REVIEW

published: 26 November 2015

doi: 10.3389/fpsyg.2015.01805

Prefrontal Cortex and Social

Cognition in Mouse and Man
Lucy K. Bicks1,2,3,4,5* , Hiroyuki Koike 1,2,3,4,5 , Schahram Akbarian1,2,5 and
Hirofumi Morishita 1,2,3,4,5*
1
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 2 Department of Neuroscience,
Icahn School of Medicine at Mount Sinai, New York, NY, USA, 3 Department of Ophthalmology, Icahn School of Medicine at
Mount Sinai, New York, NY, USA, 4 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount
Sinai, New York, NY, USA, 5 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Social cognition is a complex process that requires the integration of a wide variety
of behaviors, including salience, reward-seeking, motivation, knowledge of self and
others, and flexibly adjusting behavior in social groups. Not surprisingly, social cognition
represents a sensitive domain commonly disrupted in the pathology of a variety of
psychiatric disorders including Autism Spectrum Disorder (ASD) and Schizophrenia
(SCZ). Here, we discuss convergent research from animal models to human disease that
implicates the prefrontal cortex (PFC) as a key regulator in social cognition, suggesting
that disruptions in prefrontal microcircuitry play an essential role in the pathophysiology
of psychiatric disorders with shared social deficits. We take a translational perspective
of social cognition, and review three key behaviors that are essential to normal social
Edited by: processing in rodents and humans, including social motivation, social recognition, and
Anita Must, dominance hierarchy. A shared prefrontal circuitry may underlie these behaviors. Social
University of Szeged, Hungary
cognition deficits in animal models of neurodevelopmental disorders like ASD and SCZ
Reviewed by:
have been linked to an altered balance of excitation and inhibition (E/I ratio) within the
Sven Kroener,
The University of Texas at Dallas, USA cortex generally, and PFC specifically. A clear picture of the mechanisms by which
Ofer Yizhar, altered E/I ratio in the PFC might lead to disruptions of social cognition across a
Weizmann Institute of Science, Israel
variety of behaviors is not well understood. Future studies should explore how disrupted
*Correspondence:
Lucy K. Bicks developmental trajectory of prefrontal microcircuitry could lead to altered E/I balance
lucy.bicks@icahn.mssm.edu; and subsequent deficits in the social domain.
Hirofumi Morishita
hirofumi.morishita@mssm.edu Keywords: social cognition, social behavior, prefrontal cortex, autism, schizophrenia

Specialty section:
This article was submitted to INTRODUCTION
Cognitive Science,
a section of the journal Social behavior deficits are a fundamental dimension of many psychiatric disorders including
Frontiers in Psychology
the neuordevelopmental disorders ASD and SCZ, yet much remains to be learned about the
Received: 20 August 2015 underlying pathophysiology of these deficits. In 2010, the NIMH put forward a Research
Accepted: 09 November 2015 Domain Criteria1 initiative, which establishes a framework aimed at encouraging researchers to
Published: 26 November 2015
investigate common behavioral domains and neurobiological mechanisms that underlie multiple
Citation: disorders. This collaborative effort identified five major domains that are disrupted across
Bicks LK, Koike H, Akbarian S psychiatric disorders including cognitive systems, negative valence systems, positive valence
and Morishita H (2015) Prefrontal
systems, arousal/regulatory systems, and last but not least, social processing1 . While defects in
Cortex and Social Cognition in Mouse
and Man. Front. Psychol. 6:1805.
1
doi: 10.3389/fpsyg.2015.01805 http://www.nimh.nih.gov/research-priorities/rdoc/social-processes-workshop-proceedings.shtml

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Bicks et al. Prefrontal Cortex and Social Cognition

social processing underlie multiple disorders, it is still unclear if contacts (Chevallier et al., 2012). Behaviors such as social
a common neurobiology mediates a ‘social brain.’ The prefrontal affiliation, orienting, and approach are evolutionarily conserved
cortex (PFC) may be a candidate regulator in mediating social behaviors that are present in many species, including some
cognition (see Table 1) in both humans and rodents. In humans, invertebrates (Insel and Young, 2000; Toth and Robinson, 2007;
social cognition develops throughout childhood and adolescence, Rosa Salva et al., 2011; Sheehan and Tibbetts, 2011). Social
and the appropriate maturation of the circuitry within PFC may motivation also emerges early in development (Di Giorgio
play a key role in this trajectory. However, more detailed insights et al., 2012; Jakobsen et al., 2015). For example, newborns
into the underlying molecular and cellular mechanisms can only prefer to look at faces with open eyes, showing a natural
be acquired by the study of small laboratory animals. Here we propensity for social interaction from birth (Farroni et al.,
discuss the role of the PFC in mediating a broad range of social 2006). Social motivation is disrupted in many psychiatric
behaviors in rodents, with the hope that this framework might disorders, including ASD and SCZ (Dawson et al., 1998;
provide valuable insights for evaluating animal models of human Buchanan, 2007; Chevallier et al., 2012; Blanchard et al.,
psychiatric disease. 2015; Dubey et al., 2015; Fervaha et al., 2015). The social
motivation theory of autism suggests lack of social interest
in childhood may contribute to additional social cognitive
SOCIAL COGNITION IN HUMAN: deficits that emerge later in development (Chevallier et al.,
2012), suggesting the possibility that social motivation is a
RELEVANCE TO PSYCHIATRIC developmental and evolutionary building block required for
DISORDERS other social behaviors.
Knowledge of self and others is an essential element of
Social cognition can be broadly defined as the set of mental
human social cognition. This level includes behaviors like facial
operations used to identify and interpret social signals, and
recognition, empathy, evaluating emotion and motivation of
the use of those signals to guide the flexible performance of
others [‘mentalizing’ also known as theory of mind (ToM)],
appropriate social behaviors given a changing context (Millan
knowledge about the affective state and personality traits of
and Bales, 2013). In this review, we focus on three major
the self and others, implicit and explicit biases, and moral
facets of social cognition: social motivation, knowledge of self
judgments. Behaviors in this category rely on a human ability to
and other, and group dynamics, because these aspects of social
use knowledge about ones own mental state to make inferences
behavior have shown relevance to psychiatric disorders, not only
about the mental states of others (Mitchell, 2009). Many social
in humans but also in translational animal models (Figure 1). It
behaviors require both motivation and knowledge of self and
should be noted that these three aspects of social cognition are
others, like making charitable contributions and engaging in
not necessarily mutually exclusive (Ochsner, 2008; Green et al.,
cooperation. Other behaviors, like perspective taking and moral
2015). We feel focusing on these three behaviors allows for an
judgments are somewhat independent from social motivation.
interesting comparison between social cognition in humans and
Behaviors related to knowledge of self and others are disrupted
animal models.
in a variety of psychiatric disorders including ASD and SCZ
Social motivation, or the desire to seek social contact, is
(Perner et al., 1989; Frith, 1994; Corcoran, 2001; Senju, 2012).
an elemental social behavior that includes social orienting and
For example, the majority of children with ASD do not pass the
approach, social reward and cooperation, and maintaining social
false-belief test, a common ToM test that examines the ability of
subjects to recognize that others have differing sets of knowledge
about a scenario depending on what they see (Baron-Cohen et al.,
TABLE 1 | Glossary. 1985).
Social cognition – The set of mental operations used to identify and interpret
Group living is common in mammalian societies, and the
social signals and the use of those signals to guide behavior. We use this term in a evolutionary pressure to adapt to living in groups has been
broad sense, to incorporate social behaviors including social motivation, and group proposed as a main driver of the evolution of the primate PFC
related behaviors including dominance and hierarchy. (Dunbar and Shultz, 2007; Adolphs, 2009; Dunbar, 2009). Studies
Social motivation – An intervening variable that describes the desire of an examining group living are concerned with the interaction
organism to seek out social contact and interaction with conspecifics. Experimental
between the individual and the social group as well as the
procedures examining social motivation often use dependent variables of social
approach, social investigation, and social contact, all of which are aspects of a emergent properties of the group as a whole. Dominance
more general ‘social motivation.’ hierarchies are particularly well established in many different
Social memory – The ability to recognize other individuals that have been species, and this complex group behavior involves many other
previously encountered. important social behaviors, like knowledge of the position of
Social hierarchy – The establishment of dominant and subordinate relationships the self relative to others in the group, communication, and
between animals living in groups. These relationships often relate to aggressive social decision making. Additionally, hierarchies have important
behavior and access to resources including food and mates. However,
establishment of hierarchies also includes species-specific behaviors not related to
consequences for the health and well being of individuals within
aggression. the group, making them an interesting behavior for further study.
Sociability – A tendency or trait describing the degree of social motivation. For example, in non-human primates, subordinate status within
E/I balance – This concept describes the ratio of cellular excitation to inhibition, a social hierarchy can be a potent stressor, and in humans health
usually within the cortex. is strongly influenced by socioeconomic status (Sapolsky, 2004).

