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Neuroscience and Biobehavioral Reviews 37 (2013) 2166–2180

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

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owards improved animal models for evaluating social cognition andts disruption in schizophrenia: The CNTRICS initiative

ark J. Millana,∗, Karen L. Balesb

Unit for Research and Discovery in Neuroscience, IDR Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, FranceDepartment of Psychology, University of California, One Shields Avenue, Davis, CA 95616, USA

r t i c l e i n f o

rticle history:eceived 12 September 2013eceived in revised form7 September 2013ccepted 19 September 2013

eywords:ociabilityocial recognitionmotionegative symptomsffective behavioursychosisntipsychoticxytocinaze

a b s t r a c t

Social cognition refers to processes used to monitor and interpret social signals from others, to deci-pher their state of mind, emotional status and intentions, and select appropriate social behaviour. Socialcognition is sophisticated in humans, being embedded with verbal language and enacted in a complexcultural environment. Its disruption characterises the entire course of schizophrenia and is correlatedwith poor functional outcome. Further, deficits in social cognition are related to impairment in othercognitive domains, positive symptoms (paranoia and delusions) and negative symptoms (social with-drawal and reduced motivation). In light of the significance and inadequate management of socialcognition deficits, there is a need for translatable experimental procedures for their study, and iden-tification of effective pharmacotherapy. No single paradigm captures the multi-dimensional nature ofsocial cognition, and procedures for assessing ability to infer mental states are not well-developed forexperimental therapeutic settings. Accordingly, a recent CNTRICS meeting prioritised procedures formeasuring a specific construct: “acquisition and recognition of affective (emotional) states”, coupled toindividual recognition. Two complementary paradigms for refinement were identified: social recogni-tion/preference in rodents, and visual tracking of social scenes in non-human primates (NHPs). Social

ye-trackingouse

aton-human primate

recognition is disrupted in genetic, developmental or pharmacological disease models for schizophrenia,and performance in both procedures is improved by the neuropeptide oxytocin. The present arti-cle surveys a broad range of procedures for studying social cognition in rodents and NHPs, discussesadvantages and drawbacks, and focuses on development of social recognition/preference and gaze-following paradigms for improved study of social cognition deficits in schizophrenia and their potentialtreatment.

© 2013 Elsevier Ltd. All rights reserved.

ontents

1. The CNTRICS initiative for improving animal models of cognitive impairment in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21672. Social cognition: core features of the processing of social information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2167

2.1. Multiple dimensions of social cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21672.2. Neural substrates of social cognition and relevance to animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2168

3. Disruption of social cognition and social processing in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21684. Procedures available for characterising social cognition and their further development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2169

4.1. Overview of nominated procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21694.2. Significance of social interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21704.3. Prioritisation of two complementary procedures for further study and development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2170

5. Procedures for monitoring social recognition, sociability and social preference in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21715.1. Background to common experimental procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21715.2. CNTRICS selection: measures of sociability, social recognition and preference using a three chamber test in rodents . . . . . . . . . . . . . . . . . 21725.3. The neuropharmacology of social recognition and social preference in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2172

∗ Corresponding author. Tel.: +33 1 55 72 24 25.E-mail addresses: [email protected] (M.J. Millan), [email protected] (K.L. B

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M.J. Millan, K.L. Bales / Neuroscience and Biobehavioral Reviews 37 (2013) 2166–2180 2167

5.4. Insights from comparative studies: partner preference in monogamous prairie voles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21735.5. Limitations and prospects for future development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21735.6. Parallel studies in non-human primates of social recognition/preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2173

6. Emotional and intention recognition: studies in non-human primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21746.1. Eye-tracking and studies of gaze . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21746.2. Limitations and prospects for future development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2174

7. Other potential models for studying social cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21758. Concluding comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2175

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2176 . . . . . .

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. The CNTRICS initiative for improving animal models ofognitive impairment in schizophrenia

Over the past several years, the National Institute of Mentalealth, in collaboration with academia and industry, has fosteredfforts to improve treatment of the disabling cognitive deficits thatharacterise schizophrenia (Kalkstein et al., 2010; Millan et al.,012). Initially, a consensus was built on the nature of cognitive

mpairment and the need for its treatment by dedicated med-cation (Buchanan et al., 2010; Green et al., 2008; Keefe et al.,011; Nuechterlein et al., 2004). More recently, a subsequentNTRICS (Cognitive Neuroscience Treatment Research to Improveognition in Schizophrenia) initiative (Barch and Carter, 2008;arter and Barch, 2007; Carter et al., 2008, 2009) has focussedn: (1) development of improved (and translatable) proceduresor human and experimental study of specific cognitive domains;2) characterisation of their disruption in genetic, developmentalnd pharmacological models for schizophrenia; (3) exploration ofnnovative mechanisms for countering cognitive deficits; and (4)valuation of novel, pro-cognitive medication both pre-clinicallynd, via translational strategies, clinically in patients. In parallel,fforts have been promoted to find improved neuroimaging andther biomarkers for the monitoring of cognitive impairments andhe validation of new therapies.

Social cognitive constructs and their translation through ani-al paradigms were addressed at CNTRICS meetings on animalodels (St. Louis, 2010; Washington, DC, 2011). Following dis-

ussions on specific social cognitive constructs, specialists in theeld were asked to nominate experimental tasks justifying fur-her refinement. During the 2011 meeting, specific breakout groupsonsidered individual cognitive domains including social cogni-ion, the topic of this contribution. To harmonise the process andutcome amongst the various cognitive domains, several criteriaere adopted for selection of the most promising animal proce-ures for development and wider use in basic research and drugiscovery:

Construct validity: that is, isolation of the mediating cognitiveprocesses and their neural substrates across humans and speciesused in experimental animal models for schizophrenia.

Cross-species homology, with an emphasis on rodents andnon-human primates (NHPs) – bearing in mind that certaindimensions of social cognition may be absent or not easily mea-surable in laboratory species.

Translatability: along the lines of the above comments, theprocedure should tap into common neural substrates engagedin animals and humans as established both by conven-tional behavioural-cognitive readouts and by studies of neural
substrates with techniques usable in humans such as elec-troencephalographic and neuroimaging technologies. Ideally,comparable procedures and common readouts should be adoptedin animal and human procedures of drug evaluation.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2176

- Parametric properties allowing for quantification of deficits anddetection of drug effects.

- Reliability, reproducibility across laboratories, potential stan-dardisation and automation of the core paradigm, relativelystraightforward introduction and validation of the procedure.

- Other factors include rigorous respect of ethical imperatives andanimal welfare (van der Staay et al., 2009), and non-prohibitivecost for screening of candidate medication.

Ultimately, the major goal of CNTRICS is to promote devel-opment of well-founded procedures for the identification,characterisation and validation of novel treatment targets/conceptsfor improving cognitive deficits in schizophrenia, and for the exper-imental, translational and clinical proof of the efficacy of newagents. The present article focuses on animal paradigms for mea-suring social cognition and the processing of social information.

2. Social cognition: core features of the processing of socialinformation

2.1. Multiple dimensions of social cognition

There is no simple or universal definition of social cognition,which is a multi-facetted and complex construct. Nonetheless,there is a broad consensus that social cognition refers to the paletteof cerebral mechanisms and mental operations used to detect, ana-lyse and interpret social signals transmitted by conspecifics; andto discern and understand their beliefs, intentions and actions.This ultimately permits appropriate social (and other) behavioursadapted to the social situation (Adolphs, 2009; Brüne, 2005; Derntland Habel, 2011; Green et al., 2008; Millan et al., 2012). This def-inition encompasses a broad and interacting suite of capacities,including: (1) the perception of emotional and cognitive statesvia, for example facial expressions; (2) an awareness of the (pos-itive and negative) motivational nature of social interactions; (3)an understanding of social situations, including rules governingactions, like etiquette and proximity; (4) an awareness of the causesof social situations and social behaviours and (5) social inference,meaning the ability to predict the behaviour of another, based notonly on previous actions but also on the assessment of social signalssuch as gaze, gestures or vocalising.

