohypophysial hormone precursors in mammals: Comparative genomics reveals novel mammalian oxytocin and vasopressin analogues.
). In parallel to the genetic and biochemical evolution of nonapeptides and their receptors, a new population of neurons appeared within the magnocellular system in which the expression of mesotocin progressively overcame that of vasotocin. However, despite this differentiation process, which likely occurred ~ 500 MYA, individual magnocellular cells still co-expressed both neuropeptides in modern mammals (
Quantitative analysis of oxytocin and vasopressin messenger ribonucleic acids in single magnocellular neurons isolated from supraoptic nucleus of rat hypothalamus.
). OT and AVP cells emerging from the two phenotypically distinct neuronal populations of first vertebrates progressively diverged in terms of anatomy and projections: while the AVP neurons remained primitive, OT-producing neurons differentiated into multipolar neurons.
Figure 3Potential evolutionary trajectories of the nonapeptide system in vertebrates. Parallel evolution of ligands and receptor genes is based on comparative analysis of chromosomal location and sequence information (
). The differentiation of the magnocellular system is based on the analysis of neuropeptide expression and neuroanatomical morphology in the brain of basal and advanced vertebrates (
Ancestral OT/AVP-related peptides and receptors have been identified in invertebrates that commonly have only one peptide and a variable number of receptors (from 1 to 3). The investigation of invertebrate OT/AVP-related peptides and their receptors is particularly relevant to highlight the common functional motif of this neuropeptide family. In invertebrates, the role of brain OT/AVP-related receptors in associative learning and mating behavior has recently emerged in organisms as simple as C. elegans. OT/AVP-related receptors, which in C. elegans can be precisely localized in specific neurons, are implicated in reconfiguring the neuronal circuits for a form of gustatory plasticity (
). Very interestingly, to regulate gustatory plasticity, nematocin interacts with serotoninergic and dopaminergic neurotransmission; OT/dopamine interactions have been demonstrated to be crucial in rodents to regulate more complex social behavior such as pair bonding and maternal behavior, suggesting an ancient origin of the OT/dopaminergic cross-talk (
During evolution, the pattern of OT/AVP receptor distribution should have adjusted to sustain diversified, progressively acquired functions: a broad and overlapping expression of vasotocin receptors is expected in the most ancient chordates (primarily basal vertebrates), followed by a progressively more localized and specialized expression of OT/AVP-related receptor subtypes.
Unfortunately, due to technical difficulties in establishing the selective profile of available pharmacologic radiotracers in the different animals, the expression of OT/AVP-related receptor subtypes has been systematically analyzed and quantified only in a few basal vertebrate species and general trajectories are difficult to extrapolate. However, it is generally accepted that OT/AVP receptors are expressed in every vertebrate class in at least two networks that, together, have been proposed to constitute the mesolimbic social decision-making networks (
). The first of these networks regulates aggressive and sexual behaviors and parental care (includes the lateral septum, bed nucleus of the stria terminalis, medial amygdala, preoptic area, anterior and ventromedial hypothalamus, and periaqueductal and central gray). The second network regulates the salience of incoming stimuli (includes the basolateral amygdala, bed nucleus of the stria terminalis, lateral septum, nucleus accumbens, striatum, ventral pallidum, ventral tegmental area, and prefrontal cortex in mammals). For OTR expression within these two networks from teleosts to primates, see Figure 4.
Figure 4Expression of oxytocin receptors (OTRs) within the mesolimbic social decision-making network (
) in four classes of vertebrates. Autoradiography, in situ hybridization, and immunohistochemistry studies presented in the literature are schematically summarized here; references include for teleosts (
). Areas of the mesolimbic social decision making network include: nucleus accumbens (NAcc); ventral pallidum (VP); lateral septum (LS); preoptic area (POA); ventromedial nucleus of hypothalamus (VMH); basolateral amygdala (blAMY); medial amygdala, (meAMY); bed nucleus of the stria terminalis (BNST); anterior hypothalamus (AH); hippocampus (HIP); ventral tegmental area (VTA); periaqueductal gray (PAG); and striatum (Str). Teleost areas of the network (A) include: anterior nucleus tuberal (aNT), lateral pallial (dorsal) part of the telencephalon (Dl); medial pallial (dorsal) part of the telencephalon (Dm); periventricular nucleus of the posterior tuberculum (TPp); central part of subpallial (ventral) telencephalon (Vc); dorsal nucleus of subpallial (ventral) telencephalon (Vd); ventral tuberal nucleus (VnT); supracommissural nucleus of subpallial (ventral) telencephalon (Vs); ventral part of subpallial (ventral) telencephalon (Vv). Other areas involved in social behavior depicted here include: medial septum (MS); high vocal center (HVC); robust nucleus of the arcopallium (RA); and motor nucleus of the XII cranial nerve (XII) in panel (B); olfactory bulb (Ob) and anterior olfactory nucleus (AON) in panel (C); nucleus basalis of Meynert (NBM); superior colliculus (SuC); pedunculopontine tegmental nucleus (PPT); and trapezoid body (TB) in panel (D).
