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Oxytocin Discrepancies in Social Dynamics

2020; Cell Press; Volume: 107; Issue: 4 Linguagem: Inglês

10.1016/j.neuron.2020.07.027

1097-4199

Federica Maltese, Francesco Papaleo,

Neuroscience of respiration and sleep

Social group dynamics are highly complex. In this issue of Neuron, Anpilov et al. use a novel wireless optogenetic device to demonstrate that the repeated stimulation of oxytocin neurons modulates pro-social and agonistic behaviors in a time- and context-dependent manner. Social group dynamics are highly complex. In this issue of Neuron, Anpilov et al. use a novel wireless optogenetic device to demonstrate that the repeated stimulation of oxytocin neurons modulates pro-social and agonistic behaviors in a time- and context-dependent manner. Social behavior refers to several processes associated with interactions with others; however, behaviors can differ greatly depending on social contexts and the goal of the interaction. This complexity may be reflected by the underlying brain mechanisms. Diverse neuronal processes may drive similar social responses, or the same neuronal pathway may differentially influence disparate social behaviors. The development of cutting-edge techniques has enabled the study and manipulation of brain circuits in rodents with increasing spatial and temporal resolution. However, these technical achievements are not always paired with the proper assessment of distinct social behaviors. Mechanistic studies in rodents often rely on basic measurements within a single context to drive conclusions regarding social behaviors. The comprehensive investigation of cellular and circuital mechanisms must occur in parallel with the awareness of social process complexity; otherwise, the findings may remain incomplete or misleading. Several paradigms can efficiently assess different social behaviors among rodents, including reciprocal exploration, communal nesting, sexual-parenting behaviors, territorial marking, aggressiveness, social memory, social hierarchies, social reward, emotion discrimination, consolation, pair-bonding, and harm avoidance. Similar to humans, rodents show complex group dynamics, forming multifaceted social structures that are shaped by the surrounding environment. Intriguingly, extended observations of groups of mice living in enriched environments have revealed that group dynamics may change over time, and individual differences may be identifiable that approximate human personality traits (Forkosh et al., 2019Forkosh O. Karamihalev S. Roeh S. Alon U. Anpilov S. Touma C. Nussbaumer M. Flachskamm C. Kaplick P.M. Shemesh Y. Chen A. Identity domains capture individual differences from across the behavioral repertoire.Nat. Neurosci. 2019; 22: 2023-2028Crossref PubMed Scopus (23) Google Scholar; Freund et al., 2013Freund J. Brandmaier A.M. Lewejohann L. Kirste I. Kritzler M. Krüger A. Sachser N. Lindenberger U. Kempermann G. Emergence of individuality in genetically identical mice.Science. 2013; 340: 756-759Crossref PubMed Scopus (243) Google Scholar). These considerations highlight the importance of combining disparate and complimentary social assessments, using different timescales, to make appropriate inferences regarding social behaviors. In this issue of Neuron, Anpilov et al., 2020Anpilov S. Shemesh Y. Eren N. Harony-Nicolas H. Benjamin A. Dine J. Oliveira V.E.M. Forkosh O. Karamihalev S. Hüttl R.E. et al.Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors.Neuron. 2020; 107: 644-655Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar developed a novel wireless optogenetic tool that was used to manipulate oxytocin (OXT) neurons in the paraventricular nucleus (PVN) of the hypothalamus of male mice. Two different social contexts were used: (1) a semi-naturalistic arena, in which grouped mice live together for several days, and (2) a resident-intruder task. The social arena setting can be used to study the social dynamics of groups and individual behaviors across several days (Forkosh et al., 2019Forkosh O. Karamihalev S. Roeh S. Alon U. Anpilov S. Touma C. Nussbaumer M. Flachskamm C. Kaplick P.M. Shemesh Y. Chen A. Identity domains capture individual differences from across the behavioral repertoire.Nat. Neurosci. 2019; 22: 2023-2028Crossref PubMed Scopus (23) Google Scholar). The resident-intruder test, in contrast, allows the assessment of environmentally induced agonistic behaviors during a discrete period. The wireless optogenetic device was magnetically activated approximately every 2 h, for 2 consecutive nights, in both social contexts. In the social arena, the magnetic activation was paired with food retrieval, whereas in the resident-intruder task, magnet activation was performed for two nights preceding a short interaction with a stranger male after 6 days of housing with a female mouse. The authors used a Stabilized Step-Function Opsin (SSFO), which allowed them to obtain a prolonged physiological-like activation of targeted neurons through the increased sensitization to afferent inputs following a single light pulse, rather than inducing firing directly. The activation of PVN OXT neurons induced membrane depolarization for up to 30 min and increased OXT plasma levels. Moreover, this manipulation did not lead to OXT receptor (OXTR) downregulation, which normally occurs after exogenous OXT applications (Huang et al., 2014Huang H. Michetti C. Busnelli M. Managò F. Sannino S. Scheggia D. Giancardo L. Sona D. Murino V. Chini B. et al.Chronic and acute intranasal oxytocin produce divergent social effects in mice.Neuropsychopharmacology. 