A more sophisticated expression of the latter capacity is “the-ory of mind”; the ability to internally represent the mental stateof others, and hence to infer their beliefs, desires, knowledge,intentions and future behaviour (Brüne, 2005; Fitch et al., 2010).It is debated to what extent theory of mind is present in non-human species, though compelling evidence has been acquiredwith Corvids like scrub jays which, in hiding food-caches, dis-play an advanced theory of mind, as well as social (individual)
recognition, gaze-following and genuine episodic memory (Calland Tomasello, 2008; Emery and Clayton, 2009; Fitch et al., 2010;Hermann et al., 2007; Premack, 2007; Smith, 2009). The possiblydistinctive nature of human social cognition, a crucial issue for

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168 M.J. Millan, K.L. Bales / Neuroscience and

xperimental modelling, is also underpinned by the significancef cultural context and its reciprocal interaction with verbal lan-uage. In particular, the need to decipher abstract use of languages well as “prosody” (intonation, emphasis) and to express one-elf in accordance with accepted codes of “pragmatics” (adapted toocial context) (Fitch et al., 2010; Millan et al., 2012). It is uncer-ain to what extent such facets of language are represented in otherystems of communication like ultrasonic vocalisations (USVs) inodents (Wöhr and Schwarting, 2013; Scattoni et al., 2009). Thus,lthough theory of mind and language-related social cognitive con-tructs are important, it was felt among CNTRICS participants thatrocesses related to the general construct of social and emotionalecognition (and appropriate response selection) would be moreranslatable across the species commonly used drug developmentesearch.

.2. Neural substrates of social cognition and relevance to animalodels

No single cerebral region or circuit underpins the various com-onents of social cognition (Adolphs, 2009; Ishai et al., 2005;an Overwalle and Baetens, 2009; Millan et al., 2012; van derooij and Sandi, 2012). Rather, distinct but interlinked cerebraletworks are harnessed in the human and NHP brain for spe-ific functions including: (1) theory of mind (precuneus, inferiorrontal gyrus, cingulate and frontal cortex, superior temporal gyrus,emporo-parietal junction); (2) facial perception and facial recogni-ion (fusiform face area and gyrus, inferior occipital gyrus, temporalyrus and superior temporal sulcus, temporo-parietal junction andnferior parietal cortex) and (3) gaze-following (superior tempo-al sulcus, inferior parietal cortex and the oculomotor loop linkinghe frontal eye fields to the striatum, superior colliculus, thala-

us and cortex). An additional network including the amygdala,nsula, ventral striatum, anterior cingulate cortex and prefrontalortex is important for identification of and responding to emo-ional social cues (Millan et al., 2012; Ochsner, 2008; Phillips et al.,003).

Since imaging and related techniques are difficult to apply toreely moving rodents in social paradigms (Kerr and Nimmerjahn,012), and rodents do not display all features of human socialognition, comparable information on circuits recruited in socialnteractions is less available. For the models of social recognitionnd preference discussed below, apart from processing in the pri-ary and accessory olfactory systems (Rennie et al., 2013; Wacker

nd Ludwig, 2012), the lateral septum, medial amygdala and pos-ibly pre-optic area of the hypothalamus appear to be of particularmportance, with the nucleus accumbens also playing a role inewarding aspects. Conversely, a contribution of the hippocampalomplex to consolidation remains to be confirmed (Ferguson et al.,002; van der Kooij and Sandi, 2012).

Key evidence for an implication of the above-mentioned brainegions has been acquired in microinjection studies (mice, rats andrairie voles) of the “pro-social” neuropeptides, oxytocin and vaso-ressin; and their use is fundamental to the characterisation ofny animal model of social cognition (Bielsky and Young, 2004;holeris et al., 2009; Goodson and Thompson, 2010; Veenema andeumann, 2008; Young et al., 2010) – not least in view of their ben-ficial actions on social cognition in schizophrenic patients (Davist al., 2013; Feifel et al., 2010; Fischer-Shofty et al., 2013a; Goldmant al., 2011; Pedersen et al., 2011). Oxytocin is particularly involvedn acquisition, likely acting in the medial amygdala and perhapshe medial preoptic area of the hypothalamus. Vasopressin may be

ore implicated in retention and acts preferentially in the lateraleptum (Ferguson et al., 2002; Gabor et al., 2012; Popik et al., 1992;

inslow and Insel, 2002). Possible roles of these neuropeptidesn primary olfactory processing should also be mentioned, though

havioral Reviews 37 (2013) 2166–2180

this would not negate their influence upon social cognition exertedat higher levels of integration indicated above (Bielsky and Young,2004; Bielsky et al., 2005; Rennie et al., 2013; Wacker and Ludwig,2012).

Other modulators involved in social cognition include thoseaffecting motivational and rewarding facets of social behaviour,including dopamine and cannabinoids, as well as neurotransmit-ters implicated in its more cognitive aspects, like monoamines andacetylcholine, although it is not entirely clear how and where theyact (Bielsky and Young, 2004; Millan et al., 2012). In this light, itis important to note the role of the frontal cortex in the modu-lation of social cognition as shown using procedures measuringsocial recognition in rodents. Its role may reflect a more general“top-down” control of cognitive processing – especially attention– that is likewise relevant to other cognitive tasks lacking socialconnotations, such as novel object recognition (Amodio and Frith,2006; Loiseau and Millan, 2009; Luck et al., 2012; Rossi et al., 2009;Watson et al., 2012). The implication of the frontal cortex is con-sidered further below in discussing the pharmacology of socialrecognition/preference models in rodents.

3. Disruption of social cognition and social processing inschizophrenia

Like several other cognitive domains, social cognition is consis-tently impaired in schizophrenia, including both its emotional andcognitive facets (Brüne, 2005; Derntl and Habel, 2011; Green et al.,2008; Penn et al., 2008; Millan et al., 2012). Further, impaired socialcognition is present throughout the course of schizophrenia fromthe first episode on, and it is apparent in high-risk patients priorto diagnosis (Addington et al., 2013; Barbato et al., 2013; Bora andPantelis, 2013; Galderisi et al., 2008; Green et al., 2011; Horan et al.,2012; Pinkham et al., 2007; Thompson et al., 2012). This disruptionof social cognition is strongly related to poor functional outcome(Fanning et al., 2012; Fett et al., 2011; Millan et al., 2012; Schmidtet al., 2011) and, together with poor motivation, it has been sug-gested that deficits in social cognition at least partially mediate thedeleterious impact of impairments in other cognitive domains uponreal world function (Barbato et al., 2013; Barch and Dowd, 2010;Couture et al., 2006; Fanning et al., 2012; Foussias et al., 2013; Gardet al., 2008; Green et al., 2008; Murray et al., 2008; Pijnenborg et al.,2009; Schmidt et al., 2011).