A striking, and unexpected, feature of OTR expression during evolution is the confinement, in primates, of OTR expression in a very limited number of regions of the social decision-making network. In particular, in the Rhesus monkey brain (
), OTR are expressed at detectable levels in only one region of the social decision-making network, the ventromedial hypothalamus, which thus represents the most conserved region of OTR expression within this network in vertebrates. Identified as the primary satiety center in the hypothalamus, the ventromedial hypothalamus is also crucially involved in female sexual behavior and in particular in the lordosis response, a hallmark of female receptivity [reviewed in (
), suggesting that the role played by the ventromedial hypothalamus in the processing of social responses may be more relevant than previously recognized. Another open issue is to determine the distribution of the V1a (and V1b) receptors, which are also crucially involved in the regulation of social behavior. Has the expression of V1a (and V1b) receptors in primates also become restricted to very selected areas or has it remained widely expressed in the mesolimbic social network, as it is in other species? In the latter case, have some of the functions of the OT system been substituted by the AVP system? If yes, to what extent?
OTR expression is not limited to the social decision-making network and enormous differences in regional OTR distribution linked to species-specific behaviors that have been reported (Figure 4). It has been proposed that OT provides salience to sensory inputs by the gating of attention toward sensory stimuli linked to social clues. In songbirds, OTR are expressed in the pallium avian social behavior network and in most of the motor nuclei of the cranial nerves, suggesting a role in the efferent pathways of the vocal response (
Appearance and transient expression of oxytocin receptors in fetal, infant, and peripubertal rat brain studied by autoradiography and electrophysiology.
The origin of OTergic innervation of motor and cranial nerve nuclei is parvocellular OT neurons, which are allocated in specific subnuclei of the PVN (
). We did not expose here these OT neurons because their evolution, ontogenesis, and connectivity are poorly studied.
Rodents, which primarily use olfactory inputs for social recognition and social memory, present as a common feature a high level of OTR expression in the olfactory system, which is the primary modality of social investigation and interaction. Finally, in primates, OTR are found in the nucleus basalis of Meynert and the superior colliculus in the four primate species analyzed so far [marmoset (
)]. The presence of OTRs in regions that modulate visual attention supports the hypothesis that, in primates, OTRs act at the most relevant sensory modalities to regulate social approach and behavior (
The progressive restriction in OTR distribution observed in evolution is reflected, in rodents, in the complex pattern of OTR expression during ontogenesis: OTRs are widely distributed in the embryonic rat brain and become more restricted in the first weeks after birth, when OTRs appear in new areas [reviewed in (
)]. Interestingly, the role of OT in promoting excitatory synaptic transmission in sensory cortices was recently demonstrated in mice at very early postnatal developmental stages, leading to the identification of a new function of OT in shaping early cortical development (
), suggesting a window in which OTR expression levels can be involved in shaping individual behavioral traits. In Figure 4, we outlined regions in which variable OTR expression is linked to gender, reproductive state, and species-specific behaviors. As can be seen, the spatial pattern of OTR expression greatly impacts on specific behaviors, as was first shown in the pioneering work of Insel and Shapiro (
) on variation of OTR in the nucleus accumbens and pair bonding in voles. A final consideration here is on the extreme intraspecific individual variability in OT/AVP receptor expression reported in strains not subjected to strong genetic inbreeding, such as songbirds (
Social investigation in a memory task relates to natural variation in septal expression of oxytocin receptor and vasopressin receptor 1a in prairie voles (Microtus ochrogaster).
