Review article
The neurobiology of social play and its rewarding value in rats

https://doi.org/10.1016/j.neubiorev.2016.07.025Get rights and content

Highlights

  • Social play behaviour is a highly rewarding social activity abundant in young animals.

  • Social play behaviour facilitates the development of brain and behaviour.

  • The rewarding properties of social play can be studied using pertinent paradigms.

  • Social play behaviour is mediated by a distributed network of corticolimbic structures.

  • Opioids, dopamine and endocannabinoids interact in the modulation of social play.

Abstract

In the young of many mammalian species, including humans, a vigorous and highly rewarding social activity is abundantly expressed, known as social play behaviour. Social play is thought to be important for the development of social, cognitive and emotional processes and their neural underpinnings, and it is disrupted in pediatric psychiatric disorders. Here, we summarize recent progress in our understanding of the brain mechanisms of social play behaviour, with a focus on its rewarding properties. Opioid, endocannabinoid, dopamine and noradrenaline systems play a prominent role in the modulation of social play. Of these, dopamine is particularly important for the motivational properties of social play. The nucleus accumbens has been identified as a key site for opioid and dopamine modulation of social play. Endocannabinoid influences on social play rely on the basolateral amygdala, whereas noradrenaline modulates social play through the basolateral amygdala, habenula and prefrontal cortex. In sum, social play behaviour is the result of coordinated activity in a network of corticolimbic structures, and its monoamine, opioid and endocannabinoid innervation.

Introduction

During development, humans and animals acquire a wide variety of social behaviours that enable adaptive functioning directed at survival and reproduction in adulthood. Of these, one form of social behaviour that is particularly abundant during post-weaning development, is social play behaviour, also referred to as play fighting or rough-and-tumble play (Fagen, 1981, Graham and Burghardt, 2010, Panksepp et al., 1984, Pellis and Pellis, 2009, Vanderschuren et al., 1997, Himmler et al., 2013, Vanderschuren and Trezza, 2014). One important function of social play behaviour is to facilitate the development of a rich and flexible social repertoire (Pellis and Pellis, 2009, Vanderschuren and Trezza, 2014), and as such, it can be considered a trigger for social development.

Social play behaviour is observed in the majority of mammalian species, including humans. It is most abundant from weaning until after puberty (Panksepp, 1981, Pellis and Pellis, 2009). In rodents, this covers the juvenile phase until mid-adolescence, equivalent to childhood through early/mid adolescence in humans (McCutcheon and Marinelli, 2009, Spear, 2000). Social play behaviour is known for its energetic, vigorous nature. It contains elements of aggressive, predatory and sexual behaviour, performed in a modified or exaggerated form (Panksepp et al., 1984, Pellis and Pellis, 2009, Vanderschuren et al., 1997). Furthermore, these behaviours are accompanied or preceded by explicit physical, facial or vocal signals that the intention of the behaviour is playful in nature. This makes social play behaviour typically easy to recognize and quantify. This is particularly true for several rodent species, including the rat. As a result, the vast majority of our knowledge on the neural underpinnings of social play behaviour stems from rat studies (Siviy and Panksepp, 2011, Trezza et al., 2010, Vanderschuren and Trezza, 2014), and the present overview therefore focuses on social play behaviour in rats.

Social play behaviour is a highly pleasurable, rewarding activity (Trezza et al., 2010, Trezza et al., 2011a, Vanderschuren, 2010), which was already recognized by Charles Darwin, who in The Descent of Man (1871) wrote that ‘Happiness is never better exhibited than by young animals, such as puppies, kittens and lambs, when playing together, like our own children’. On the one hand, this has spurred thinking about the importance and functions of social play, since most naturally rewarding activities such as feeding and sexual behaviour are clear promotors of survival, whereas this is less obvious for social play. On the other hand, this provides us with the opportunity to study social reward mechanisms in developing animals. The importance hereof should not be underestimated, because of the fact that social impairments, including aberrant social play, are core symptoms of pediatric mental disorders, such as autism, disruptive behaviour disorders, attention-deficit/hyperactivity disorder and early-onset schizophrenia (Alessandri, 1992, Helgeland and Torgersen, 2005, Jones et al., 1994, Jordan, 2003, Møller and Husby, 2000). In addition, studying the mechanisms of social play reward, in comparison with studies on other social (e.g. sexual behaviour), non-social (e.g. feeding) and artificial rewards (i.e. drugs of abuse) will paint a picture of how the brain processes pleasurable events and activities, and how these processes overlap or differ between different types of rewards (Berridge and Kringelbach, 2015).