A further distinctive feature of social cognition concerns itsinterrelationship with positive and negative symptoms (Foussiaset al., 2013; Green et al., 2008; Millan et al., 2012; Sergi et al.,2007; Van Hooren et al., 2008). Thus, as summarised in Fig. 1,dysfunctional social cognition leading to false attributions may trig-ger or exacerbate positive symptoms of paranoia and delusions.Further, though the reciprocal interrelationship between impair-ment of social cognition and negative symptoms remains underdiscussion, poor social cognitive abilities may be associated withdisengagement from social interaction (withdrawal) and bluntedmotivation for engaging in social relationships (Sergi et al., 2007;Foussias et al., 2013; Green et al., 2008; Millan et al., 2012). Finally,impaired social cognition may be related to social anxiety and, viasocial withdrawal and reduced motivation, favour the genesis ofco-morbid depression (Corcoran et al., 2011; Foussias et al., 2013;Green et al., 2008; Nakagami et al., 2010).

These interfaces between disruption of social cognition inschizophrenia and its other cardinal and co-morbid features shouldbe borne in mind in the characterisation and interpretation of datafrom experimental models of schizophrenia discussed below since
anomalous responses to social cues in animal paradigms have beenassimilated into discussions of both negative symptoms and aber-rant social cognition (Peleg-Raibstein et al., 2012; Pratt et al., 2012;Wilson and Koenig, 2013).


Social moti vati on Social anxiet y

Social Wi thd rawal

Inappropri atesocial responses

(in cl. em otion al flatt ening )

Impaire d social cognition

Inaccurate assessmentof threa t or opportunity

Positive Symptoms Negative Sympto ms

Impaired acquisition and recognition of emotional valueCNTRICS Select ed Construct for Tas k De velo pment

Other socioemotional constructs

Poor Functiona l Outcome

Fig. 1. Relationships between impaired acquisition and recognition of emotional value and symptom domains of schizophrenia. The processes by which social cognitivedeficits may contribute to symptoms and lead to poor functional outcome are illustrated here through one social cognitive construct “Acquisition and Recognition of EmotionalValue”, selected during CNTRICS meetings as a construct amenable for development and optimisation of tasks for humans and animals to be used to develop and test noveltreatments to improve social cognition in schizophrenia. In schizophrenia, social cognitive deficits, including the inability to assign the appropriate emotional value to socialcues emitted by others, can manifest as exaggerated or impaired assessment of risk (or threat) and, will generally result in inappropriate responding. Deficits in socioemotionalcue encoding can also lead to a devaluation or aversion to social situations, manifesting as decreased social motivation and/or increased social anxiety. Though it is uncertainwhether the relationships are direct and causal, these social cognitive and behavioural abnormalities may contribute to paranoiac beliefs and delusions (positive symptoms)as well as apparent emotional blunting, avolition, and social withdrawal (negative symptoms). Both directly and through exacerbation of symptoms, social cognitive deficitsa

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re hypothesised to lead to poor functional outcome.

. Procedures available for characterising social cognitionnd their further development

.1. Overview of nominated procedures

As indicated above, and by distinction to other cognitiveomains like short-term memory or attention, social cognition is aarticularly rich construct which may have distinct components inumans (Millan et al., 2012; Smith, 2009; Tomasello et al., 2005). It

s unlikely, then, that any single animal model could fully capturehe complexity, subtlety and multidimensionality of social cogni-ion in humans. Indeed, the measurement of cognitive constructselated to theory of mind is at best challenging – even in highlyocial and highly encephalised species like dolphins and corvidsConnor, 2010; Emery and Clayton, 2009; Marino, 2002; Millant al., 2012), let alone laboratory rodents (Barrett et al., 2007; Emerynd Clayton, 2009; Smith, 2009; van Schaik et al., 2012; Tomasellot al., 2005). Hence, the CNTRICS meeting focused on the more emo-ional dimension “acquisition and recognition of affective values”oupled to social (that is, individual) recognition (Carter et al., 2009;ring and Moran, 2008; Ochsner, 2008; Phillips et al., 2003). Thistrategy is well aligned with the previous CNTRICS consensus on
ask selection for human studies which correspondingly selectedwo tasks for measurement of the identification of and response tomotional cues and their context-based modulation (Carter et al.,009) (Figs. 1 and 2).
The animal paradigms nominated prior to 2011 CNTRICS meet-ing were: (1) the social recognition procedure, allied to its variants,social novelty discrimination and habituation–discrimination inrodents; (2), sociability (preference for social vs non-social stimuli)and social preference (preference for unfamiliar vs familiar con-specific) in rodents and NHPs (the latter using measurements ofvisual scan of social stimuli); (3) juvenile social play; (4) socialstimulus- and social play-induced conditioned place preferencesin rodents; and (5) spontaneous social interaction in rodents in afamiliar environment.

The literature on proposals 3 and 4 was considered to be rich(e.g. Colonnello et al., 2011; Schneider and Koch, 2005; Pankseppand Lahvis, 2011; Siviy and Panksepp, 2011; Wöhr and Schwarting,2013). Play in juveniles – studied by both behavioural observationsand recordings of USVs – is especially relevant to the notion ofshared goals and role-playing, to developmental risk factors andto the prodromal phase of schizophrenia. Further, it is disrupted byearly-life lesions of the cortex. Nonetheless, the paradigm by defi-nition does not apply to adults and data relevant to schizophreniaremain limited. As for place preference procedures, social inter-action is sufficient to sustain a conditioned preference in rats,and sub-chronic phencyclidine in adolescence interferes with this
response (Schwabe et al., 2006; Yates et al., 2013). Further, oxytocingenerates a conditioned preference both alone and under socialconditions (presence of a conspecific) in mice (Kent et al., 2013).However, the rewarding properties of social interaction, even if

2170 M.J. Millan, K.L. Bales / Neuroscience and Biobehavioral Reviews 37 (2013) 2166–2180

Facialexpression

Gaze shift etc..

Bod y post ure and motio n

(Affec tive state)

Olfactory Cue s

Auditory Cues

(Social Object Identity)

Facialfeatures

Body features

Olfactory Cue s

Auditory Cues

Acquisition of emotional value(and social object properties )

Appropri ate response

Recognition of affe ctive state (and soci al objec t identit y)

Further process ing (affect- moto r inter face )

Fig. 2. Flow of information during acquisition, recognition and retrieval of affective value, and adaptive social responding. The animal paradigms selected for furtherdevelopment as screens for treatment for social cognitive deficits in schizophrenia measure the cognitive/affective processes shown in the large, pink ovals at the top whenappropriate control conditions are used. Both the social preference/recognition task in rodents and the primate paradigm of gaze tracking during presentation of social stimulic righr

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isrupted by risk genes for schizophrenia, may be more closelyelated to hedonia and reward than social cognition (Burbridge andarch, 2007; Lipina et al., 2013). Further, place preference studiesre time-consuming and challenging to set up reliably (even forimple, pharmacological manipulations). Overall, these paradigmsere considered to require significant development before they

ould be used for evaluating potential pharmacotherapies.The rodent paradigm ultimately selected for further develop-

ent is a hybrid of social preference, sociality and social recognitionemory tasks using a 3-chamber apparatus that allows sufficient

ontrol of important non-social factors. The second nominatedaradigm was visual scan of social stimuli in NHPs. Before discus-ion of these paradigms, however, the conceptual underpinningsf social interaction studies (proposal 5) warrant comment sinceocial interaction is widely studied in rodent models of psychiatricisease and is inherent to any rodent procedure for interrogatingocial cognition (De Jaegher et al., 2010).