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Bicks et al. Prefrontal Cortex and Social Cognition

FIGURE 1 | Working model for prefrontal regions involved in social cognition in human and mouse. Medial regions of the prefrontal cortex (PFC) are
specifically related to social behavior, while the lateral regions, dlPFC and vlPFC, are sometimes active during social tasks, but are considered ‘domain general.’ The
dmPFC is involved in perceptions of others as well as cooperation (Amodio and Frith, 2006; Mitchell et al., 2006). The mPFC has also been associated with
perceptions of others, but some research suggests that it is more strongly associated with perceptions of self and similar others (Johnson et al., 2002; Mitchell et al.,
2006; Mitchell, 2009). Ventral regions of the PFC are involved in social reward and punishment, motivation and ‘value’ (including economic) (de Quervain et al., 2004;
Fehr and Camerer, 2007; Kohls et al., 2012). Parts of these divisions in the human brain share homology with the rodent PFC, as indicated. VmPFC contains BA 25,
which is homologous to the rodent IL region, and area 32 is homologous to the PL. Area 24 in humans shares homology with the rodent ACC. These regions thus
may play a shared role in social cognition across mammalian lineages.

In addition to hierarchies, some social phenomena that emerge 32) (Meyer-Lindenberg and Tost, 2012) (Figure 1). Many lines
from group living in humans are organization of governments, of evidence have demonstrated the importance of the vmPFC for
societies, and cultures. social motivation and reward. For example, patients with vmPFC
lesions demonstrate social isolation and apathy (Barrash et al.,
2000) and decreased prosocial behavior in several social decision
PFC REGULATION OF SOCIAL making games (Krajbich et al., 2009). Additionally, subjects who
COGNITION IN HUMAN HEALTH AND rate highly on a psychopathy scale show a decrease in the
DISEASE activity of the vmPFC when choosing to cooperate compared
with controls (Rilling et al., 2007). The vmPFC is engaged when
The PFC has been implicated in a wide range of behaviors subjects feel social acceptance (Moor et al., 2010), and is activated
including working memory, decision making, goal-directed when learning which cues predict social reward (Lin et al.,
behaviors, and social behavior (Duncan and Owen, 2000; Wood 2012). Interestingly, performance on a vmPFC dependent task
and Grafman, 2003; Wood et al., 2003). The PFC is connected in ASD patients ages 3–4 correlates with joint-attention ability,
with other cortical and sub-cortical regions of the brain, suggesting a relationship between social motivation deficits and
including hub regions of ‘the social brain’ such as the nucleus vmPFC functioning in early ASD development (Dawson et al.,
accumbens (NAc), amygdala, ventral tegmental area (VTA), 2002b). Children with ASD show decreased vmPFC and striatal
hypothalamus, and regions of the cortex involved in processing responses to social reward in an implict learning task (Scott-Van
sensory and motor inputs and responses (Ongur and Price, 2000; Zeeland et al., 2010). Interestingly, children with ASD also show
Croxson et al., 2005; Wise, 2008). Additionally, regions of the decreased responses to peer rejection in regions of the vmPFC
PFC are densely interconnected (Passingham et al., 2002). and vlPFC (Masten et al., 2011), including in the subgenual
Social behaviors within all three levels of social cognition are ACC. These findings show impaired vmPFC responses to social
subserved by the PFC acting in conjunction with other cortical reward and rejection in ASD patients, which are closely related
and subcortical regions (Figure 1). However, different regions to social motivation. Regions of the subgenual ACC (BA 32 and
within the PFC are associated with different categories of social 24) have been implicated in social motivation in primates as well.
cognition (Wood, 2003; Wood and Grafman, 2003; Amodio and For example, lesions of the ACC gyrus (BA 32 and 24) disrupt
Frith, 2006; Mitchell, 2009). The primary brain regions that social interest and valuation in macaques (Rudebeck et al., 2006;
underlie social motivation are regions that are related to reward Noonan et al., 2010).
behaviors in general, including the ventral striatum, amygdala, Social behaviors requiring knowledge of self and other
and the ventromedial prefrontal cortex (vmPFC: Brodmann are consistently related to activation within the PFC, and in
cytoarchitectonic areas (BA) 25, 32 11,12 and parts of 10) (Kas particular a medial region of the PFC that includes the mPFC
et al., 2014) which includes the medial orbital frontal cortex and the dmPFC (Amodio and Frith, 2006) (Figure 1). This
mOFC (BA 11 and parts of 10) (Chevallier et al., 2012) and the area is activated by a diverse range of social cognitive tasks
perigenual anterior cingulate cortex (ACC: BA 25 and parts of that include evaluating one’s own mental state or determining

