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Oxytocin Mobilizes Midbrain Dopamine toward Sociality

2017; Cell Press; Volume: 95; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2017.07.002

1097-4199

Alexandre Charlet, Valery Grinevich,

Evolutionary Psychology and Human Behavior

Oxytocin and dopamine possess significant overlap in the modulation of life-essential behaviors. Here, Xiao et al., 2017Xiao L. Priest M.F. Nasenbeny J. Lu T. Kozorovitskiy Y. Neuron. 2017; 95 (this issue): 368-384Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar show that the activity of dopamine neurons of the ventral tegmental area and the substantia nigra is finely tuned by axonal release of oxytocin. Oxytocin and dopamine possess significant overlap in the modulation of life-essential behaviors. Here, Xiao et al., 2017Xiao L. Priest M.F. Nasenbeny J. Lu T. Kozorovitskiy Y. Neuron. 2017; 95 (this issue): 368-384Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar show that the activity of dopamine neurons of the ventral tegmental area and the substantia nigra is finely tuned by axonal release of oxytocin. Oxytocin (OT) and dopamine (DA) systems are two neuromodulators of brain functions that exhibit similarity in organization and project sites. In the brain, OT neurons are exclusively present in the hypothalamus, while DA neurons are primarily found in the ventral tegmental area (VTA) and substantia nigra (SN). Interestingly, OT and DA neurons project to similar forebrain regions, including prefrontal cortex, nucleus accumbens, and striatum, to control social and affiliative behaviors, such as sexual behavior and pair bonding (Neumann, 2009Neumann I.D. Front. Neuroendocrinol. 2009; 30: 483-496Crossref PubMed Scopus (121) Google Scholar). Given that DA receptors are present on OT neurons and OT receptors (OTRs) are detected in both VTA and SN, it is tempting to hypothesize that both systems are regulating each other. However, physiological relevance, anatomical connections, and intracellular signaling between OT and DA systems have not been dissected. In this issue of Neuron, Xiao et al. first used viral-based and latex bead-based retrograde tracing to identify two small subsets of parvocellular OT neurons separately projecting to the VTA or SN. Next, the authors detected both OTR immunoreactivity and OTR mRNA in DA neurons of the VTA, and in GABAergic neurons of the SN. Finally, using ex vivo pharmacological and optogenetic approaches applied on acute midbrain slices, Xiao et al. showed that OT distinctly modulates DA neuronal populations: while OT seems to directly increase VTA neuron activity, this neuropeptide indirectly inhibits SN neurons via local recruitment of GABAergic interneurons (Figure 1). Hence, Xiao et al. provided a comprehensive set of data that bring a new level of complexity in the OT system and raise numerous basic questions. First, the authors demonstrated that pharmacological block of OTRs, and to a lesser extent vasopressin (VP) receptors (V1aRs), prevents the OT-induced increase in firing rate of DA neurons of the VTA. This OTR and V1aR dual action of OT is currently under debate as physiologically relevant high concentrations of OT seem to be capable of activating V1aR in several brain and spinal cord regions (Busnelli et al., 2012Busnelli M. Saulière A. Manning M. Bouvier M. Galés C. Chini B. J. Biol. Chem. 2012; 287: 3617-3629Crossref PubMed Scopus (122) Google Scholar). This is particularly important as OT and VP are often presented as antagonists in their function. It is particularly well described in the amygdala-mediated control of anxiety, where VP enhances fear, while OT exerts an anxiolytic function. Given that the VP system also projects to the VTA (Beier et al., 2015Beier K.T. Steinberg E.E. DeLoach K.E. Xie S. Miyamichi K. Schwarz L. Gao X.J. Kremer E.J. Malenka R.C. Luo L. Cell. 2015; 162: 622-634Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar), the VP-induced modulation of the DA system may be as important as the OT one. Hence, the interplay between OT and VP in the regulation of the DA system has to be deciphered. Second, OT neurons express glutamate as the main neurotransmitter. While an evoked release of OT also results in a release of glutamate (Knobloch et al., 2012Knobloch H.S. Charlet A. Hoffmann L.C. Eliava M. Khrulev S. Cetin A.H. Osten P. Schwarz M.K. Seeburg P.H. Stoop R. Grinevich V. Neuron. 2012; 73: 553-566Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar, Eliava et al., 2016Eliava M. Melchior M. Knobloch-Bollmann H.S. Wahis J. da Silva Gouveia M. Tang Y. Ciobanu A.C. Triana del Rio R. Roth L.C. Althammer F. et al.Neuron. 