.2. Significance of social interaction

The basic “social interaction test” involves the measurementf social interactions between two freely moving rodents, usuallynfamiliar adults in an open field or similar arena (File and Hyde,978; File and Seth, 2003). This procedure has been predominantlyxploited under anxiogenic conditions, such as high light, in thetudy of anxiety and the detection of potential anxiolytic agentsFile and Seth, 2003; Millan, 2013). A significant challenge withhis basic version of the task is that both animals are freely moving,

aking it difficult to disentangle factors such as social motiva-ion, emotional status, attention and motor drive, etc. Further, andf particular importance for translational research in schizophre-ia, the unmodified procedure does not specifically address the

ssue of social cognition. Nonetheless, social interaction is indeederturbed in many rodent models designed to recapitulate thechizophrenia-related genetic, developmental or neurobiologicalbnormalities (De Jaegher et al., 2010; Hida et al., 2013; Millan androcco, 2008; Papaleo et al., 2012; Peleg-Raibstein et al., 2012; Prattt al., 2012).

Social interaction is likewise disrupted by (usually sub-chronic)dministration of phencyclidine (PCP) to adult rodents (Koros et al.,
007; Pratt et al., 2012; Sams-Dodd, 1999; Seillier et al., 2006).CP-induced disruption of social behaviour has been argued to beelevant to the social withdrawal associated with negative symp-oms (Foussias et al., 2013; Green et al., 2008; Koros et al., 2007;
t). (For interpretation of the references to colour in this figure legend, the reader is

Pratt et al., 2012; Sams-Dodd, 1999; Seillier et al., 2006; Yee et al.,2010). However, the cognitive and affective processes underlyingthis abnormal behaviour are not understood. Moreover, the neu-ral substrates of this effect of PCP, and mechanisms underlying itsreversal by antipsychotic drugs (which do not reverse social deficitsin schizophrenia patients), also remain to be elucidated. Overall,observation of spontaneous social interaction with minimal impo-sition of experimental controls may increase our knowledge ofspecies-appropriate behaviours and how, at a qualitative level, theyrespond to drugs and are disrupted in schizophrenia-disease mod-els. They however lack sufficient experimental control to determinecognitive and neural mechanisms. As such, these paradigms mightbe best used for qualitative characterisation of disease models andfor generation of neuropsychopharmacological hypotheses.

4.3. Prioritisation of two complementary procedures for furtherstudy and development

As pointed out above, several proposed paradigms embrace thegeneral theme of social interaction and recruit to some extentthe animal’s ability to encode, retrieve/recognise, and appropri-ate respond to information about affective state (or “value”). TheCNTRICS workgroup focussed on core parameters of social pref-erence and recognition: as processes that could be selectivelymeasured in tasks that would permit demands to be placed on theseprocesses with some degree of parametricity and reliability. Theinterrelated tasks considered below assess several fundamentalfeatures of social behaviour, including: sociability, i.e. the moti-vation to engage in social behaviour or interact with social overnon-social objects; social (partner) preference, i.e. the preferenceof one individual (usually unfamiliar) over another; social recogni-tion, i.e. the ability to remember an individual and discriminatebetween individuals; and typical social behaviour, i.e. appropri-ate patterns of social interaction with conspecifics. The followingdiscussion also draws on principles revealed by studies of pair-bonding in prairie voles, where the preference is for the familiarpartner over unknown conspecifics. A second paradigm for NHPswas also proposed (by Dan Hutcheson): emotion and intentionrecognition, as assessed by eye-movement tracking and gaze anal-ysis as the animal views social stimuli. Eye movement is considered
to be ecologically valid and particularly important for humansocial interactions (Millan et al., 2012; Sprenger et al., 2013; Tohet al., 2011). Key features of these procedures are outlined below,together with their limitations and prospects for progress.


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Fig. 3. Schematic representation of use of a 3-chamber apparatus to monitor sociability, social recognition/memory and social preference. There are several versions of a3-chamber choice task available to test social preference and social recognition in rodents. The basic protocol shown here presents the rodent with a choice of exploring 2objects, or not exploring at all. All versions of the task include a period of habituation (H) in the centre, empty chamber. This is followed by a period of exploration–choice(E–C) during which the animal is allowed to freely explore the other chambers for a set duration, usually around 5–30 min. For sociability, the choice is between a social(conspecific) vs a non-social object. The test can be modified to test social recognition and preference with or without a memory load. For this, an encoding phase duringwhich the animal explores and encodes 2 conspecifics is followed (immediately or after a variable delay) by a recognition phase during which the task is repeated with one ofthe object rodents from the encoding phase replaced with a novel rodent. Primary and secondary outcomes for these paradigms are shown in the bottom left box. Propertiesof the objects including visual, olfactory and auditory salience, as well as activity, can be controlled for or systematically varied, depending on the hypothesis. Selected controlv , the td .

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. Procedures for monitoring social recognition, sociabilitynd social preference in rodents

.1. Background to common experimental procedures

Social preference (or sociability) is tested by comparisons of theesponse to socially neutral stimuli vs a conspecific. A commonlysed procedure is the three-chambered sociability/social prefer-nce task in rodents (Fig. 3) (Crawley, 2000; Kaidanovich-Beilint al., 2011; Moy et al., 2007; Roullet and Crawley, 2011; Yang et al.,011). This test, which allows free choice between three cham-ers, has several types of design allowing for evaluation sociability,eaning a relatively greater motivation to spend time with a social

timulus (conspecific) vs an identical chamber with a non-socialbject (usually a toy). These tasks are argued to be relevant to social

drive’, or motivation to engage in social interactions in humans.The basic principle of social recognition procedures is to evalu-

te the capacity of the rodent to differentiate between a conspecifico which it has previously been exposed (‘familiar’) vs a new

arget animal is not restrained under an inverted wire cup: the significance of this

conspecific. Procedures employed to study social recognitioninclude the study of behaviours towards novel vs familiar socialstimuli (conspecifics) (Brown et al., 1987; Sundberg et al., 1982;Yang and Crawley, 2009). As originally summarised in Fergusonet al., 2002, there are several complementary procedures forachieving this goal. One commonly used is a simple “habitua-tion/dishabituation” paradigm in which the (usually adult) rodentis repeatedly exposed to a juvenile animal followed by its sub-stitution with an unfamiliar animal (novel social stimulus) andexploration time compared. Exposure to the same social stimulusshould result in progressively lower amounts of investigation bythe test animal, with increased investigation towards the novelsocial stimulus taken as evidence of discrimination. By contrastto the “habituation/dishabituation” paradigm, in the more widelyused “social recognition” procedure, the (usually adult) rodent
encounters a juvenile just twice consecutively for 5 min and thetime of active exploration is measured and compared. Betweenthe tests, delay can be increased to induce forgetting (usuallyseveral hours vs a few minutes), or a drug administered to disrupt

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etention. In a control experiment for interfering factors like motorctivity, the familiar rodent is replaced by an unfamiliar animalMillan et al., 2007; Perio et al., 1989; Mathiasen and DiCamillo,010). Finally, in the social novelty discrimination procedureBoulay et al., 2008; Engelmann et al., 1995; Meffre et al., 2012;erranova et al., 1996, 2005), a juvenile is presented to an animalor 30 min then, after a variable delay, it is re-represented togetherith another, unfamiliar novel juvenile (for 5 min), and theyust be distinguished. This procedure requires a particularly

igh degree of attention accentuating the point that, for all suchrocedures, other dimensions of cognition inevitably come intolay, and cerebral structures other than those classically mediatingocial cognition are likely to be relevant (See above).