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Bicks et al. Prefrontal Cortex and Social Cognition

whether certain personality traits apply to you, perception the PFC, many theories dissociate contributions of lateral PFC
and judgment of the mental states of others (ToM), moral with medial PFC. Some research suggests that lateral PFC
decision making, cooperation, and empathizing about the pain regions are ‘domain general’ and are recruited to resolve conflicts
of others (Amodio and Frith, 2006). In healthy adults, this in social cues while medial PFC regions are specific to the
region is typically more active in joint attention tasks than in use of contextual social cues to guide social behaviors like
solo attention tasks, but this difference does not exist in adults joint-attention, social reward, moral judgments and mentalizing
with ASD (Redcay et al., 2013). In ASD patients, alterations in (Wood, 2003; Wood and Grafman, 2003; Amodio and Frith,
mPFC activity and connectivity are a consistent finding, and 2006; Zaki et al., 2010). An alternative theory to explain medial
these deficits likely relate to social deficits in this disorder. For and lateral PFC contributions to social cognition posits that the
example, decreased blood flow in the mPFC in children with ASD mPFC is involved in tasks that require internal social processing
correlates with poor social functioning (Ohnishi et al., 2000). of both self and other, for example empathy, mentalizing, self-
ASD patients performing a ToM task that involves attributing reflection and personal moral reasoning whereas the lateral
mental states to geometric figures show decreased activity within PFC is part of a network that is activated by externally guided
the mPFC relative to controls (Castelli et al., 2002; Kana et al., processing in the social domain, for example imitation, abstract
2015) and decreased functional connectivity between mPFC and social reasoning, and resolving conflict in social cues (Lieberman,
parietal regions (Kana et al., 2009). SCZ patients and their 2007). In psychiatric diseases that share social deficits, lateral
unaffected relatives show impaired performance on ToM tasks regions of the PFC have also been associated with poor social
and decreased mPFC (Mohnke et al., 2015) and inferior frontal functioning. For example, activation in the dorsolateral PFC
gyrus (Das et al., 2012) activation while performing this task. (dlPFC: BA 9, 46: Figure 1) in response to social cues is
These findings demonstrate a common mPFC hypoactivation aberrant in patients with SCZ (Shin et al., 2015). Interestingly,
in behaviors related to knowledge of self and other in ASD transcranial direct simulation of the dlPFC improved some
and SCZ. Since ASD and SCZ both share neurodevelopmental parameters of social cognition, such as ‘emotion identification,’
origins, it is important to examine the development of these in subjects with SCZ (Rassovsky et al., 2015). Additionally, both
deficits in social processing. The mPFC is responsive to social paranoid SCZ and ASD patients show decreased activation in the
stimuli in developing infants (Grossmann, 2015). In particular, ventrolateral PFC (vlPFC: BA 47, 45, 44: Figure 1) when making
the mPFC is sensitive to signs that an interaction is directed trustworthiness judgments (Pinkham et al., 2008). Finally, some
at the infant (‘self relevance’) (Grossmann, 2013). For example research dissociates functions of the dorsal and medial regions
viewing a mothers smile, or hearing infant directed speech of the PFC, suggesting the dmPFC is engaged when mentalizing
activates this region (Saito et al., 2007; Minagawa-Kawai et al., about others, while the mPFC is engaged preferentially in self-
2009). Additionally, the mPFC is engaged in joint engagement referential tasks like preference and affective state judgments
tasks in infants, in which an adult uses gaze to direct the (Gusnard et al., 2001; Johnson et al., 2002) as well when taking the
attention of an infant to a third object (triadic interaction) as well perspective of similar, but not dissimilar others (Mitchell et al.,
as during a dyadic mother–infant social interaction (Urakawa 2006). While no theory provides a conclusive description of the
et al., 2014; Grossmann, 2015). Joint engagement tasks and gaze contributions of sub-regions of the PFC to different aspects of
following rely on both social motivation and interpretation of knowledge about self and other, there is a consensus that both the
social signals, and are some of the earliest behavioral predictors dmPFC and mPFC are specifically related to this form of social
of ASD (Toth et al., 2006). These findings suggest that some cognition.
of the same brain regions may underlie knowledge about self The third category of social cognition, group dynamics, relies
and other throughout development. The mPFC shows decreased on both motivation and knowledge of self and other. Living
glucose metabolism in a population of Romanian orphans that in groups often involves a hierarchical organization, and this
show social and cognitive impairments, suggesting this region is organization requires that individuals perceive both their own
sensitive to early life stressors that result in social deficts (Chugani status within the group, as well as the status of others around
et al., 2001). Interestingly, patients who sustained damage to them in order to behave appropriately (Rowell, 1974; Watanabe
their mPFC during infancy demonstrated anti-social behavior and Yamamoto, 2015). The neural mechanisms supporting
and poor moral decision making in adulthood, in contrast to perception of hierarchy in humans rely largely on the PFC acting
patients who sustained damage to this region as adults (Anderson in conjunction with subcortical regions including the amygdala
et al., 1999). This finding suggests that this region may have and ventral striatum, which help interpret the stressful or
a developmental critical period for establishing an appropriate rewarding values often associated with changes in status (Wang
social cognition in humans. et al., 2014; Watanabe and Yamamoto, 2015). In macaques, gray
Within the category of knowledge of self and other, attempts matter volume in the rostral and dorsal PFC correlates with the
have been made to dissociate contributions of different brain size of a social network and with social status (Sallet et al., 2011;
regions. For example, emotional/implicit social cognition has Noonan et al., 2014) and in humans the gray matter volume of
been contrasted with explicit or effortful social cognition. Regions the vmPFC varies with both metalizing competence and social
outside of the PFC including the inferior frontal gyrus and network size, showing a shared neural circuit for distinct facets
amygdala are primarily associated with the former, and dmPFC of social cognition (Lewis et al., 2011). Patients with lesions
and mPFC are primarily associated with the later (Frith and spanning vmPFC and mPFC do not alter their behavior according
Frith, 2008; Mitchell, 2009; Shamay-Tsoory et al., 2009). Within to differing ranks in a professional setting, suggesting disruptions