Studying the neural mechanisms of social play behaviour therefore provides insight into how the brain processes positive social signals to generate meaningful social behaviour. The positive emotions that accompany social play contribute to emotional well-being, and as such are important for human health and animal welfare (Bateson, 2015, Ginsburg, 2007, Held and Špinka, 2011). In addition, the study of play will increase our knowledge on how adaptive social experiences shape proper brain development during childhood and adolescence (e.g. Crone and Dahl, 2012). Indeed, dysfunctional social interactions during childhood and adolescence are known to have a long-lasting negative impact on social abilities and cognitive function in humans (Braun and Bock, 2011, Cacioppo and Hawkley, 2009). Investigating the brain mechanisms that underlie social behaviour in the young will also enhance our understanding of child and adolescent mental disorders in which aberrant social behaviour is prominently manifest, such as autism, disruptive behaviour disorders, attention-deficit/hyperactivity disorder and early-onset schizophrenia (American Psychiatric Association, 2013). In the present review, we will provide an overview of studies on the neural underpinnings of social play behaviour in rats, with a focus on its rewarding properties.

In rats, an episode of social play behaviour usually starts off when a rat approaches a conspecific and attempts to touch its neck with the snout (Panksepp and Beatty, 1980, Pellis and Pellis, 1987, Poole and Fish, 1975, Vanderschuren et al., 1997). This behaviour is called pouncing or nape contact, and it is considered the most important parameter of play initiation, perhaps reflecting a motivational aspect of social play. Although pouncing most often occurs from the side, it can also occur from behind, in which case it superficially resembles sexual mounting. The most characteristic response to this play initiation is when the recipient rats rolls onto its dorsal surface, which is commonly known as ‘pinning’, although pinning is not invariably preceded by pouncing. From this position, the animal on bottom will attempt to gain access to the initiating animals’ neck area, so that pinning functions to prolong an ongoing play bout. Being pinned is an otherwise unusual posture for a rat and hence, it is easy to recognize. Note here that one animal on its back with the other standing over it also occurs during aggressive encounters. Thus, social play behaviour in rats clearly combines elements of sexual and aggressive behaviours. Importantly, there are clear distinctions in the microstructure of social play and aggressive behaviour (Blanchard and Blanchard, 1977; Pellis, 1988, Pellis and Pellis, 1987). Most important perhaps is the fact that the on-top and on-bottom positions alternate during social play, whereas this is obviously not the case during aggression. Furthermore, the targets of initiation/attack differ between social play and aggression: the nape of the neck for the former and rump, flanks, back for the latter.

Pinning and pouncing are considered to be the main indices for social play behaviour in rats, because they strongly co-vary with other playful social behaviours (such as following and wrestling) (Panksepp and Beatty, 1980), and are stimulated by brief periods of social isolation (hours to several days) (Niesink and Van Ree, 1989, Vanderschuren et al., 1995a, Vanderschuren et al., 2008). Indeed, responding to a pounce with a full rotation to supine is the most common response during the time when social play behaviour peaks in development (i.e. roughly between postnatal days 28–40). Before and after this period, male rats more often use a partial rotation strategy, whereby the hind legs stay on the ground, which can result in a brief period of upright wrestling. Interestingly, this shift in response to pouncing is much more pronounced in male rats, as compared to females. Thus, how a rat responds to play initiation is age- and sex-dependent (Pellis and Pellis, 1987, Pellis and Pellis, 1990). Another type of response to pouncing is evasion, whereby the recipient animal moves away. The initiator animal may then start to chase the recipient, so that evasion can also function to prolong the playful interaction. An alternative approach used to measure the effects of experimental manipulations on social play focuses on the measurement of the defensive tactics performed by the recipient of a playful attack (Himmler et al., 2013). The frequency of play fighting can be assessed by counting the number of playful nape attacks occurring per unit of time and playful defense can be measured as a percentage (number of attacks defended/total number of attacks X 100%; Himmler et al., 2013).