2016; 89: 1291-1304Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar), the physiological relevance of such a co-release is still unknown. Hence, the general function of glutamate and OT axonal co-release should be investigated, and particularly in the context of the proposed complex and dual DA system modulation. Finally, although the authors demonstrated the contribution of Gq-mediated pathway in excitatory effects of OT, other subunits such as Gi and Go can be recruited by the OTR (Busnelli et al., 2012Busnelli M. Saulière A. Manning M. Bouvier M. Galés C. Chini B. J. Biol. Chem. 2012; 287: 3617-3629Crossref PubMed Scopus (122) Google Scholar) and such differential recruitment could be driven by different OT concentrations. It should be noted here that most of the current studies neither display a dose-response curve for OT-mediated effects nor use a biased agonist for OTR, raising a potential caveat regarding the intra-cellular signaling pathway involved. Given that physiological concentrations of OT are dramatically modulated in life-essential behaviors and upon events of different emotional valences, the mechanism described by Xiao et al. may be involved in the life-reproduction cycle, dampened by deleterious events, and attuned after achievement. The current results seem critical for deeper understanding of the complex interactions between OT and DA systems, as well as the general neuropeptide signaling in the CNS. Importantly, Xiao et al. successfully evoked OT release from axons by optogenetics, which is reported as a demanding task for distant OT axons. Interestingly, the observed effect on neuronal firing remains rather limited in amplitude, while statistically significant and physiologically relevant. Similar orders of evoked-OT release were observed on the firing of GABAergic interneurons of the central amygdala (Knobloch et al., 2012Knobloch H.S. Charlet A. Hoffmann L.C. Eliava M. Khrulev S. Cetin A.H. Osten P. Schwarz M.K. Seeburg P.H. Stoop R. Grinevich V. Neuron. 2012; 73: 553-566Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar) and on projecting neurons of the spinal cord (Eliava et al., 2016Eliava M. Melchior M. Knobloch-Bollmann H.S. Wahis J. da Silva Gouveia M. Tang Y. Ciobanu A.C. Triana del Rio R. Roth L.C. Althammer F. et al.Neuron. 2016; 89: 1291-1304Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar), thus questioning the precise network, cellular, and molecular mechanisms underlying this evoked change as well as its precise functions in brain circuits. This supports the relatively recent vision of the functional relevance of a precise, targeted axonal release (Knobloch et al., 2012Knobloch H.S. Charlet A. Hoffmann L.C. Eliava M. Khrulev S. Cetin A.H. Osten P. Schwarz M.K. Seeburg P.H. Stoop R. Grinevich V. Neuron. 2012; 73: 553-566Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar). Furthermore, Xiao et al. demonstrate a high-level specialization of a minor component of the OT system: parvocellular neurons. Indeed, two populations of parvocellular neurons precisely projecting to VTA or to SN were identified, supporting anatomical segregation of parvocellular neurons innervating midbrain, brainstem, and spinal cord. This is particularly interesting since, despite identification of parvocellular OT more than 30 years ago, only now do we start to understand the functional relevance of this cell type. Several reports suggest the contribution of parvocellular OT neurons in distinct brain circuits and physiological processes, including food intake regulation, as well as other autonomic functions, such as breathing, cardiovascular reactions, and gastric reflexes (Dölen, 2015Dölen G. J. Neuroendocrinol. 2015; 27: 516-535Crossref PubMed Scopus (25) Google Scholar). Most recently, it was demonstrated that the specific population of about 30 parvocellular neurons concomitantly projects to the spinal cord and magnocellular neurons of the supraoptic nucleus, to exert analgesic effects via central and peripheral mechanisms (Eliava et al., 2016Eliava M. Melchior M. Knobloch-Bollmann H.S. Wahis J. da Silva Gouveia M. Tang Y. Ciobanu A.C. Triana del Rio R. Roth L.C. Althammer F. et al.Neuron. 