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Bicks et al. Prefrontal Cortex and Social Cognition

in this region lead to poor understanding of the social cues there are common underlying functions that are achieved
dictated by hierarchy (Karafin et al., 2004). The lateral PFC has in species-specific ways. For this reason, it is important to
also been shown to have an important role in perceptions of use ethologically relevant behavioral models that capitalize on
hierarchy. For example, viewing an individual that ranks above natural rodent behaviors requiring social processing (Thompson
you in a hierarchy activates the dlPFC in both stable and unstable and Levitt, 2010). Here we review a burgeoning literature
hierarchy conditions, and activates the mPFC and the amygdala examining the PFC contribution to social behaviors in rodents.
only in unstable hierarchy conditions (Zink et al., 2008). This We focus on behaviors that are not directly related to mating
suggests that the lateral regions of the PFC may be important for or parent–offspring relationships but that are ethologically
knowledge about your own place in a hierarchy, while activity relevant to social processing demands in rodents, including
in the mPFC and amygdala may help coordinate appropriate social motivation/affiliation, social memory/recognition, and
behaviors when a hierarchy is changing, and knowledge must be dominance. These behavioral domains can be conceptually
continually updated. compared to the human categories: social motivation, knowledge
Overall, there is strong evidence in the field of social cognition of self and others, and hierarchies within groups.
that medial regions of the PFC including the mPFC, dmPFC, and In rodents, behavioral paradigms that assess social motivation
the vmPFC are crucial for a wide variety of behaviors that include often rely on social preference tests that assess time spent with a
motivation, understanding of the self and others, and formation novel social target compared with time spent with a novel object
of complex group behaviors (Figure 1). In the following, we (Moy et al., 2004) (Figure 2A). These tests have frequently been
compare the human data presented above with rodent models used to assess social deficits in genetic mouse models of ASD
that converge on the hypothesis that evolutionarily shared (Silverman et al., 2010). The interaction typically takes place in
regions of the mPFC mediate social behavior across species. a three chamber apparatus that allows for preference of the social
chamber to be assessed. In these tests, the novel social stimulus
is generally constrained in a compartment that allows sniffing
SOCIAL COGNITION AND THE PFC IN and interaction but no physical contact. This controls for the
RODENTS behavior of the stimulus to influence the social interaction. Other
paradigms simply measure the time spent investigating in an
If animal models are to provide useful insights in evaluating how unconstrained interaction.
alterations within the PFC circuitry can lead to social deficits in In mice and rats, paradigms aimed at measuring levels of social
models of human disease, we must first determine to what extent recognition exploit a natural propensity of mice to habituate
‘social cognition’ is related to a consistent neural mechanism to a familiar conspecific, and to explore a novel mouse more
across mammalian lineages, including rodents. Some controversy than a familiar one (Thor and Holloway, 1982) (Figure 2B).
exists in translational neuroscience about the existence of the A focal mouse is exposed to a novel stimulus mouse, generally
rodent PFC, and many researchers have debated the homology an ovariectomized female or a juvenile to diminish aggressive
between specific regions in primate and rodent forebrain (Preuss, behavior. The presentation of the stimulus mouse is repeated
1995; Uylings et al., 2003; Wise, 2008). A consensus has emerged multiple times with a delay between presentations. A decrease
that regions of the human mPFC including the vmPFC and in the sniffing time across the repeated trials reflects recognition
the dmPFC share some homology with regions within the that the mouse is familiar. After repeated presentations, a novel
rodent mPFC (Figure 1). The rodent prelimbic (Riedel et al., mouse is presented, and increased investigation of the novel
2009) cortex is considered homologous to BA 32, which lies mouse reflects social novel preference (Thor and Holloway, 1982)
within the mPFC and vmPFC (Wise, 2008), although some have (Figure 2B). This can also be assessed in the three chamber
suggested this region contains some similarities with human apparatus: After the social vs. object presentation, a second
dlPFC as well (Uylings et al., 2003). The rodent infralimbic social target is added to the opposite chamber, and increased
cortex (IL) is considered homologous to BA 25, and lies within investigation of the novel vs. the familiar animal reflects a social
the vmPFC (Wise, 2008). Additionally, the rodent mOFC is novelty preference that relies on the recognition of a novel animal
considered homologous with the human mOFC (Preuss, 1995). (Moy et al., 2004) (Figure 2A).
The human dmPFC includes parts of the dorsal ACC, which An interesting line of translational research aims to study
shares homology with the rodent ACC (Wise, 2008). Other empathy behavior in rodent models. This research generally
regions of the human PFC are generally considered not to follows one of two behavioral paradigms. The first capitalizes on
share homology with the rodent brain. Rodents do not have the ability of mice and rats to alter their behavior by observing
a granular PFC, and therefore granular regions of the human conspecifics (Choleris et al., 1997; Chen et al., 2009). For example,
PFC including the dlPFC do not have a homologous structure mice and rats demonstrate social transmission of pain (Langford
within the rodent brain (Preuss, 1995; Wise, 2008; but see et al., 2006), fear (Chen et al., 2009; Kim et al., 2012), and food
Uylings et al., 2003). In this review, we discuss the evidence preference (Choleris et al., 1997). The second general method
that the PFC might regulate social behaviors in rodents, as assays prosocial behavior by placing rats in a situation where they
well as in humans, and that pathologies leading to social have the opportunity to free a trapped conspecific in the presence
deficits in rodent models of psychiatric disease might be related of a valued food source (Bartal et al., 2011).These tests provide an
to altered functioning in the PFC. Although there are clear interesting opportunity to examine changes in empathy behavior
differences between social cognition in humans and rodents, in animal models of ASD and SCZ.

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FIGURE 2 | Common behavioral paradigms for studying social cognition in rodents. (A) The three chamber test (Moy et al., 2004). In the first phase social
preference is assessed. A focal mouse chooses between a social target and an object and time spent investigating both is measured and compared. In the second
phase social novelty preference is assessed when a novel mouse is added and the focal mouse chooses to investigate a novel vs. familiar mouse. Graphs show
common findings demonstrating the natural wildtype (black bars) propensity to investigate a social target more than an object, and to investigate a novel mouse
more than a familiar mouse. Red bars demonstrate a hypothetical treated group showing no social preference and no novel social preference. (B) The Habituation –
Dishabituation paradigm (Thor and Holloway, 1982) in which a juvenile mouse is presented to a focal mouse, usually in the home cage, for four consecutive 1 min
trials with an intertrial interval of 10 min. A novel juvenile is presented on the fifth trial. The graph shows commonly reported wildtype social investigation time (black),
which decreases over the four trials and then increases with the presentation of the novel mouse on the fifth trial, demonstrating recognition of a novel animal.
Hypothetical red data shows floor levels of social investigation, similar to that seen when animals are treated with NMDAR antagonists (Zou et al., 2008; Jeevakumar
et al., 2015). Data indicated by the green line shows a ceiling level of social investigation showing hypothetical intact social motivation and decreased social
recognition. This effect is seen in animals lacking the oxytocin gene (Ferguson et al., 2000). (C) The tube test. Tests for dominance by placing two mice into a tube
and recording which mouse forces the other to back out of the tube (Lindzey et al., 1966). A fictitious experiment is shown in which the rank of the four control mice
(black) is compared over time. The top ranked mouse is treated (red) and drops rank within the hierarchy. This effect is similar to that seen when the synaptic efficacy
within the PFC is decreased (Wang et al., 2011a).