An important methodological issue that needs to be considered when performing environmental, genetic or pharmacological manipulations of social play is the strain of rats used. Thus, one should be aware that the magnitude of the experimentally-induced changes in social play parameters may differ between rat strains, and this needs to be considered in order to avoid ceiling or floor effects (Siviy et al., 2003, Reinhart et al., 2006, Siviy et al., 2011, Manduca et al., 2014a, Manduca et al., 2014b).

Since social play behaviour involves behaviours that resemble social acts from different contexts, such as aggressive and sexual behaviour, it is important to provide signals to conspecifics that the intention of the behaviour is playful in nature (Palagi et al., 2016). In some animal species, there are specific signals that are used to communicate this intention, such as the ‘play-bow’ in dogs, and particular facial and vocal expressions in primates. In rats, a jumpy type of gait is associated with social play (but not with sex or aggression). Furthermore, during social play, rats emit high-frequency, 50 kHz vocalizations (Knutson et al., 2002, Palagi et al., 2016, Wöhr and Schwarting, 2013), that are also associated with other rewarding activities. These vocalizations may signal positive mood or playful intent (Palagi et al., 2016, Wöhr and Schwarting, 2013). However, the relationship between social play behaviour and these high-frequency vocalizations is not as straightforward as initially assumed (Kisko et al., 2015, Manduca et al., 2014a), so that their exact initiating or facilitating contribution to social play remains to be determined.

Play behaviour is widespread in the animal kingdom, yet does not appear to have an obvious direct function. This paradox has inspired a lively debate on the functions of play (Fagen, 1981, Graham and Burghardt, 2010, Groos, 1898, Huizinga, 1949, Martin and Caro, 1985, Panksepp et al., 1984, Pellis and Pellis, 2009, Small, 1899, Smith, 1982). With regard to the functions of social play behaviour in rats, laboratory experiments in the past decades have provided evidence that it facilitates the development of social, cognitive, emotional, and motor skills, in particular the ability to use these capacities flexibly in a changeable and unpredictable environment (Pellis and Pellis, 2009, Špinka et al., 2001, Vanderschuren and Trezza, 2014). We concede that these findings pertain to one form of play in one species, and extrapolations must therefore be made with caution.

By and large, the studies referred to above have investigated the long-term consequences of social isolation in young rats, in particular during the developmental period when social play is most abundant (i.e. temporary post-weaning social isolation, also referred to as ‘play deprivation’). It is beyond the scope of this review to provide an extensive overview of these studies, that we have recently summarized elsewhere (Vanderschuren and Trezza, 2014). In brief, these studies have found that play-deprived rats are particularly impaired under novel, changeable or challenging situations. For example, although play-deprived rats are well capable of displaying aggressive and defensive behaviour, they have trouble adjusting their behaviour to the context and circumstances. That is, when confronted with an aggressive resident rat, play-deprived rats evoke more aggression, incur more injuries, take more time to assume a submissive posture and show inappropriate exploration of the resident’s territory after defeat (Van den Berg et al., 1999a, Von Frijtag et al., 2002). This kind of deficits stretches beyond the social domain. In tests of cognitive function, play-deprived rats show slower habituation to a novel environment, retarded response reversal learning, slower acquisition of a rat gambling task and increased premature responses in the 5-choice serial reaction time task when task contingencies unexpectedly change (Baarendse et al., 2013, Einon et al., 1978, Einon and Morgan, 1977). Note that with sufficient training, or under baseline test conditions, there were no differences in task performance between play-deprived and control animals. Together, these findings resonate well with the hypothesis that play serves to equip animals for unexpected circumstances (Špinka et al., 2001), i.e. that by combining subsequences of behaviours out of their primary context, animals experiment with their own behaviour and in so doing, acquire a rich behavioural repertoire that they are able to use in a flexible way. Broadly speaking, play therefore serves to facilitate the development of functions such as flexibility and creativity (Bateson, 2015, Špinka et al., 2001). In addition to this, social play, most likely by virtue of its emotional dimensions, i.e. that play is accompanied by the sensation of excitement and pleasure, also has a function in emotional development. Studies addressing this have indeed shown that play-deprived animals show increased levels of anxiety (Leussis and Andersen, 2008, Lukkes et al., 2009, Wright et al., 1991) and augmented sensitivity to the positive effects of substances of abuse (Baarendse et al., 2014, Lesscher et al., 2015, Whitaker et al., 2013).