), as such extreme variability is expected to contribute to the diversity of individual human social behaviors.
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 (
). However, in our previous work employing viral vector-based techniques and soluble fluorescent marker Venus to fill OT axons, we described projections in all main regions of the forebrain (
). The detection of OT immunosignal in those Venus-positive axons was limited due to low peptide content under basal conditions, reflecting the results obtained by a number of previous reports that employed direct detection of OT by immunohistochemistry. However, this weak OT staining can just reflect the functional status of OT neurons, i.e., axons can be filled with OT in the case of cell activation. And indeed, under the strong physiological activation of OT neurons during lactation, OT immunosignal has been found in axons of forebrain structures, previously considered as structures lacking OT axons (Figure 5).
However, in some structures, such as the ventromedial hypothalamic nucleus, no OT axons have been detected, even after physiological stimulation. Despite that, OT-containing axons make axo-dendritic synapses at the external border of the nucleus (
). Due to the fact that OT neurons are glutamatergic in nature, they can modulate activity of the ventromedial hypothalamic nucleus in a classical transsynaptic fashion.
Similarly, the detection of OTR sites may depend on the functional state of the OT system. In regions with very high OT concentrations, OTRs may be downregulated to such low levels as to become undetectable; in lactation, OTRs were visualized in the PVN, SON, and accessory nuclei only after acute intracerebroventricular injection of an OT antagonist that prevented the downregulation of OTRs (
Figure 5Oxytocin (OT) axons in the forebrain of lactating rat. Using monoclonal antibodies against mature form of OT generated by the Harlod Gainer team (
) followed by diaminobenzidine-based method of visualization, axons containing OT immune product were detected in previously known places such as the lateral septum (LS), nucleus accumbens core (AcbC), and central nucleus of amygdala (CeA). In addition, OT-immunoreactive axons can be visualized in the hippocampus (CA1), barrel field (S1BF) of the somatosensory cortex, and septohippocampal nucleus (Shi)—structures that are devoid of OT immunosignal in nonlactating rats. The latter suggests that the functional state may activate both synthesis and transport of OT along axons to various forebrain regions.
Appearance and transient expression of oxytocin receptors in fetal, infant, and peripubertal rat brain studied by autoradiography and electrophysiology.
) in the rat brain (Figure 6), it is now evident that there is basically complete overlap: regions expressing OTRs at moderately high levels are innervated by a relevant number of OT fibers. An apparent mismatch between OT fibers and OTRs is limited to only four forebrain regions: the olfactory bulb, ventral pallidum, medial preoptic area, and ventromedial hypothalamic nucleus. These regions express moderate to high OTR levels but seem to not receive direct OT projections. While enrichment of the olfactory bulb by OT can occur via transventricular pathway [more specifically, via cerebrospinal fluid-subarachnoid-lymphatic outflow (
)], three other regions are very close to the sites where OT is produced; hence, OTRs can be efficiently activated by dendritically released OT. These observations indicate that axonal and dendritic OT release both contribute to activating OTRs and that axonal projection of hypothalamic OT neurons is probably a mechanism used for OTR activation at long distances to overcome the limits of simple diffusion.
Figure 6Spatial distribution of oxytocin receptors (OTR) and oxytocin (OT) axons in the rat brain. For the OTR topography, the results obtained using autoradiography and in situ hybridization are summarized here and derive from references (
Appearance and transient expression of oxytocin receptors in fetal, infant, and peripubertal rat brain studied by autoradiography and electrophysiology.
). There is a basically complete overlap between OTR and OT fibers and an apparent mismatch is limited to four regions that express OTR but do not receive direct OT projections. These regions are the olfactory bulb (Ob), ventral pallidum (VP), medial preoptic area (POA), and ventromedial nucleus of hypothalamus (VMH). AH, anterior hypothalamus; AON, anterior olfactory nucleus; blAMY, basolateral amygdala; BNST, bed nucleus of the stria terminalis; HIP, hippocampus; LS, lateral septum; NAcc, nucleus accumbens; meAMY, medial amygdala; PAG, periaqueductal gray; Str, striatum; VTA, ventral tegmental area.
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 (
Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine-tolerant and -dependent anesthetized rats: Push-pull perfusion study.
Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine-tolerant and -dependent anesthetized rats: Push-pull perfusion study.
Release of vasopressin within the rat paraventricular nucleus in response to emotional stress: A novel mechanism of regulating adrenocorticotropic hormone secretion?.
)], OT concentrations were only twofold to fourfold lower than in the SON itself. Such quantity was calculated to correspond to a local concentration in the extracellular fluid of 1000 pg/mL (
). This means that at a concentration of 1 nmol/L, a considerable fraction of the receptors present at the cell surface is occupied and activated and will undergo internalization and desensitization. At such high OT concentration, the turnover of the receptor between the plasma membrane and the intracellular compartments will thus have a crucial impact on the onset and entity of the receptor response.
Upon diverse physiological and experimental stimuli [i.e., parturition, suckling, and pharmacologic treatments, for a review see (
Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine-tolerant and -dependent anesthetized rats: Push-pull perfusion study.
) and these changes can be due to the axonal release of neuropeptides that can provide a local precise spatiotemporal, point-to-point regulation, in addition to delivery by continuous diffusion. This regulatory capacity of the OT release can underlie the fine-tuned control of complex behavior including prosocial behaviors, learning, and memory processes that are modulated by OT [reviewed in (
OT concentrations are also regulated by clearance and degradation mechanisms. Brain OT is degraded by placental leucine aminopeptidase (P-LAP), an enzyme that is also cleaving AVP, met-enkephalin and leu-enkephalin, bradykinin, and somatostatin (
Autoradiographic identification of brain angiotensin IV binding sites and differential c-Fos expression following intracerebroventricular injection of angiotensin II and IV in rats.
), including all brain regions expressing the OTRs, where it can actively control the availability of OT to its receptor and thus OTR signaling. In the hypothalamus of lactating rats, an increase in P-LAP expression was shown to play an important role in regulating the pattern of OT neuronal bursting by increasing OT availability (
By comparing the number of OT fibers with levels of OTR and P-LAP in different brain areas, we did not find any straightforward correlation. For example, in the lateral septum, a region particularly enriched in OT fibers, only modest levels of P-LAP were reported, suggesting that OT may remain available in this region at high local concentrations for quite a long time. On the contrary, high levels of P-LAP are present in the basolateral amygdala, where a low number of OT-immunoreactive axons has been reported, suggesting a very transient availability of the peptide.
Finally, we have recently demonstrated that at a concentration of around 1 nmol/L, OT induces the activation of Gq/phospholipase C and intracellular calcium release, whereas at concentrations that are fivefold to fiftyfold higher, compatible with the OT levels after stimulation, OT also promotes the activation of Gi and Go proteins, respectively (
). While the precise role of these OTR signaling pathways within the brain are largely unknown, in immortalized neuronal cells, OTR coupling to Gq or to Gi/Go results in opposite effects on cell excitability: OT inhibits inward rectifying potassium conductance through Gq activation and activates inward rectifying currents through pertussis toxin-sensitive Gi/Go proteins (
). An interesting hypothesis is that, depending on the local concentration reached by OT, different signaling pathways can be engaged, resulting in highly modulable signaling mechanisms and responses.
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 (
Nevertheless, in preclinical animal models characterized by autistic-like symptoms, OT administration has been reported to rescue social deficits when given just after birth or in the first postnatal days (
An early postnatal oxytocin treatment prevents social and learning deficits in adult mice deficient for Magel2, a gene involved in Prader-Willi syndrome and autism.
Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autism.
Mice heterozygous for the oxytocin receptor gene (Oxtr(+/−)) show impaired social behaviour but not increased aggression or cognitive inflexibility: Evidence of a selective haploinsufficiency gene effect.
). Notably, in some of the animal models in which the OT treatment was successful, a dysregulation of the OT/OTR system was concomitantly reported. In particular, an accumulation of OT immunosignal was observed in both the Magel2 knockout mice (a faithful model of Prader-Willi syndrome that includes autism spectrum disorder traits) (
An early postnatal oxytocin treatment prevents social and learning deficits in adult mice deficient for Magel2, a gene involved in Prader-Willi syndrome and autism.
). These reports provide evidence on alteration of trafficking and/or release of OT from axonal terminals in the forebrain in translational models of neurodevelopmental disorders. At the receptor side, OT administration has been reported to rescue autistic-like symptoms in young adult mice in which OTR expression was completely or partially absent (
Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autism.