2016; 89: 1291-1304Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). These highlight a complex organization of the OT system that was still unexpected few years ago and promise to be crucial to understanding the complex behavioral action of this neuropeptide (Figure 1). Given that the DA system has been under intense scrutiny for many years, the depicted dual action of OT on the DA system will catch much attention and raise several key questions. Xiao et al. show that while OT directly activates VTA DA neurons, it also indirectly inhibits SN DA neurons (Figure 1). This questions the precise DA circuits involved in OT-sensitive behaviors. An attractive hypothesis could involve one of the core common functions of OT and DA outputs: social interactions. Indeed, it is well known that OT and DA synergistically facilitate social behavior, involving direct VTA DA projections to the ventral hippocampus and the nucleus accumbens (Love, 2014Love T.M. Pharmacol. Biochem. Behav. 2014; 119: 49-60Crossref PubMed Scopus (193) Google Scholar), where OT inhibits drug-induced DA signaling. In line with this, DA projections from both VTA and SN are found toward both the prefrontal cortex and the caudate putamen, where they may have opposite functions. Indeed, while VTA DA may enhance social interest (Gunaydin et al., 2014Gunaydin L.A. Grosenick L. Finkelstein J.C. Kauvar I.V. Fenno L.E. Adhikari A. Lammel S. Mirzabekov J.J. Airan R.D. Zalocusky K.A. et al.Cell. 2014; 157: 1535-1551Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar), the SN DA can presumably dampen the socially irrelevant exploratory behavior through the control of the motor activity (Patel et al., 2012Patel J.C. Rossignol E. Rice M.E. Machold R.P. Nat. Commun. 2012; 3: 1172Crossref PubMed Scopus (58) Google Scholar). Thus, the local OT release in VTA and SN may be crucial to estimate and modulate the salience of a social encounter, leading to the inter-individual interaction. Hence, OT-driven inhibition of SN DA neurons may dampen the non-social exploratory behaviors while OT-driven activation of VTA DA neurons may enhance the partner-directed behaviors (Figure 1). Thus, by a dual mechanism the OT-DA interactions described by Xiao et al. may be at the basis of the social interaction-focused behaviors. Although the regulation of DA neuron activity has been demonstrated by Xiao et al., the effects of DA on the OT system remain enigmatic. In fact, it is not clear which DA neurons project onto OT neurons and whether other DA structures, such as the zona incerta or arcuate nucleus, are involved. In addition, we do not know if there is any difference in innervation of parvocellular and magnocellular OT neurons by DA, which DA receptors are expressed in OT neurons, and whether the activation of endogenous DA affects OT release into the brain or blood. Despite the absence of direct functional in vivo evidence, it is proposed that DA and OT may act together on postsynaptic cells via receptor crosstalk and/or heteromeric receptor complexes. All these are indeed not restricted to the OT and DA systems: on a larger scale, all neuromodulatory systems are obviously interacting with each other, especially in the context of social behavior, but our current understanding of their interacting points and mechanisms is far from assembling the whole picture. Finally, during the last decade several clinical trials on intranasal OT treatment of human patients afflicted with social deficits have been successfully accomplished. Since the administration of DA or its agonists to human patients causes long-known broad aversive side effects, the stimulation of DA signaling via OT administration can be profitable for treatment of various diseases ranging from social deficits to motor disorders, in which both OT and DA play significant role. Thus, translational studies applying external OT and subsequent monitoring of the activity of the DA system, especially in primates, are required. The authors thank Thomas Splettstoesser (SciStyle; http://www.scistyle.com/) for his help with the preparation of the figure and University of Strasbourg Institute for Advanced Study (USIAS) fellowship, NARSAD Young Investigator Grant 24821 (A.C.), ANR-DFG grant GR 3619/701 (A.C. and V.G.), Schaller Research Foundation, and DFG within the Collaborative Research Center SFB 1134 and SFB 1158 for financial support (V.G.). Biased Oxytocinergic Modulation of Midbrain Dopamine SystemsXiao et al.NeuronJune 29, 2017In BriefXiao et al. reveal oxytocinergic projections from PVN to VTA and SNc, where, by different circuit and receptor mechanisms, oxytocin release biases dopamine neuron activity in opposite directions. This work places dopamine signaling under prominent control of a peptide neuromodulator. Full-Text PDF Open Archive