A third dimension of social behavior in rodents is social SOCIAL MOTIVATION AND PFC IN
hierarchy and dominance. In mice, social hierarchies develop RODENTS
when mice live in high-density conditions, and this likely allows
for a decrease in aggressive behavior and an increase in social
tolerance (Anderson, 1961). These social hierarchies can be PFC Regulation of Social Motivation in
assessed in several ways. A simple way is to observe behaviors Rodents
of animals in their home cage, or to observe aggressive behavior Social motivation describes the motivation of an animal to
interactions that typically happen when a group is placed into approach, explore, and otherwise interact with a social target.
a new cage. Measurements of biting, attacks, and submissive Social motivation is disrupted in ASD (Chevallier et al., 2012)
postures can be used to infer dominance relationships in a and SCZ (Fervaha et al., 2015). Research from animal models
group. New automatic systems used to track social dynamics supports the human literature implicating the contribution of
of large groups of mice in complex environments have added the PFC in social motivation, in conjunction with subcortical
to this body of work (Shemesh et al., 2013; Weissbrod et al., areas that mediate rewarding aspects of social interaction like
2013). Another way to measure dominance is through a tube the NAc and VTA (Gunaydin et al., 2014; Kas et al., 2014).
test method (Lindzey et al., 1966) (Figure 2C). In this paradigm, Lesions of regions within the rodent PFC have demonstrated its’
mice are placed in pairs, facing each other, into a tube that does importance in social functioning. For example, lesioning the rat
not allow enough space for mice to pass each other or for either OFC disrupts play behavior and increases aggressive behavior
mouse to turn around. One mouse is forced to back out of the (Pellis et al., 2006; Rudebeck et al., 2007). Lesions of the ACC
tube (‘loser’) by the other mouse (‘winner’). This test allows for disrupt social memory and decrease social interest (Rudebeck
the inference of dominance relationships between pairs of mice, et al., 2007) and lesions of the PL region of the rodent PFC
and is very highly correlated with other measures of dominance actually increase social investigation, possibly due to an increase
including marking in a novel environment and vocalizations in a in aggression (Avale et al., 2011). Therefore, lesion studies have
mating context (Wang et al., 2011a, 2014). provided evidence for the necessary role of the PFC in social
In the following, we review evidence that rodent social motivation, however, lesions are a crude manipulation that often
behavior including social motivation, recognition of conspecifics, damages adjacent regions and passing axons. A recent study
empathy behavior, and hierarchy are altered by activity within the examined whole brain cfos activity in a social context and found
rodent PFC. that the mouse PFC was activated in a social interaction (Kim

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Bicks et al. Prefrontal Cortex and Social Cognition

et al., 2015), showing a correlative involvement of the PFC in

social behavior.
The microcircuitry of the PFC contains a complex
array of interneurons that inhibit circuit activity, as well
as neuromodulator inputs including acetylcholine (ACh),
dopamine (DA), and oxytocin (OT). The concept of
Excitatory/Inhibitory balance (E/I balance) is a broad term
that attempts to capture alterations within the circuit that
alter the ratio of excitatory:inhibitory neurotransmission.
The influence of changing E/I balance in the developing
cortex has been extensively linked to critical period plasticity
(Hensch, 2003, 2004, 2005). Interestingly, decreases in inhibitory
neurotransmission are a common finding in animal models
of ASD (Gogolla et al., 2009). Many human studies of ASD
(Rubenstein and Merzenich, 2003) and SCZ (Sun et al., 2013)
patients also show decreases in inhibitory neurotransmission
measured by decreased power of gamma oscillations, an
indication of decreased activity of fast-spiking inhibitory basket
cells (Bartos et al., 2007). Human post mortem studies of ASD
patients have shown increases in dendritic spines in cortical
regions, and overall increased within-region interconnectivity
FIGURE 3 | Modulators of social cognition in the rodent PFC. Red text
and decreased long-range interconnectivity, particularly in the represents nodes of the circuit that, when disrupted, decrease social
frontal cortex (Wass, 2011). Post mortem studies of SCZ PFC motivation. For example, synaptic scaffolding proteins on excitatory synapses
has shown decreased markers of inhibitory neurons (Akbarian like Shank3 and IRSp53 have been associated with social motivation in the
et al., 1995; Mitchell et al., 2015). Examining how alterations in PFC, as have cytoskeleton remodelers, actin and cofilin. NMDARs at
excitatory synapses are also a key node of the social motivation circuit. ACh
the balance of circuits within the PFC alters social motivation
input to the PFC and nicotinic receptors have also been shown to modulate
is crucial to identifying underlying pathology of social deficits. social motivation, however, it is unclear which cell types are important for ACh
In the following we review evidence that alterations within action or whether these effects are pre or post-synaptic. Blue text represents
the microcircuitry of the PFC interfere with social motivation, nodes of the circuit that, when disrupted, decrease social recognition. For
and provide a framework for understanding human psychiatric example, disrupting gabaergic neurotransmission by removing the NR1
subunit on cortical gabaergic interneurons disrupts social recognition. Green
diseases with social deficits (Figure 3). text represents nodes of the circuit that are involved in dominance behavior.
Direct alterations of E/I balance within the PFC in adult mice For example, bidirectional modulation of AMPARs and mutations in the fmr1
have a strong effect on social motivation. For example, Yizhar gene. ACh, acetylcholine; AMPAR, α-amino-3-hydroxy-5-methyl-4
et al. (2011) used optogenetics to independently manipulate -isoxazolepropionic acid receptor; dlgap2, disks large-associated protein 2,
the activity of excitatory pyramidal neurons and inhibitory fmr1, fragile X mental retardation 1; IRSp53, insulin receptor substrate protein
of 53 kDa, mAchR, muscarinic acetylcholine receptor, nAChR, nicotinic
parvalbumin (PV) interneurons within the PFC both during acetylcholine receptor, NMDAR, N-Methyl-D-aspartate receptor, PV,
a social exploration task, and in the three chamber sociability parvalbumin postitive interneuron, vAChT, vesicular acetylcholine transporter.
test (Figure 3) (Yizhar et al., 2011). They found elevating the See text for references.
excitatory balance by stimulating pyramidal neurons in the PFC
abolished social exploration and disrupted social preference in
the three chamber test. On the other hand, there was no effect on significantly reduces social motivation (Savage et al., 2011).
social motivation when inhibition was increased by stimulating However, in mice lacking the ß2 nicotinic receptor there is
PV interneurons. The effects of increased excitation were actually an increase in social contact, which is normalized with
ameliorated by simultaneously stimulating PV interneurons, virally mediated ß2 rescue within the PL region of the PFC.
showing that an appropriate E/I ratio in the PFC is required This suggests that ACh signaling through nicotinic receptors
for social motivation in mice. These findings corroborate human in the PL may actually attenuate social motivation, perhaps in
literature that shows a role for altered E/I balance within the favor of novel context exploration (Avale et al., 2011) (Figure 3).
PFC in psychiatric disorders including SCZ and ASD (Toro et al., Other neuromodulators, like neuropeptides may alter social
2010; Morishita et al., 2015). motivation through signaling in the PFC. OT has been shown to
mediate many pair bonding and social affiliative mechanisms,
Neuromodulators in the PFC Modulate but much of this work has examined OT within subcortical
Social Motivation structures (Insel and Young, 2000). New research examining
In addition to direct alterations in glutamatergic and gabaergic the role of OT in the cortex has shown that OT mediates the
neurotransmission, many neuromodulators alter microcircuitry salience of pup calls through modulating E/I balance in the
activity. The neuromodulator acetylcholine (ACh) acting auditory cortex of dams (Marlin et al., 2015), and modulates
within the cortex modulates social motivation, since selective cross modal experience-dependent plasticity between multiple
denervation of cholinergic input to the neocortex in rats sensory cortices (Zheng et al., 2014). Additionally, there is a