For both social preference and social recognition tasks, the targetocial animal may be either an adult or a juvenile or an ovariec-omised female; these social objects provoke interest (but notexual behaviour) in the test animal, are not aggressive, and areasily distinguished from the subject animal. The stimuli may beestrained or unrestrained (usually in a wire cage). For instance,t may be more appropriate to test for a social preference using

restrained stimulus animal, thereby offering the test animalhe choice of not interacting socially at all and minimising activenfluence by the social object. Further, this prevents exposure tootentially aggressive behaviour and reduces the attentional bur-en on the animal under study. However, restraint is a stress whichay alter the pattern of signals (e.g. olfactory, USV) emitted by the

arget animal (van der Kooij and Sandi, 2012). By contrast, testsnvolving animals which are able to engage in physical contact with

non-restrained conspecific permit reciprocal interaction, moreigorously explore normative social behaviour, and more closelyesemble real-world enactment of social cognition (Crawley, 2000;aidanovich-Beilin et al., 2011; Yang et al., 2011).

Potential readouts for such tasks are considered in moreetail below and include behaviours such as: approach or avoid-nce; species-appropriate social behaviours such as subordinateesponses vs a dominant animal; active exploration, sniffing androoming, etc. In addition, endocrine and autonomic state can beonitored, for example non-invasively by telemetry (Grippo and

ohnson, 2009). An additional readout of increasing interest isocalisation, particularly the emission of USVs in rodents (Ey et al.,012; Scattoni et al., 2009, 2011; Shepard and Liu, 2011).

Finally, certain related tasks can also be used to measure aggres-ion, such as resident-intruder paradigms. Perhaps by convention,ntagonistic interactions rarely fall under the rubric of “socialognition”, the study of which is usually oriented towards posi-ive social relationships. It is nevertheless worth mentioning thatxytocin can reduce aggressive behaviour – which is known to com-licate the treatment of psychotic patients (Calcagnoli et al., 2013;illan et al., 2012).

.2. CNTRICS selection: measures of sociability, social recognitionnd preference using a three chamber test in rodents

The task selected by CNTRICS is a hybrid that allowseasurement of sociability, social preference and social recog-

ition/memory. The paradigm is based on the 3-chamberedociability/social preference task for rodents (Fig. 3) (Crawley,000; Kaidanovich-Beilin et al., 2011; Moy et al., 2007; Roulletnd Crawley, 2011; Yang et al., 2011). Versions of this paradigman be used to measure sociability as described above, but alsoocial recognition and memory, and social novelty preference.ig. 3 illustrates use of this paradigm to isolate these constructs
hat, in turn, are hypothesised to underlie social motivation andppropriate social behaviour. To measure social recognition andemory, a number of variants were proposed by CNTRICS partic-
pants. In one variant, the test animal first receives a cohabitation


period with the animal that is to be the familiar stimulus. Thiscohabitation period will vary depending on whether any intendedtreatment is expected to facilitate formation of a preference, orto inhibit formation of the preference. One can also use a variantof the habituation/dishabituation paradigm in which the rodentis exposed once or repeatedly to the same two conspecifics (onein each chamber) and recognition is tested by replacing one ofthe familiar rodents with a novel one. Differences in behaviourtowards the pre-exposed vs novel conspecific are interpreted asevidence for social recognition and memory. Thus the paradigmcan also be modified to include a memory load (a variable delay).Further, using appropriate controls (including comparison of eachsocial object with a familiar non-social object), the mechanisms (i.e.related to aversion or attraction) underlying apparent social prefer-ence can be determined. As noted above, social recognition is alsomeasured by a number of ‘one chamber’ tasks that either allowinteraction or place a familiar or novel animal ‘under a cup’. Theproposed adaptation of the three-chamber paradigm is designedto capture this same construct, but using the same apparatus thatallows direct comparison with data from sociability and socialpreference tests.

5.3. The neuropharmacology of social recognition and socialpreference in rodents

The pharmacology and genetics of social preference assayedwith one or multi-chamber choice paradigms informed theCNTRICS task design. Social preference (and other socialbehaviours) are modulated by oxytocin and disrupted by geneticdeletion of this peptide (Crawley et al., 2007; Choleris et al., 2009;Young et al., 2010; Meyer-Lindenberg et al., 2011; Teng et al., 2013).Further, several studies have examined how sociability and socialpreference may be affected in genetic and developmental modelsof schizophrenia. Sociability and/or social preference is disruptedby glutamatergic transmission/NMDA receptor hypofunction, inmouse models with mutations of the risk genes Neuregulin-1 andDisrupted in Schizophrenia-1, and in offspring of rodent dams withinduced immune activation (Duncan et al., 2004; Li et al., 2007;Lipina et al., 2013; O’Tuathaigh et al., 2007; Takao et al., 2013;Wilson and Koenig, 2013). However, not all results have beenpositive. In addition, outcome in this procedure has not necessarilybetween interpreted as related to social cognition, but moregenerally to social behaviour and also to negative symptoms, witha diminution of social motivation and social preference consideredindicative of social withdrawal.

Studies using the “habituation/dishabituation” have beeninstrumental in revealing the important role of oxytocin (andvasopressin) in promoting social recognition, based on studies ofits administration or genetic deletion (Bielsky and Young, 2004;Bielsky et al., 2005; Ferguson et al., 2002; Winslow and Insel, 2002).The limitations of this test in its ability to isolate cognitive mecha-nisms become a critical issue in these studies. While the influence ofoxytocin upon performance in procedures of social recognition andsocial discrimination can mainly be attributed to its “social” roleper se (Bielsky and Young, 2004; Choleris et al., 2009; Goodson andThompson, 2010; Popik et al., 1992), it is not clear that the rich phar-macology of positive observations with other classes of agent canbe assigned exclusively to a genuine and direct facilitation of socialprocesses compared to an impact (perhaps synergistic) upon othercognitive – or affective – functions. For example, enhancement anddisruption of social recognition by dopamine D3 and D2 receptorantagonists, respectively, reflects their effects in the frontal cor-
tex (Loiseau and Millan, 2009; Millan et al., 2007; Watson et al.,2012), likewise the site of action for 5-HT6 antagonists (Schreiberet al., 2007; Loiseau et al., 2008): both classes of agent likely actatleast partly by strengthening top-down control of attention. On

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he other hand, cannabinoid antagonists may act by interactingith reward mechanisms (Terranova et al., 1996; de Bruin et al.,

010). It remains to be determined how and where other types ofrug exert their actions, for example, those that enhance activityt NMDA receptors or block 5-HT1A receptors (Boulay et al., 2008;illan et al., 2004).Despite these reservations, it might be argued that, irrespective

f the mechanisms involved, any class of substance that directlyr indirectly favours social (re)cognition is of interest as a poten-ial strategy for palliating its perturbation in schizophrenia. In thisegard, it is of note that Brattleboro rats lacking vasopressin per-orm poorly in social recognition procedures (Bielsky et al., 2005;arich et al., 2007; Feifel et al., 2009) and that social recogni-

ion/novelty discrimination is consistently disrupted across a broadange of models for schizophrenia: (1) developmental, such aseonatal exposure to PCP and neonatal immune activation (Boulayt al., 2008; Ibi et al., 2010; Meffre et al., 2012); (2) genetic, suchs disruption of DISC1 or microtubules (Bégou et al., 2008; Ibit al., 2010); and (3) pharmacological, such as sub-chronic inter-erence with NMDA receptor-mediated transmission by ketamineGao et al., 2009; Millan et al., 2007). Further, in certain mod-ls, it has been shown that deficits can be either: (1) preventedy adolescent, pre-symptomatic treatment with metabotropic glu-amate receptor 5 positive allosteric modulators (Clifton et al.,013) or (2) restored by administration of, for example, 5-HT6ntagonists (Meffre et al., 2012). It is unclear how glutamatergicodulators exert their prophylactic effects, but 5-HT6 antagonists

ormalise a hyperactivation of the cellular signal, mammalian tar-et of rapamycin, that leads to disruption of social recognitionollowing neonatal exposure to phencyclidine (Meffre et al., 2012).t would be valuable to determine if oxytocin can normalise deficitsn social recognition in animal models of the genetics and neurobi-logy of schizophrenia.