Mice heterozygous for the oxytocin receptor gene (Oxtr(+/−)) show impaired social behaviour but not increased aggression or cognitive inflexibility: Evidence of a selective haploinsufficiency gene effect.
). Early postnatal events have been shown to influence adult OT and OTR levels, such as parental care, maternal separation, late weaning, and communal rearing possibly via epigenetic mechanisms (
). However, the role of these events on the OT/OTR system in humans has not yet been addressed. At present, genetic association studies have revealed reproducible and significant links of some OTR gene polymorphisms to specific social traits and behaviors (
). Therefore, although expression of OTRs, modified by genetic and epigenetic factors, may have a large impact on defining social personalities and traits, the alteration of axonal delivery of OT can be seen as a new mechanism underlying social alterations and a potential target for effective therapies in social core deficits.
On the basis of evidence gathered so far, it can be speculated that the efficacy of OT treatment will depend on OT/OTR dysfunctions present in patients; by consequence, OT supplementation should be guided by a selection of patients based on the functionality of their OT/OTR system. A conundrum here is the measure of OT in peripheral fluids: in addition to experimental technical problems resulting in unreliable assays determination (
), peripheral OT does not represent, in our opinion, a suitable marker of central OT release. Indeed, the relationship between centrally and peripherally released OT is not well understood, as extensively discussed in recent reviews (
). From our point of view, a subtle OT release from axons in discrete brain regions may well not influence the general concentration of OT in the brain and cerebrospinal fluid.
In conclusion, a deeper look into the mechanisms and targets of central OT release and signaling is strongly needed to provide a solid mechanism-based therapeutic strategy focused on early and long-lasting restoration of impaired social function in neurodevelopmental disorders.
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 Research Program RGP0019/2015 (to VG), Telethon Foundation Grant No. GGP12207, National Council of Research Project on Aging and Regione Lombardia (Project MbMM-convenzione n°18099/RCC), and Ministero della Salute RF2010-2311148 (to BC).
We thank Dr. Günter Giese for contributing the clearing method for light sheet microscopy and for help with the analysis of the light sheet data; Annemarie Scherbarth for the sample clearing, light sheet microscopy, and recording; Thomas Splettstoesser (SciStyle; www.scistyle.com) for his help with the preparation of figures; and Anne Seller for proofreading the manuscript.
Drs. V. Grinevich, H. S. Knobloch-Bollmann, M. Eliava, M. Busnelli, and B. Chini report no biomedical financial interests or potential conflicts of interest.
Evolutionary basis of the general principle of neuroendocrine regulation. Interaction of peptide and monoamine neurohormones in a dual control mechanism.
in: Bargmann W. Oksche A. Polenov A. Scharrer B. Neurosecretion and Neuroendocrine Activity. Springer,
Berlin, Heidelberg, New York1978: 15-30
Molecular evolution of the neurohypophysial hormone precursors in mammals: Comparative genomics reveals novel mammalian oxytocin and vasopressin analogues.
Quantitative analysis of oxytocin and vasopressin messenger ribonucleic acids in single magnocellular neurons isolated from supraoptic nucleus of rat hypothalamus.
Appearance and transient expression of oxytocin receptors in fetal, infant, and peripubertal rat brain studied by autoradiography and electrophysiology.
Social investigation in a memory task relates to natural variation in septal expression of oxytocin receptor and vasopressin receptor 1a in prairie voles (Microtus ochrogaster).
Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine-tolerant and -dependent anesthetized rats: Push-pull perfusion study.
Release of vasopressin within the rat paraventricular nucleus in response to emotional stress: A novel mechanism of regulating adrenocorticotropic hormone secretion?.
Autoradiographic identification of brain angiotensin IV binding sites and differential c-Fos expression following intracerebroventricular injection of angiotensin II and IV in rats.
An early postnatal oxytocin treatment prevents social and learning deficits in adult mice deficient for Magel2, a gene involved in Prader-Willi syndrome and autism.
Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autism.
Mice heterozygous for the oxytocin receptor gene (Oxtr(+/−)) show impaired social behaviour but not increased aggression or cognitive inflexibility: Evidence of a selective haploinsufficiency gene effect.
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