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Bicks et al. Prefrontal Cortex and Social Cognition

population of SST interneurons in the mPFC that express the mating context (Saunders et al., 2013). Many genetic models
OT receptor and have differential responses to OT in male and of ASD and SCZ that result in social deficits are caused by
female mice (Nakajima et al., 2014). These OTR expressing loss of function of synaptic adhesion molecules or scaffolding
neurons in the mPFC specifically regulate the social motivation proteins in the PSD. For example, mice with deletions or
of female mice to interact with male mice during estrus, without mutations in the cell adhesion proteins Neuroligin-1 (NL-1)
affecting the motivation to interact with another female mouse. (Blundell et al., 2010), Neuroligin-3 (NL-3) (Tabuchi et al.,
Therefore OT acting in conjunction with steroid hormones could 2007), and Neuroligin-4 (NL-4) (Jamain et al., 2008) show social
play a key role in modulating other aspects of social cognition motivation deficits. Alterations in neuroligins have widespread
through actions in the mPFC. More research delving into the effects on excitatory/inhibitory balance throughout the brain
effects of neuropeptides in the cortex will elucidate mechanisms (Maćkowiak et al., 2014). Additionally, mice with mutations in
by which these modulators may affect E/I balance within the PFC the ASD- associated post-synaptic density (PSD) protein Shank3
and social motivation. (Wang et al., 2011b; Betancur and Buxbaum, 2013) show social
motivation deficits and altered E/I balance (Lee et al., 2015).
Findings from these studies show that an altered E/I ratio, most
Cortical E/I Balance and Social often caused by disruptions in inhibitory neurotransmission can
Motivation: Relevance to Genetic Animal lead to social motivation deficits.
Models of ASD and SCZ While many of the genetic contributions to social motivation
Other studies have examined E/I balance in the context of deficits alter global E/I balance, some of these deficits have
genetic risk factors for ASD and SCZ, and found alterations shown specific PFC related deficiencies. One study examining
in E/I balance within the cortex in general, and in some cases Shank3 deficient mice, found that decreased social motivation
in the PFC specifically, in animal models showing decreased in this genetic model is specific to the PFC. Shank3 deficient
social motivation (Figure 3). For example, transgenic mice mice show decreased NMDA mediated excitatory post-synaptic
expressing only ∼10% of normal levels of the NR1 subunit of current (EPSC) amplitude in layer 5 pyramidal neurons as
the N-Methyl-D -Aspartate (NMDA) receptor show decreased well as a decrease in F-actin filaments within this region. The
social motivation, decreased ultra sonic vocalizations (USVs), social deficits, as well as the decreases in NMDAR expression
and abnormal gamma synchrony (Gandal et al., 2012a). This and function, can be rescued by inhibiting the main actin
study also demonstrated that this model of hypofunction of depolymerizing factor, cofilin, either systemically or specifically
NMDARs increased E/I ratio, specifically pyramidal neuron in the PFC (Duffney et al., 2015). Additionally, inhibiting
excitability (Gandal et al., 2012b). This model is relevant to NMDARs in the PFC is sufficient to reproduce the loss of
both ASD and SCZ, as it models overlapping symptoms of social motivation. This study suggests that an intact actin
the social motivation deficits and the abnormal cortical E/I cytoskeleton is required for normal excitatory transmission
balance. Mice lacking the expression of PV, a calcium binding through NMDARs, and that these components are required
protein that defines a population of interneurons, show a in the PFC for intact social motivation (Figure 3). Another
constellation of ASD behavioral phenotypes, including decreased study examined the loss of a different excitatory PSD protein,
social interaction (Wohr et al., 2015). The loss of this calcium the insulin receptor substrate protein, (IRSp53) and found that
binding protein also increases inhibition within the cortex. mice lacking this gene show decreased social motivation and
Therefore, decreasing E/I ratio in the cortex, as well as increasing reduced excitatory neurotransmission in layer 2/3 of the mPFC
it, interferes with normal social motivation. These findings as well as decreases in dendritic spine number and maturity
can be interpreted in the context of SCZ as well as ASD, in this region. The social deficits, as well as the decreased
since SCZ patients show PV interneuron dysfunction in post excitatory neuronal firing rate in the mPFC, are rescued by
mortem brain (Lewis et al., 2005). The phosphatase PTEN has normalizing the altered E/I balance with an NMDAR antagonist
also been implicated in ASD (Butler et al., 2005), and in a (Chung et al., 2015) (Figure 3). Mice lacking the methyl
recent paper, Vogt et al. (2015) used a conditional knockout CpG binding protein 2 (MeCP2) that is known to cause Rett
strategy targeted to the medial ganglionic eminence to remove syndrome (Amir et al., 1999), show social avoidance (Moretti
PTEN in interneuron progenitors. Using this strategy, they et al., 2005) and a mPFC specific dysfunction of excitatory
observed an overall loss of interneurons and a preferential loss neurotransmission (Sceniak et al., 2015). These findings taken
of somatostatin (SST) positive interneurons compared with PV together suggest that altered social motivation in animal models
neurons in cortex, hippocampus, and striatum. Surprisingly, of ASD is linked to alterations in the E/I balance that is in
the loss of these inhibitory interneurons actually resulted in some cases specifically relates to the microcircuitry of the PFC.
an increase in inhibition onto layer 2/3 neocortical pyramidal In contradiction to this theory, causing NMDAR dysfunction
neurons, decreased social motivation, and increased gamma specifically in adulthood in the mPFC of mice with a cre-
oscillations during social interaction compared with controls. mediated excision of the NR1 subunit did not decrease either
Genetic ablation of the NR1 subunit of NMDARs on PV social preference or social novelty preference in the three
interneurons causes alterations in mouse electroencephalograph chamber test (Finlay et al., 2015). This finding points to the
(EEG) recordings in response to an auditory stimulus, a finding importance of studying how circuits within the PFC develop,
seen in Autistic patients (Roberts et al., 2010). These mice as supposed to their functioning in adulthood (Ueda et al.,
also show social motivation deficits and reduced USVs in a 2015).