.4. Insights from comparative studies: partner preference inonogamous prairie voles

Prairie voles (Microtus ochrogaster) were originally used toevelop a partner-preference test for the study of pair-bonding,ith the length of time needed to form a preference well-arameterised and different for males vs females (DeVries andarter, 1999). It is worth noting that these parameters can varyetween different prairie vole colonies (Bales, K. and Carter, C.S.,npublished data). This partner-preference procedure resemblesand anticipated) the mouse three-chamber test, and the stimu-us animals are restrained by collars yet accessible to touch by theest subject (Williams et al., 1992). Tests in prairie voles can also

onitor motivation to participate in any social behaviour vs spend-ng time in the empty cage or exploring non-social object, as wells the relative predilection for a familiar social stimulus (“part-er”) vs a novel social stimulus (“stranger”). The neurobiology andharmacology of partner bonding in monogamous prairie voles vsolygamous meadow voles, including the important role of oxy-ocin and vasopressin in cementing relationships (though see Balest al., 2013), has been extensively reviewed elsewhere (Bielsky andoung, 2004; Choleris et al., 2009; Young et al., 2010). This model isf clear heuristic value and has generated important insights intoocial recognition and affiliation, partner-bonding and cooperativepbringing of young, yet it does not per se embrace study of rela-ionships with unfamiliar conspecifics (towards whom behaviour

ay be antagonistic). Further, it is still uncertain whether oxytocin
romotes familiar partner preference in humans in a manner sim-
lar to prairie voles (Liu et al., 2013). How social cognition mighte disrupted by putative models of schizophrenia in prairie volesemains to be determined.

havioral Reviews 37 (2013) 2166–2180 2173

5.5. Limitations and prospects for future development

The above paragraphs clearly exemplify the utility of rodentmodels to probe mechanisms involved in at least certain dimen-sions of social cognition, to characterise its disruption in animalmodels of disease processes relevant to schizophrenia, and to iden-tify mechanisms for its restoration.

These procedures can realistically be engaged early in drugdiscovery programmes as components of broad-based cognitivescreens, with comparison of performance in social cognitionvs other neurocognitive domains of particular interest. Further,these tasks have strong construct validity, though most of theinformation on neural substrates comes from the prairie voleand/or oxytocin–vasopressin literature in which the underpin-nings of social recognition, social preference and partner preferencehave been carefully delineated (Carter et al., 1995; Goodson andThompson, 2010; Lim et al., 2004; McGraw and Young, 2009; Wil-son et al., 1992; Young et al., 2010).

Oxytocin remains an important validator of behaviour in theseparadigms, not least since it can be given intra-nasally to humansubjects, has shown beneficial actions in schizophrenia and itsmechanisms of action are well-defined (Davis et al., 2013; Feifelet al., 2010; Fischer-Shofty et al., 2013b; Goldman et al., 2011;Pedersen et al., 2011). On the other hand, by analogy to dopamineD3 antagonists, there remains a need for elucidation of mechanismsinvolved in the actions of other drug classes active in models ofsocial cognition in order to discern the precise significance of socialprocesses per se.

It is also important to incorporate controls for a potential impactof agents upon other neurocognitive domains, and upon motor,olfactory, affective and sexual function, etc. since such effects mightimpact performance – though comparable controls are requisitefor studies of other cognitive domains as well. Amongst paramet-ric considerations in further developing these tasks, session lengthneeds to be carefully validated for optimisation (Williams et al.,1992) and possible automation of some aspects justifies consid-eration (Ahern et al., 2009; Moy et al., 2007; Yang et al., 2011).Recent data suggest that the persistence (long-term effects) ofdrug actions upon social cognition should be carefully established,especially when administered developmentally (Bales et al., 2013).More encouragingly, since at least some drug classes may be ableto prevent the onset of disrupted social cognition when appliedduring adolescence (Clifton et al., 2013), greater attention to suchadministration schemes is warranted. This is great relevance to cur-rent interest in treating high risk patients – with oxytocin and itsanalogues – to improve social cognition and hence prevent con-version to psychosis (Fusar-Poli et al., 2009). While readouts havebeen almost exclusively behavioural to date, incorporation of addi-tional parameters like USV emissions (Wöhr and Schwarting, 2013)would undoubtedly lead to novel insights.

Reverse translation of neuroimaging from humans to rodentshas still not met great success (Kerr and Nimmerjahn, 2012), soit cannot yet be coupled to measures of behavioural performanceas in humans. Thus, further thought should be considered as tohow to bridge studies of social recognition in rodents, both nor-mal and models of schizophrenia, to comparable translational workon (affective and non-affective) oxytocin-sensitive facial recogni-tion and processing in human probands and schizophrenic patients(Addington et al., 2013; Darke et al., 2013; Kalkstein et al., 2010;Shahrestani et al., 2013).

5.6. Parallel studies in non-human primates of social
recognition/preference
In addition to rodents, variations on the partner-preference testcan be conducted in NHPs (Jarcho et al., 2011; Smith et al., 2010).

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esting depends crucially on the predisposition of the species andndividual to perform under novel conditions (vs testing in theome cage). This is important since NHPs can display different

evels of neophobia (Hennessy et al., 1995). One task consists ofequential, randomised presentations of a partner, stranger, or amall empty cage within the home cage of the subject and, interest-ngly, high levels of intranasal vasopressin increased frequency ofontact with the partner cage (Jarcho et al., 2011). Mirroring prairieoles, oxytocin mediates partner-bonding in several other socialpecies (Klatt and Goodson, 2013), including NHPs. Thus, Smitht al. (2010) undertook a study of the facilitatory influence of oxy-ocin upon social behaviour, partner-preference and food-sharingsing a procedure similar to that used in prairie voles (vide supra).urrently, data from these procedures have only been published

or marmosets, and the choice of the partner over the stranger tooklace over a longer time period than with prairie voles (Smith et al.,010). It is unclear if these differences are due to more a generalodent–primate mismatch, or whether it may reflect a species dif-erences with marmosets which are not necessarily considered toorm selective social bonds (Fuentes, 1999) and possess a differentorm of the peptide, oxytocin (Lee et al., 2011). Nonetheless, thisype of work will be interesting to pursue in parallel to other socialognition studies in NHPs outlined below.

. Emotional and intention recognition: studies inon-human primates

.1. Eye-tracking and studies of gaze

The CNTRICS workgroup on social cognition also consideredevelopment of social cognitive assays in NHPs to be a high priority,iven that there may be social cognitive processes relatively specifico primates (weakly homologous in rodents). The CNTRICS workingroup selected measurement of gaze and eye-tracking patterns inHPs during visual scanning of social scenes. The task is based on

he rationale that NHPs have evolved for visual encoding of socialcenes, including facial expressions of other primates (e.g. Machadot al., 2011). Further, recent technological advances have reducedhe level of invasiveness needed to undertake such studies (Fairhallt al., 2006; Machado and Nelson, 2011), and eye-tracking tech-ologies are now compatible with Magnetic Resonance technologyOeltermann et al., 2007).