The studies summarized above all indicate that social play behaviour in rats has an important function in the development of brain and behaviour. However, these are all delayed benefits, that are highly unlikely to be the primary immediate drivers of social play. It is most likely its rewarding, pleasurable effects (Pellis and Pellis, 2009, Trezza et al., 2011a, Vanderschuren, 2010) that motivate animals to play in the short term. In other words, animals play because they enjoy doing so. In addition, its social aspects, i.e. seeking out pleasurable company, engaging in interactions with conspecifics, and establishing and maintaining social bonds, also contribute to the immediate motivation to play.

Interestingly, while early life adverse events have negative consequences on brain function and behavior, environmental enrichment in rats positively affects social play behaviour. Thus, it has been shown that maternal exposure to environmental enrichment before and during gestation increased social play behaviour in male (but not female) rats (Zuena et al., 2016). Similarly, post-weaning environmental enrichment was shown to counteract the deleterious effects of prenatal stress on play behaviour and corticosterone secretion in rats (Morley-Fletcher et al., 2003).

Social play has a strong emotional component, its most characteristic feature being its high reward value (Panksepp et al., 1984, Vanderschuren et al., 1997, Trezza et al., 2011a, Pellis and Pellis, 2009). The rewarding properties of social play are reflected by its ability to support T-maze learning and runway performance as well as place and operant conditioning. These behavioural paradigms have been used to disentangle several aspects of social play reward (Trezza et al., 2011a), including: 1. The subjective feeling of pleasure, i.e. hedonic impact or ‘liking’. 2. Approach behaviour towards or the willingness to work for social play, i.e. incentive motivation. 3. Associative learning and memory, i.e. cognitive aspects of social play.

Place conditioning is among the most widely used tests to study the rewarding properties of natural and drug rewards in laboratory animals (Tzschentke, 2007, Bardo and Bevins, 2000). Place conditioning has been used to demonstrate the pleasurable aspects of (playful) social interactions (Calcagnetti and Schechter, 1992, Crowder and Hutto, 1992, Douglas et al., 2004, Lahvis et al., 2015, Panksepp and Lahvis, 2007, Van den Berg et al., 1999b), access to pups (Mattson et al., 2001), sexual behaviour (Camacho et al., 2004, Jenkins and Becker, 2003), as well as aggressive social interactions (Martinez et al., 1995, Tzschentke, 2007).

A typical place conditioning set-up consists of two or three linked chambers: two conditioning chambers with different visual, tactile and/or olfactory cues, sometimes separated by a third neutral middle compartment. The paradigm is based on the principle that through coupling of the pleasurable properties of social play with the distinct environmental cues of a particular chamber, these cues will come to elicit approach behaviour, so that a rat will spend more time in that environment, when allowed to choose. During conditioning, animals will have the opportunity to play with a conspecific in one chamber and they will be placed alone or with a non-playful partner (e.g., a partner treated with a drug that selectively suppresses social play) in the other chamber. Usually, one day after the last conditioning session, animals are placed in the middle compartment (or on the border of the two chambers, if a two-chamber setup is used) and the animal can freely move about the apparatus for a certain amount of time. The time spent in each of the chambers or the time spent in the play-paired chamber pre- vs post-conditioning is used as an indication of conditioned place preference (CPP).

Calcagnetti and Schechter (1992) were the first to demonstrate that CPP could be acquired with social play. Young rats (postnatal day (PND) 29–33) were conditioned with a partner that had been rendered non-playful by treatment with the muscarinic receptor antagonist scopolamine in one compartment, and with a playful partner in the other compartment. During testing, the rats significantly preferred the compartment previously paired with a playful social partner. Comparable findings were reported by Crowder and Hutto (1992), who used a hybrid of a place and an operant conditioning setup. Douglas et al. (2004) showed that isolated adolescent and adult rats of both sexes acquired social CPP, with adolescent males showing the strongest preference. No social CPP was found in group-housed adults whereas group-housed adolescents showed preference for the compartment previously paired with similarly housed partners. However, when socially housed adolescents were conditioned with isolated partners, no social CPP occurred. These results show that social play is most rewarding for isolated adolescent male rats and suggest that a comparable level of social motivation facilitates the rewarding experience of a social interaction.