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Bicks et al. Prefrontal Cortex and Social Cognition

SOCIAL RECOGNITION AND PFC IN NMDAR hypothesis of SCZ have revealed the importance of
RODENTS NMDAR functioning and intact E/I balance in social recognition,
yet no study has pointed to disrupted E/I balance specifically
within the PFC as causally disrupting social recognition. Acute
Does the PFC regulate Social
injections of MK801 decrease social exploration of a novel
Recognition in Rodents? juvenile and decrease social recognition (Zou et al., 2008) and
Social recognition and memory are key aspects of social postnatal ablation of the NR1 subunit of the NMDA receptor in
cognition and normal social functioning, and are considered 40–50% of γ –Aminobutyric acid (gabaergic) interneurons in the
requirements for forming long-term attachments, hierarchies, cortex and hippocampus abolishes short-term social memory,
and other complex social strategies in animals. In humans, without affecting overall levels of social investigation (Belforte
social recognition is one component of knowledge of self and et al., 2010). Both of these studies suggest loss of inhibitory tone
others, and is an important prerequisite for other forms of social decreases social recognition. When ketamine is given during the
cognition including empathy and moral decision-making. Early second postnatal week of development it preferentially decreases
social recognition is also disrupted in children with ASD, and PV expression in the mPFC, decreases GABA release in layers
performance on a facial recognition task predicts future symptom 2/3, and increases spontaneous glutamatergic inputs onto PV
severity (Dawson et al., 2002a; Eussen et al., 2015). cells, consistent with an increase in the E/I balance within
Circuits involved in social recognition in rodents depend in the cortex (Jeevakumar and Kroener, 2014). This treatment
part on the hippocampus and medial amygdala (MeA), perhaps decreases social exploration and disrupts social recognition
not surprisingly given the importance of the hippocampus (Jeevakumar et al., 2015). Collectively, these studies suggest
for memory formation (Kogan et al., 2000), and the MeA in that increased E/I ratio in the cortex caused by NMDAR
processing volatile scent cues (Noack et al., 2015). In mice, the hypofunction on inhibitory neurons leads to deficits in social
volatile fraction of the scent cue is required for recognition recognition (Figure 3). Retention of social memories is enhanced
memory (Noack et al., 2010) and retrieval of these cues depends by activating NMDARs (Hlinak and Krejci, 2002), showing
on the MeA (Noack et al., 2015). The neuropeptides oxytocin a bidirectional modulation of social recognition by NMDAR
(OT) and vasopressin (AVP) are also part of a canonical social activity. Taken together these findings demonstrate the robust
recognition circuit and signaling of these peptides through the importance of NMDARs and intact E/I balance for social
MeA and Lateral Septum (LS), respectively, is required for social memory. While most of these studies aim to investigate animal
recognition. (Ferguson et al., 2000, 2001; Bielsky et al., 2004, models of the glutamate hypothesis of SCZ, these findings are
2005a,b). There is some evidence that the PFC is involved in also likely to be relevant for ASD, since human studies have
social recognition. For example, one study showed that lesioning shown disinhibition and decreased inhibitory functioning in
the ACC, but not the OFC disrupts social recognition in rats humans with both ASD (Rubenstein and Merzenich, 2003) and
(Rudebeck et al., 2007). Fibroblast growth factor 17 (Fgf17) SCZ (Uhlhaas and Singer, 2015). However, future studies are
is a secreted signaling molecule involved in patterning the required to determine which specific regions within the cortex
development of the rostral forebrain (Cholfin and Rubenstein, require NMDAR mediated responses in order to perform normal
2007). Fgf17 deficient mice show deficits in social recognition social recognition.
and decreased activation of the immediate early gene, Fos,
in the frontal cortex after exploring a novel environment
with an opposite sex partner (Scearce-Levie et al., 2008). This Neuromodulators in the PFC Modulate
evidence points to the importance of the frontal cortex in social Social Recognition
recognition (Scearce-Levie et al., 2008) and the ACC specifically Some evidence for a PFC contribution to normal social
in rats (Rudebeck et al., 2007), however, evidence for a role of the recognition comes from studies examining the pharmacology
PFC in social recognition in rodents is not yet conclusive. of social recognition in rats. These studies have outlined
the importance of the neuromodulators acetylcholine (ACh)
E/I balance and Social Recognition: and dopamine (DA) within the frontal cortex for normal
Translational Relevance social memory (Figure 3). The muscarinic receptor antagonist,
An influential hypothesis links SCZ pathology, and in particular scopolamine, decreases short-term social memory in the three
the negative symptoms of this disease, including defects in social chamber test in mice without affecting social preference
cognition, to hypofunction of the NMDA receptors on inhibitory (Riedel et al., 2009). In rats, a scopolamine-induced social
interneurons (Kehrer et al., 2008). Non-competitive NMDA recognition deficit is attenuated by administering a nicotinic
receptor antagonists like MK801 or ketamine preferentially receptor agonist (Van Kampen et al., 2004). Other findings
decrease activity of inhibitory interneurons within the have suggested the reduced social recognition seen after
cortex, thereby increasing glutamatergic tone and E/I ratio scopolamine injection may be mediated through the melanin-
through disinhibition (Moghaddam et al., 1997; Homayoun concentrating hormone (MCH) receptor, since in a separate
and Moghaddam, 2007; Gordon, 2010). Pharmacologically study the effect of scopolamine was dose-dependently blocked
disrupting E/I ratio with these agents also produces a variety of using an MCH receptor blocker (Millan et al., 2008). MCH
schizophrenia-like behaviors in animal models (Moghaddam and ACh neurotransmission interact in the Frontal Cortex
et al., 1997; Homayoun and Moghaddam, 2007). Tests of the to produce effective social recognition, since MCH receptor