Usually, chair-trained NHPs are fitted with either a head-poststainless steel or titanium) or custom thermoplastic helmet inrder to limit movement of the head. Animals are habituated to theraining chair and screen, then trained to fixate on random imagesn random locations with a positive reward (such as juice admin-stered through a tube connected by a mouthpiece). In a secondhase of training, the animal is rewarded for fixating on a targetox within a photograph or movie. An infrared eye-tracking cameraecords directly to software, which must be calibrated at the begin-ing of the testing session (Machado and Nelson, 2011). During theest of socio-affective recognition, visual social stimuli include theollowing: photos or video images of primate faces with a range ofmotional expressions; familiar vs unfamiliar individuals (includ-ng comparison of animals which are dominant or subordinate tohe test subject); and videos of social interactions. Areas of inter-st on the images designated by the researcher might include theyes, mouth and other facial areas corresponding to major zones formitting social cues (Machado and Nelson, 2011). Total fixation,requency of fixations, and average gaze-dwell duration on areas
f interest, as well as reaction times of saccades to or away frommotional vs non-emotional stimuli, provide good indices of socialesponsiveness to facial signals. Scanpath patterns and speed cane calculated to assess gaze following (Shepherd et al., 2010); these

measures can be correlated with simultaneous autonomic and/orendocrine readouts.

Importantly, it is now possible for gaze-following in NHPsto be used in more naturalistic and less constraining circum-stances (Shepherd and Platt, 2006, 2008). Harnesses holding dualinfrared camera gaze tracking systems were carried by lemurs dur-ing normal social interactions (Shepherd and Platt, 2008). Furtherminiaturisation of this type of equipment will continue to makeit more feasible for use in various species (e.g. peahens, Yorzinskiet al., 2013) and in more naturalistic situations.

Supporting the translatability of these approaches, the neurobi-ology of visual scans has been well-studied. There is, for example,a role for neurons of the middle temporal visual area (“MT or V5”)and the medial superior temporal area in the control of visual scan-path (Levy et al., 2010; Newsome et al., 1985, 1988; Newsomeand Pare, 1988; Shadlen et al., 1996). Further, as mentioned above(Section 2.2), neural pathways underpinning gaze-analysis arewell-characterised in NHPs and show strong homology to theirhuman counterparts. Reinforcing its translational credentials, eye-tracking oculomotor paradigms are commonly used in humanresearch, and have, for example, been employed to examine theactions of antipsychotic agents and the performance of patientswith schizophrenia (Hill et al., 2008; Reilly et al., 2008). In addition,mirror neurones are thought to be implicated in shared intention-ality – and theory of mind/empathy – so studies of their activitycould be undertaken in parallel with observations of gaze sharingto link primate and human studies of social cognition (Cattaneoand Rizzolatti, 2009). Further, paralleling interest in top-downfrontocortical control of social recognition in rodents (vide supra),similar frontocortical processes for modulation of eye-momentscan be investigated in NHPs, making this a potential basis for cross-species comparisons (Millan et al., 2012; Noudoost and Moore,2011; Sprenger et al., 2013).

Interestingly, visual scan-paths in rhesus monkeys have beenassociated with genes of psychiatric interest as well as relevantbehaviours like impulsivity (Gibboni et al., 2009; Watson et al.,2009). In addition, NHPs such as rhesus monkeys display consid-erable variation in sociality, suggesting that this could serve as abasis for a naturalistic exploration of social deficits across geneti-cally diverse populations, mirroring the situation in human subjects(Watson and Platt, 2012).

Several pharmacological manipulations have been shown toaffect emotion and intention recognition as measured by eye-tracking in rhesus monkeys. It is, thus, sensitive to dopaminergicmanipulations (Ando et al., 1986), as well as to psychoactivedrugs such as diazepam (Ando et al., 1983; Holzman et al., 1975).Most significantly, the effects of oxytocin on eye gaze have beendemonstrated in NHPs (Ebitz et al., 2013). Rhesus monkeys givenintranasal OT showed increased attention to faces and eyes, mim-icking findings in humans treated with OT (Guastella et al., 2008).Further, oxytocin induces reduced attention to negative faces (Parret al., 2013), a finding likewise documented in human subjects(Domes et al., 2013).

6.2. Limitations and prospects for future development

The above observations underpin the potential utility ofeye-tracking/gaze paradigms in NHPs for focused study of thisdimension of social cognition which is known to be disrupted inschizophrenia, and specifically for the characterisation of medica-tion for its potential amelioration. Further, the translatability of thisNHP model is particularly appealing, oculomotor procedures tap
into similar neural substrates in NHPs as in humans, and there isconvergence in known cerebral substrates underpinning social cog-nition in NHPs and humans, whereas this is less certain for rodents(Adolphs, 2009; Van Overwalle and Baetens, 2009; Millan et al.,

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012). Despite these positive aspects, there currently remain sev-ral limitations concerning the use of this procedure which may beighlighted below – together with some proposals for progress.

First, the paradigm is currently appropriate only for human andHP research and there is no comparable eye-tracking procedure

or a comparison to rodents in which most studies and first-linerug screening are performed. Second, such a complex NHP pro-edure could only be adopted late in a screening programme at

phase of final clinical candidate selection, and studies wouldainly be done under “normal conditions” (increase in baseline

erformance) or with normalisation of the disrupted performancelicited by parametric (delay) or pharmacological (likely scopol-mine) manipulations. Third, NHP models are not as advanced asodents as regards genetic interrogation of the substrates of flawedocial cognition. However, the recent sequencing of the genomes ofhe more common biomedical models (such as rhesus monkeys and

armosets), the closeness of relatedness to humans, and advancesn gene-neutralisation techniques like siRNA silencing may even-ually overcome these hurdles. Fourth, developmental models ofchizophrenia are not currently established in NHPs. One possibil-ty, mirroring rodent work on neonatal lesions of the amygdala orippocampus, would be to extend studies in NHPs of the influencef early life lesions of these structures upon social behaviour andognition (Bachevalier and Málková, 2006; Bauman et al., 2006).urther, mirroring studies in rodents, irradiation disruption of pre-atal neurogenesis (e.g. Selemon and Friedman, 2013) and maternaluto-immune challenge during gestation in NHPs (Martin et al.,008) lead to enduring cognitive dysfunction, suggesting that thisight provide a relevant model for studying gaze and other param-

ters of social cognition in a NHP. Other possibilities for applyingye-tracking/gaze analysis approaches in social cognition in poten-ial NHP models of schizophrenia-related pathophysiology includese of sub-chronic exposure to ketamine or psychostimulants,lone or in association with transient social isolation (Condy et al.,005; Knobbout et al., 1996; Sams-Dodd and Newman, 1997).

Thus, there remain some important constraints, but the aboveomments point to future possibilities for expanding the trans-ational use of eye-gaze/oculomotor studies in NHPs in theharacterisation of novel agents designed to restore social cognitionn schizophrenic patients in particularly in unrestrained subjects.

. Other potential models for studying social cognition

Though not originally nominated, several other procedures maye useful for exploring social cognition in rodents, characterising its

mpairment in models for schizophrenia, and identifying therapeu-ically useful agents. Certain of these, though still at a preliminaryhase of characterisation, address the more challenging issue of

nterrogating the cognitive dimensions of social cognition (relatedo theory of mind and social inference) in rodents.