2014; 39: 1102-1114Crossref PubMed Scopus (124) Google Scholar). Thus, the remotely controlled system, together with SSFO, allowed the induction of a physiologic and prolonged OXT release in a complex social environment without interfering with social interactions. Endogenous PVN OXT signaling has been reported to usually have “pro-social” effects, being necessary for social fear extinction (Menon et al., 2018Menon R. Grund T. Zoicas I. Althammer F. Fiedler D. Biermeier V. Bosch O.J. Hiraoka Y. Nishimori K. Eliava M. et al.Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation.Curr Biol. 2018; 28: 1066-1078Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar) and for the discrimination of altered affective states in others (Ferretti et al., 2019Ferretti V. Maltese F. Contarini G. Nigro M. Bonavia A. Huang H. Gigliucci V. Morelli G. Scheggia D. Manago F. et al.Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice.Curr Biol. 2019; 29: 1938-1953Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). Exogenous OXT treatments have been reported to produce both pro-social and anti-social responses and no effects at all (Huang et al., 2014Huang H. Michetti C. Busnelli M. Managò F. Sannino S. Scheggia D. Giancardo L. Sona D. Murino V. Chini B. et al.Chronic and acute intranasal oxytocin produce divergent social effects in mice.Neuropsychopharmacology. 2014; 39: 1102-1114Crossref PubMed Scopus (124) Google Scholar; Quintana, 2018Quintana D.S. Revisiting non-significant effects of intranasal oxytocin using equivalence testing.Psychoneuroendocrinology. 2018; 87: 127-130Crossref PubMed Scopus (20) Google Scholar). Anpilov et al. support this OXT complexity by showing that the same prolonged PVN OXT stimulation reduced agonistic behaviors in the resident-intruder test and increased them in the semi-naturalistic arena. These discrepant effects may depend on the diversity of social contexts and the salience of social cues. In the social arena, mice spend many days with their cagemates in an enriched environment (Forkosh et al., 2019Forkosh O. Karamihalev S. Roeh S. Alon U. Anpilov S. Touma C. Nussbaumer M. Flachskamm C. Kaplick P.M. Shemesh Y. Chen A. Identity domains capture individual differences from across the behavioral repertoire.Nat. Neurosci. 2019; 22: 2023-2028Crossref PubMed Scopus (23) Google Scholar). In contrast, in the resident-intruder setting, following a prolonged pairing with a female, the resident mouse must interact in his homecage with a stranger male from another strain for a short period. Living in isolation or in groups, interacting with cagemates or with strangers, and having a mating experience are all factors that can influence the OXT system. Furthermore, in the social arena, all mice received the optogenetic stimulation, whereas only the resident mouse was stimulated in the resident-intruder test. Thus, the differential effects of opto-stimulated OXT neurons may depend on the distinct basal status of the OXT system in each individual within the social interactions, which could be relevant when considering the development of personalized treatments targeting the OXT system. The opposing effects of OXT stimulation reported by Anpilov et al. appear to agree with the OXT salience hypothesis, which states that OXT effects can be different depending on the surrounding environment and the goal of the social interaction. However, their findings (reduced aggression versus a stranger and increased agonistic behaviors versus cagemates) appear to disagree with evidence on OXT differential impact on in-group versus out-group sociability. Some human studies have shown that OXT may increase trust and empathy toward in-group but not out-group members, and OXT may also increase aggression toward out-group members (De Dreu et al., 2010De Dreu C.K. Greer L.L. Handgraaf M.J. Shalvi S. Van Kleef G.A. Baas M. Ten Velden F.S. Van Dijk E. Feith S.W. The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans.Science. 2010; 328: 1408-1411Crossref PubMed Scopus (678) Google Scholar). These latter studies utilized exogenous OXT, which, by downregulating the OXTR, could potentially produce opposite outcomes. The approach applied by Anpilov et al. demonstrated the importance of assessing and comparing different social settings to reach meaningful conclusions regarding the OXT modulation of social processes. Within the same social environment, Anpilov et al. found that prolonged OXT activation could differently modulate social dynamics in a time-dependent manner. The first day of PVN OXT manipulation within the enriched social arena resulted in increased affiliative behaviors. However, starting from the second day of activation, increased agonistic behaviors became evident. The reason for this time-sensitive differential effect of OXT stimulation remains unclear. Nevertheless, the wireless device activation was linked to the feeders, which were accessible for only a limited time to mimic competition for food. Under aversive conditions, OXT may increase responses toward threat signals more than those associated with positive social cues (Shamay-Tsoory and Abu-Akel, 2016Shamay-Tsoory S.G. Abu-Akel A. The Social Salience Hypothesis of Oxytocin.Biol. Psychiatry. 