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Bicks et al. Prefrontal Cortex and Social Cognition

blocking elevates extracellular dialysates of ACh in the PFC TABLE 2 | Questions for future research.
and enhances social recognition (Millan et al., 2008). Dopamine
This review presented evidence that the PFC is a common regulator across
signaling also modulates ACh levels in the PFC and social social behaviors in rodents, and that E/I balance, specifically within the PFC
recognition: Administration of a dopamine (D3) receptor effects social cognition. However, many outstanding questions remain:
antagonist creates an elevation of ACh specifically in the PFC,
• How does the development of circuits within the PFC contribute to the
and attenuates the negative effects of scopolamine on social development of social cognition? In humans, social cognition has a clear
memory in rats (Millan et al., 2007). Additionally, mice with a developmental trajectory, but the extent of this development is still unclear
heterozygous deletion of the acetylcholine transporter VAChT in animal models. Answering questions about the ways in which
show impaired object and social recognition (Prado et al., 2006). maturation of PFC circuits leads to appropriate development of social
cognition in animals will improve our understanding of
This finding suggests that general habituation-related memory
neurodevelopmental diseases like Autism and Schizophrenia.
may be impaired after decreasing vesicular trafficking of ACh • What are the properties of the regulation of E/I balance during
and not social recognition memory specifically. In fact, many development and how does E/I balance over the course of development
studies examining social recognition deficits see broad memory contribute to normal social functioning in adulthood?
effects and not social recognition deficits specifically. Therefore, • How do different cell types and microcircuits within the rodent PFC
contribute to E/I balance development and social behavior?
ACh neuromodulation in the PFC may affect social recognition
• What are the circuits that connect the mPFC to other regions of the ‘social
through ‘domain general’ mechanisms like attention or working brain’ and how are distinct social behaviors regulated by these circuits?
memory. • What is the role of E/I balance within the PFC in social recognition? While
lots of evidence points to NMDAR functioning and E/I balance as
Does the PFC Regulate Empathy necessary for social recognition, no study has specifically tested the
causal relationship between E/I balance in the PFC and social memory.
Behaviors in Rodents? • Are there sex differences in these behaviors? Most of the research on
Learning by observing conspecifics provides a strong social behavior comes from male mice, and so while we know female
evolutionary advantage to social species. Observational learning mice also show social motivation, social recognition, and social hierarchy,
we don’t know whether there are sex differences in the neural
and emotional contagion have been put forth as the evolutionary
mechanisms underlying these behaviors.
basis of empathy (Olsson et al., 2007). Interestingly, this type of
learning engages brain regions within the mPFC, including the
ACC in both humans (Singer et al., 2004; Olsson et al., 2007) a viral strategy that increases AMPA receptor trafficking to
and rodents (Jeon et al., 2010; Jurado-Parras et al., 2012; Kim the synapse increases the mouse’s rank within the hierarchy.
et al., 2012). For example, mice acquire a conditioned contextual Conversely, dampening the efficacy of synaptic transmission
fear by observing conspecifics, and this behavior is dependent by decreasing AMPARs at the synapse decreases the rank.
on the right ACC (Kim et al., 2012). Mice also learn more This study also found an increase in the amplitude of EPSCs
quickly to lever press for food if they observe a well-trained in dominant compared with subordinate mice. Additionally,
demonstrator, and this advantage is abolished if the mPFC is dominance behavior studies in mice have been useful in animal
electrically stimulated during the observational learning (Jurado- models of social cognition deficits in ASD. For example, knocking
Parras et al., 2012). Injection of the antipsychotic haloperidol or out Dlgap2, an important PSD scaffolding protein associated with
serotonin into the ACC of mice in an observational fear-learning ASD, increases dominance and aggressive behavior and decreases
task decreased the expression of conditioned fear (Kim et al., AMPAR-mEPSCs and spine density in the mouse OFC (Jiang-
2014). Serotonin microinjection in this study reduced gamma- Xie et al., 2014). Optogenetically activating the mPFC (PL/IL)
band activity in this region, suggesting serotonin modulation in mice decreases aggressive behavior, while silencing this region
of ACC activity disrupts social learning. These results clearly leads to an escalation of aggression (Takahashi et al., 2014). This
implicate the ACC in empathy related behaviors in mice. finding is interesting in light of the findings of Wang et al.,
because these studies together demonstrate opposing regulation
of aggression and dominance by activity of the mouse PFC (Wang
PFC REGULATION OF SOCIAL et al., 2011a). In conclusion, social hierarchy is modulated by
HIERARCHY IN RODENTS excitatory neurotransmission in the PFC, and is a useful way to
investigate social cognition alterations in genetic animal models
Social hierarchies are common among mammals and likely of human disease.
confer an important adaptation to living in groups (Cummins,
2000). In humans and non-human primates a dominance
hierarchy involves recognizing dominance relationships, learning CONCLUSION
social norms, and reading intentions of others (Cummins, 2000).
For this reason, hierarchy represents a complex form of social Our knowledge and understanding of the neural mechanisms
cognition that requires plasticity of behavior in the face of governing social cognition is rapidly expanding, and a growing
changing social contexts. In mice, dominance also seems to be body of evidence points to the PFC as a central regulator.
linked to the microcircuitry in the PFC (Wang et al., 2014). Social cognition involves integrating many behavioral domains
For example, altering the efficacy of synaptic transmission in the including motivation and reward, salience, attention, flexibility,
PFC causes a bidirectional modulation of social hierarchy (Wang and a host of other processes. Not surprisingly, social cognition
et al., 2011a) (Figure 3). Specifically, increasing excitability using is affected in a wide variety of psychiatric disorders. We have

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Bicks et al. Prefrontal Cortex and Social Cognition

reviewed evidence that alterations in the microcircuitry of the in rodent models will provide novel insights into the deficits in
PFC are related to social motivation deficits in animal models the social domain frequently associated with psychiatric disorders
of ASD and SCZ. Models of social memory have pointed to the (Table 2).
importance of the neuromodulators acetylcholine and dopamine
within in the PFC. Additionally, the glutamate hypothesis of
SCZ has led to an understanding of the requirements of NMDA FUNDING
receptor functioning and E/I balance in social recognition.
Studies of social hierarchy point to a causal role of synaptic This work was supported by T32MH087004-07 (LB), March of
efficacy within the PFC in mediating dominance in mice (Wang Dimes (HM), Whitehall Foundation (HM), Brain and Behavior
et al., 2011a). These studies are supported by human literature, Research Foundation (HM), and NIH (SA, HM).
which implicates the PFC in studies of social cognition including
motivation, knowledge of self and others, and social structures.
Taken together, the evidence suggests that the PFC is a hub that ACKNOWLEDGMENT
regulates multiple components of social cognition across species.
We predict that future exploration of prefrontal microcircuitry We thank Dr. Peter Rudebeck for his insightful feedback.

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(2011b). Synaptic dysfunction and abnormal behaviors in mice lacking major Copyright © 2015 Bicks, Koike, Akbarian and Morishita. This is an open-access
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