Trezza et al. (2009b) demonstrated social play-induced CPP in animals that were socially isolated during conditioning, while animals isolated for a shorter period of time (i.e. 3.5 h) before conditioning showed a trend towards significant CPP. Importantly, this isolation period has been shown to induce a half-maximal increase in the amount of social play behaviour (Niesink and Van Ree, 1989, Vanderschuren et al., 1995c; Vanderschuren et al., 2008). No CPP developed in animals that were group-housed or housed with an adult rat. Importantly, rats conditioned with a partner treated with methylphenidate, a drug that reduces play-related behaviours without affecting general social interest (Achterberg et al., 2015, Vanderschuren et al., 2008), did not develop CPP, which underscores the importance of social play for the development of CPP. In support of this notion, we have found that the total amounts of pins and pounces during the conditioning sessions positively correlate with the magnitude of CPP. Thus, the more the animals played, the larger the CPP. This correlation was not observed for social exploration. When the play data were analyzed taking initiator and recipient of the play interaction into account (i.e. pinning/pouncing vs being pounced or pinned), both being pinned and being pounced were found to correlate positively with CPP. Importantly, since being pinned requires an active response of the animal (i.e. rotating to its dorsal surface), this suggests that it is the active engagement in social play, rather than being the initiator of the interaction, that determines its rewarding properties (Fig. 1).

In apparent contrast to the above findings, Kummer et al. (2011) and Peartree et al. (2012) found that social interaction without physically engaging in play can also support the development of CPP, albeit to a lesser extent than active social play itself. Thus, whereas two pairings with a playful partner were sufficient to develop CPP, eight pairings were required to establish CPP when the social partner was confined behind a barrier or when a ball was used as a stimulus (to evoke object play) (Peartree et al., 2012). When tactile stimulation was prevented during the social interaction, so that only visual and olfactory information could be exchanged, place aversion was found (Kummer et al., 2011). Combined, these results show whereas social play may not be strictly required for CPP to emerge, being able to actively engage in this activity markedly facilitates the development of CPP, indicating that social play is the most rewarding component of social behaviour in young rats.

The interaction between social and drug reward in rats has also been studied using place conditioning experiments. Studies by Thiel et al., 2008, Thiel et al., 2009 have demonstrated that social play can also be used to enhance the rewarding properties of drugs of abuse such as cocaine and nicotine and vice versa. Using a sub-effective conditioning paradigm, in which each condition alone (i.e. either drug or social play) was not sufficient to produce CPP, the two rewards together interacted to produce CPP, although both nicotine and cocaine reduced play itself. Grotewold et al. (2014) reported comparable findings with social interaction and cocaine. These studies are important for our understanding of the effects of social context on drug reward (El Rawas and Saria, 2016, Trezza et al., 2014, Zernig and Pinheiro, 2015). All in all, there is ample evidence to show that social play can induce CPP, which provides an excellent opportunity to study the pleasurable aspects of social play behaviour.

Social play, like palatable food, drugs of abuse and several social behaviours can be used to support operant conditioning, the procedure by which an animal can obtain a reward by performing an arbitrary action, such as pressing a lever, poking its nose in a hole or touching a screen. An operant conditioning chamber (often called ‘skinner box’, after B.F. Skinner, one of the main instigators of operant conditioning research) typically consists of a computer controlled chamber with levers, nose-poke holes or a touchscreen, and cue lights to steer the animal’s behaviour. When an animal makes a required response, it receives a reward, so that the animal learns the contingency between its response (e.g. lever-pressing) and the delivery of the reward. This increases the likelihood that the animal will repeat the action, a phenomenon known as reinforcement. Different reinforcement schedules can be used to gauge distinct aspects of the animals’ behaviour. Of these, the progressive-ratio (PR) schedule of reinforcement was developed to specifically study motivation for rewards (Hodos, 1961, Richardson and Roberts, 1996). Under a PR schedule, the number of responses to obtain the next reward is increased after every obtained reward, until the animal stops responding. The maximal number of responses performed to obtain one single reward, i.e. the breakpoint, is generally used as a measure for incentive motivation.