2016; 79: 194-202Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar). This result also agrees with the allostatic OXT theory, in which the OXT system may be able to predict environmental changes to adapt its responses depending on survival and adaptation needs (Quintana and Guastella, 2020Quintana D.S. Guastella A.J. An Allostatic Theory of Oxytocin.Trends Cogn. Sci. 2020; 24: 515-528Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). However, prolonged OXT circuit activation had no effects on identity domains (IDs), categorized by Forkosh et al., 2019Forkosh O. Karamihalev S. Roeh S. Alon U. Anpilov S. Touma C. Nussbaumer M. Flachskamm C. Kaplick P.M. Shemesh Y. Chen A. Identity domains capture individual differences from across the behavioral repertoire.Nat. Neurosci. 2019; 22: 2023-2028Crossref PubMed Scopus (23) Google Scholar. This result indicated that protracted OXT stimulation cannot change the overall behavioral status of a subject, and ID features are likely not sensitive enough to detect discrete changes in social dynamics. Similarly, the authors found that grooming behaviors were not correlated with modifications in group dynamics; therefore, the role of OXT-mediated grooming in the context of social stress remains unclear. This study emphasized the importance of combining advanced biological and computational tools, using different behavioral contexts and temporal investigations, to better define social brain functioning. The optogenetic strategy developed by Anpilov et al., combined with their enriched behavioral set-up, might present new opportunities for the investigation of social dynamics in a more ethologically relevant manner. This work introduces further outstanding questions that remain to be addressed. Depending on the social behavior investigated, OXT effects may be sex-dependent. Thus, investigating the impacts of prolonged OXT stimulation on female group dynamics or larger groups of mice, in which both males and females are present, would be highly relevant. Another question is how group dynamics would be influenced if the wireless manipulation was only applied to one or a few mice within each group. This is connected with the impacts of personal traits on OXT action, which still need to be understood. Indeed, OXT effects can vary across individuals based on their own personal traits (Shamay-Tsoory and Abu-Akel, 2016Shamay-Tsoory S.G. Abu-Akel A. The Social Salience Hypothesis of Oxytocin.Biol. Psychiatry. 2016; 79: 194-202Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar). Moreover, the consideration of individual features will be crucial to achieve biologically supported interpretations of acquired data and to better guide the development of personalized clinical interventions. Finally, the mechanisms underlying the salience hypothesis of OXT remain to be uncovered. OXT has been reported to interact with many neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, and serotonin. For example, in cooperation with the dopamine system, OXT might increase the salience of social cues by modulating attentional orienting responses (Shamay-Tsoory and Abu-Akel, 2016Shamay-Tsoory S.G. Abu-Akel A. The Social Salience Hypothesis of Oxytocin.Biol. Psychiatry. 2016; 79: 194-202Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar). Furthermore, OXT has an almost identical structure to vasopressin (AVP), potentially activating the same receptor populations. In particular, the binding of OXT with AVPRs or OXTR may vary depending on the behavior and context, and some magnocellular neurons in the PVN might co-release both AVP and OXT. Because opposite effects have been reported for AVP and OXT during different behaviors, the mechanisms underlying OXT-AVP crosstalk will be important to probe and may be implicated in the “apparent” dual role for the OXT modulation of social behaviors. Uncovering the interplay between OXT and other neurotransmitters and neuromodulators during disparate social contexts represents an essential step toward examining the role of OXT in the social brain. Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic BehaviorsAnpilov et al.NeuronJune 15, 2020In BriefAnpilov et al. present a lightweight, easily assembled wireless optogenetic device compatible with group-housed mice in a complex environment. Using this approach, they show that repeated activation of oxytocin neurons elicits both pro-social and aggressive behaviors over time, emphasizing the role of the social setting in modulating behavior. 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