Shared goals (intentionality) is an important feature of humanocial cognition requiring understanding of the mind-set andesires of a conspecific (Call and Tomasello, 2008; Tomasello et al.,005). It is hard to model experimentally but, mirroring work in ele-hants – which display impressive evidence for prominent socialognition (including individual recognition) (Hart et al., 2008;lotnik et al., 2011) – in a rat model of cooperative rope-pullingo obtain food, subjects helped a conspecific to succeed. Their pro-livity to aid was reinforced when they had previously been helpedhemselves. Interestingly, suggesting “generalised reciprocity”,hey even cooperated without direct knowledge of partner
dentity (Rutte and Taborsky, 2007; Schneeberger et al., 2012).hese observations are especially intriguing since cooperativeope-pulling requires a clear idea of the mind-set and intentionsf the partner.

Transmission of social food preference is a further possible topicfor exploration, not least since it appears to be enhanced by oxy-tocin, and the same holds for social facilitation of learning: thatis, learning enhanced by observation/imitation of social partners(Carlier and Jamon, 2006; Choleris et al., 2009; Wöhr and Scattoni,2013; van der Kooij and Sandi, 2012).

Social learning has been related to the notion of empathy, acornerstone of theory of mind in humans and a theme attractingincreasing interest as regards other species (Knapska et al., 2009;Millan et al., 2012; Panksepp and Lahvis, 2011; Wöhr and Scattoni,2013). Empathy is generally subdivided into emotional and cogni-tive components, the former encompassing the ability to recognise,feel and share another’s emotional state, and the latter defined bythe ability to internally represent another’s situation and experi-ences. The latter dimension is considered more demanding andits presence outside humans is still disputed (Vasconcelos et al.,2012). Nonetheless, since empathy is compromised in schizophre-nia (Melloni et al., 2013), it is of note that the response of mice tonociceptive stimuli is modified by exposure of a cage-mate to pain(Langford et al., 2006). In addition, rats display signs of empathy inbehaving pro-socially to release a cage-mate trapped in a restrainer(Ben-Ami Bartal et al., 2011; Panksepp and Lahvis, 2011). Empa-thy has also been specifically linked to oxytocin (Gonzalez-Liencreset al., 2013).

One criterion for recognising an at least rudimentary theoryof mind is self-recognition and, rather than visual cues (used inhumans and other vertebrates, see below), there may be greaterchance of success in rodents exploiting auditory cues like individualpatterns of USV (Wöhr and Schwarting, 2013). Further, contagiousyawning is thought to tap into a process that might be the evolu-tionary precursor to empathy; and it is promoted by oxytocin in ratsand other species (Haker et al., 2013; Miller et al., 2012; Palagi et al.,2009; Romero et al., 2013; Sanna et al., 2012). Thus, this representsan additional intriguing potential read-out for investigation of thisfacet of social cognition (Panksepp and Lahvis, 2011). To concludewith a remark linking rodents to NHPs, the relatively unexploredterritory of tactile behaviours may offer fertile territory for com-paring social cognition in NHPs to rats. As an example, mutualgrooming is a conserved across primates and rodents facilitatedby actions of oxytocin (Dunbar, 2010).

8. Concluding comments

In the sections above, we have summarised where progress isbeing and can still be made in the characterisation of animal modelsof social cognition. The two paradigms selected by CNTRICS partici-pants for this purpose, social recognition/preference in rodents andvisual tracking of social scenes in NHPs, are complementary proce-dures concerned with distinctive aspects of social cognition, eachoffering distinctive advantages and challenges for use in drug test-ing settings. We note that the selection of these paradigms is notwith the object to deter use of other paradigms designed to iso-late and measure social cognition and its neural substrates. Rather,we recommend that development of social cognition measurementparadigms continue, noting that establishment of construct valid-ity will be paramount to the translatability of these paradigms(see Introduction of this Special Issue). We conclude this articlewith a brief mention of several core issues that warrant particularconsideration in the future application of these and other animalprocedures outlined above for monitoring social cognition.

First, there is a need for more thorough characterisationof potential changes in social cognition in animal models for
schizophrenia, which should also be used to evaluate the actionsof oxytocin as compared to conventional antipsychotic agents(likely inactive) and potentially new classes of medication. Atten-tion should be afforded to the preventive influence of drugs during

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he pre-symptomatic phase prior to appearance of deficits in socialognition and other symptoms. Comparing the actions of potentialestorative agents for social cognition to their effects in procedureseasuring other cognitive domains is also of importance. In addi-

ion, it would be instructive to analyse in such models how oxytocinelease is modified in cerebral structures controlling social cogni-ion, both in the model of schizophrenia per se and also in responseo potentially useful classes of pro-social agent.

Second, using animal models it will be necessary to more care-ully clarify the boundaries, nature and modulation of the impairedocial cognition of schizophrenia as compared to negative symp-oms, in particular as regards readouts like social withdrawal, andhe use of procedures for measuring sociability and social pref-rence. It will also be important to examine whether agents thatmprove social cognition can prevent or reverse its disruptionn animal models that recapitulate the genetics or neuropatho-hysiology of schizophrenia. Systematic comparison of animalodels of autism vs those for schizophrenia using the social prefer-

nce/recognition paradigm might also be useful given evidence ofommon genetic and environmental risk factors across these disor-ers (Eack et al., 2013; Millan et al., 2012; Stone and Iguchi, 2011).

Third, to reiterate a point made previously, it would be infor-ative to expand the repertoire of behaviours monitored in social

ognition procedures to other parameters like: liberation of oxy-ocin, imaging and electroencephalographic measures of neuralctivity, stress-responsive hormones and neurotransmitters and, inarticular, spectrographic analysis of USVs. This would help clar-

fy underlying neural substrates, reveal modulatory mechanismsor targeting by novel drug classes and provide, at least for certainarameters, translatable information to guide subsequent studies

n humans. It is, then, important to optimise the linkage betweenxperimental models of social cognition and related (CNTRICS-ecommended) procedures undertaken in human subjects (Cartert al., 2009; Pinkham et al., 2013). This is crucial for enhancing therobability of finding effective treatment – both pharmacologicalnd cognitive/behavioural-based – for impaired social cognition inchizophrenia.

Much has already been learned about the neural foundationsnd core features of social cognition by using currently-used exper-mental procedures, which are generally responsive both to animal

odels of schizophrenia (reduced performance) and to the pro-ocial neuropeptide, oxytocin (enhanced). It should be equallypparent that as much – if not more – still remains to be learned,nd that considerable progress could be made in the exploita-ion and development of social recognition/preference paradigmsn rodents, eye-movement/gaze-following protocols in NHPs andther procedures outlined above. Further, with the exception ofxytocin (and possibly vasopressin), the core validator for any pro-edure designed to interrogate social cognition, we have madeittle progress in identifying mechanisms that directly taps into theore processes of social cognition disrupted in schizophrenia andhat, accordingly, could be effective in the correction of deficits inatients. This remains an important challenge for the future. Hope-ully, the CNTRICS-driven reflections herein will prove helpful in

oving towards and ultimately realising this valuable goal.

cknowledgements

We would like to thank the participants of the Social Cognitionreakout group at the Washington DC CNTRICS meeting for stim-lating discussions: Sue Carter, Greg Strauss, Tanya Wallace, Willancaster, Jim Koenig, Thomas Steckler, Sarah Morris, Akira Sawa,
an Hutcheson, Ann Wagner, Mark Geyer, Paul Patterson and Steveiegel. We thank Holly Moore for input on task design, composi-ion of figures, and editing the manuscript. We thank Marianneoubeyran for dynamic secretarial assistance.

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