Operant conditioning has been employed using different social rewards (Trezza et al., 2011a), such as access to a receptive female (Everitt and Stacey, 1987), access to pups (Lee et al., 1999) or (playful) social handling by an experimenter (Davis and Perusse, 1988). The first ever operant conditioning experiments with social play were performed in primates. Mason et al. (1962) tested in 2 young chimpanzees whether they were willing to press a lever to interact with an experimenter. Importantly, of the social behaviours on offer, they found that social play most powerfully supported responding. In a follow-up study (Mason et al., 1963), the reinforcing properties of food and social interaction were compared, in which the incentive value of the food was manipulated by testing the animals when hungry or satiated and by changing the palatability of the presented food. Social interaction consisted of being petted by the experimenter or social play with the experimenter. Food was preferred when animals were hungry or highly palatable food was present and the animals preferred play over petting. The most intriguing finding of the study was that even when the animals were hungry or when highly palatable food was available, the chimpanzees still chose play half of the time.

Recently, we developed an operant conditioning paradigm for social play reward in rats (Achterberg et al., 2016a, Achterberg et al., 2016b). In this setup, rats are trained to lever press for brief episodes of social play behaviour. In order to assess the motivational properties of social play, we used a PR schedule of reinforcement. Consistent with the notion that social isolation increases social play (Niesink and Van Ree, 1989, Panksepp and Beatty, 1980, Vanderschuren et al., 1995a, Vanderschuren et al., 2008) by enhancing the motivation to play, we found that responding for social play, as well as its performance during reinforced periods, was higher in rats isolated for 24 h before testing than in animals isolated for 2 h. Moreover, as will be discussed in detail below, we found that the performance of social play and responding for social play could be pharmacologically dissociated. This indicates that the motivation for play and its performance are modulated through distinct, although likely overlapping, neural systems. Together, these results show that operant conditioning can be used to assess motivational aspects of social play behaviour.

Motivational properties of social play have previously also been studied in a T-maze set-up (Humphreys and Einon, 1981, Ikemoto and Panksepp, 1992, Normansell and Panksepp, 1990, Werner and Anderson, 1976). In this paradigm, animals are placed in a ‘startbox’ at the bottom of a T-shaped maze and after a short delay are allowed to move towards one of the arms of the maze. This can be used to determine preference for certain stimuli as a measure for reward and motivation, whereby movement speed or choice latency are often used as readout parameters. In addition, mnemonic aspects of reward processes can be assessed. Compared to group-raised animals, it has been shown that social isolation-reared adolescent rats chose the opportunity for social interaction more often compared to a palatable food reward (Ikemoto and Panksepp, 1992). Futhermore, young rats preferred a playing partner in a ‘goal box’ compared to a social but non-playful partner (Humphreys and Einon, 1981, Normansell and Panksepp, 1990, Werner and Anderson, 1976). In addition, dominant adolescent males in a play couple needed less time to traverse a T-maze for the opportunity to play compared to their subordinate play partners (Panksepp et al., 1984).

Section snippets

Neuropharmacology of social play

Much of our knowledge on the neural underpinnings of social play behaviour derives from pharmacological intervention studies (Siviy and Panksepp, 2011, Trezza et al., 2010, Vanderschuren et al., 1997). In this section, we will provide an overview of the studies that have used pharmacological manipulations. For the most part, these have been systemic treatments, but these have more recently been followed up by intracranial administration studies. Because the main topic of the present review is

Neural modulation of social play

The neural mechanisms of social play behaviour in rats have been investigated using lesion, site-specific injection of selective agonists and antagonists and immediate early gene expression studies. Although our understanding of the brain mechanisms of social play is far from complete, these studies have so far provided a most interesting glimpse into how limbic and corticostriatal circuits modulate social play.

Discussion

Social play is being increasingly recognized as an important social activity for humans and animals alike. It is intrinsically rewarding, supports social bonding and in the long run facilitates social, cognitive and emotional development (e.g. Bateson, 2015, Burghardt, 2010, Pellis and Pellis, 2009, Vanderschuren and Trezza, 2014). It is therefore of great importance to understand the brain mechanisms underlying social play behaviour, not least because social deficits in child and adolescent

Acknowledgements

We would like to dedicate this manuscript to the memory of Professor Frauke Ohl, chair of the Department of Animals in Science and Society, who passed away on 28 January 2016. We remember her as an inspiring colleague, mentor, and friend. Our work on social play behaviour during the last decade has been generously supported by the National Institute on Drug Abuse (R01 DA022628 to L.J.M.J.V.), the Netherlands Organization for Scientific Research (NWO; Veni grant 91611052 to V.T.), the European

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