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Integrative and Comparative Biology
Integrative and Comparative Biology, volume 55, number 2, pp. 268–280
doi:10.1093/icb/icv061
Society for Integrative and Comparative Biology
SYMPOSIUM
Neural Computation and Neuromodulation Underlying
Social Behavior
Joseph F. Bergan1
Department of Psychology and Brain Sciences, University of Massachusetts, Amherst, MA 01003, USA
From the symposium ‘‘Neurohormones, Brain, and Behavior: A Comparative Approach to Understand Rapid
Neuroendocrine Function’’ presented at the annual meeting of the Society for Integrative and Comparative Biology,
January 3–7, 2015 at West Palm Beach, Florida.
1
E-mail: [email protected]
Synopsis Social behaviors are as diverse as the animals that employ them, with some behaviors, like affiliation and
aggression, expressed in nearly all social species. Whether discussing a ‘‘family’’ of beavers or a ‘‘murder’’ of crows, the
elaborate language we use to describe social animals immediately hints at patterns of behavior typical of each species.
Neuroscience has now revealed a core network of regions of the brain that are essential for the production of social
behavior. Like the behaviors themselves, neuromodulation and hormonal changes regulate the underlying neural circuits
on timescales ranging from momentary events to an animal’s lifetime. Dynamic and heavily interconnected social circuits
provide a distinct challenge for developing a mechanistic understanding of social behavior. However, advances in neuroscience continue to generate an explanation of social behavior based on the electrical activity and synaptic connections
of neurons embedded in defined neural circuits.
Introduction
Social behaviors such as reproducing and raising
young are essential for individual fitness and,
throughout evolution, the need for social interaction
has sculpted specialized circuits that respond to cues
in the environment with purposeful behaviors. As a
result of years of progress in neuroscience, the study
of social behavior is now tractable in a diverse set of
species on levels ranging from genetics to behavior
(Arnold and Breedlove 1985; Meaney et al. 1996;
Hoke et al. 2005; Toth et al. 2007; McCarthy 2008;
Maruska and Fernald 2011). However, our understanding of how interconnected networks of neurons
function in concert to produce social behavior is still
in its infancy. Deciphering common circuit principles
that facilitate social behavior remains a major challenge and will require developing theoretical frameworks that account for the connectivity and activity
of individual neurons in the context of broader functioning of circuits. The recent explosion of techniques in neuroscience enables new strategies for
understanding variation in social behavior on a
moment-to-moment basis, as well as to rapidly
modify network function with striking specificity
(Boyden et al. 2005; Lerchner et al. 2007; Dankert
et al. 2009; Dong et al. 2010; Anderson and Perona
2014). These advances make the long-standing goal
of a mechanistic understanding of social behavior
increasingly attainable.
Behavior exists on a continuum from involuntary
reflexive behaviors to mindful actions performed
under complex cognitive control. Although far
more elaborate than a spindle fiber compelling its
cognate muscle to contract, research suggests that
some social behaviors represent innate reflexes with
hardcoded circuits (Stockinger et al. 2005). For example, the pheromone 11-cis vaccenyl acetate (cVA)
binds to known olfactory receptors on the antennae
of Drosophila and reliably triggers a progression of
courtship behaviors (Kurtovic et al. 2007; Datta et al.
2008; Coen et al. 2014). The capacity of cVA to elicit
courtship behavior in male Drosophila requires stereotyped projections of cVA-detecting sensory neurons to a sexually dimorphic network of neurons in
the brain that express the transcription factor ‘‘fruitless’’ (Manoli et al. 2006; Datta et al. 2008;
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Neural computation and neuromodulation
Ruta et al. 2010). Differences in the connectivity of
cVA input serve as a bidirectional switch for courtship behavior by routing sensory information differentially in males versus females (Kohl et al. 2013).
The sex-specific behavioral changes produced by perturbing fruitless-expressing neurons demonstrate
both the necessity and sufficiency of this network
for generating courtship behaviors (Stockinger et al.
2005; Meissner et al. 2011).
The mammalian brain also exhibits loci where the
activity of distinct populations of neurons is tightly
linked to the production of specific behaviors. As
early as the 1950s, intracranial self-stimulation experiments mapped distinct regions of the brain that
produce aversive (periaqueductal gray; Olds 1958)
or rewarding (ventral tegmental nucleus; Olds and
Milner 1954) responses. Similar experiments with
rats identified specific locations in the hypothalamus
that induce aggression toward conspecific animals
when electrically activated (Kruk et al. 1983). The
most famous of these experiments involved fighting
bulls implanted with ‘‘stimoceivers’’ by Jose Delgado,
who then entered the bull-fighting ring and repeatedly stopped the implanted bulls’ charges by remotely activating the caudate nucleus (Horgan
2005). These lines of research laid the foundation
for recent experiments employing optogenetics and
chemical genetics to further dissect the relationship
between neural activity and behavior. In retrospect, it
is remarkable, and a testament to the quality of research, that these landmark experiments succeeded in
the face of tremendous genetic, anatomical, and synaptic heterogeneity within the targeted neural populations. Until recently, extremely few ways of
addressing questions of neural complexity existed.
However, the development of chemical and optogenetics, as well as viral techniques for gene transfer,
provide fantastic methods to manipulate specific
neurons and assay the affect of these neurons on
the function and behavior of circuits (Aponte et al.
2011).
The unambiguous relationships between neural activity and behavioral output described above may
initially seem at odds with clear observable variability
in social behavior. Indeed, all but the simplest animals display considerable variance in social behavior
between individuals, as well as in the same individuals interacting repeatedly (Tinbergen 1951;
Ferguson et al. 2001; Stowers et al. 2002; Olveczky
et al. 2005; Fortune et al. 2011). Variance in social
behavior has both external (sensory environment)
and internal (experience, neuroendocrines, epigenetic
effects, or chance) sources. For example, the
chemosensory-dependent memories underlying the
Bruce effect induce a pregnancy block in mice exposed to an unfamiliar male (Bruce 1959). Epigenetic
mechanisms controlling gene expression translate differences in parental care into changes in social behavior later in life (Meaney et al. 1996). In the cases
above, variability in behavior may be amplified by
the complexity inherent in natural social interactions.
Behavioral variability is even seen in isogenic animals
raised under as similar conditions as possible. The
degree of behavioral variability observed in a population of animals can be different depending on the
particular genetic strain, suggesting that behavioral
variability is influenced by genetic factors in a nondeterministic manner (Kain et al. 2012). Such variability represents both a challenge and an asset for
understanding social behavior as the function of
neural circuits.
Sensory cues that promote
social behavior
The external environment is teeming with sensory
information that could be used to guide social behavior. While not all sensory stimuli are important
for social behavior, the array of social cues that
impart some effect on social behavior is diverse
(Insel and Fernald 2004). Specific sensory cues dedicated to social behavior are used to distinguish the
sex, status, and health of individuals within the same
species (Ben-Shaul et al. 2010; Wang et al. 2011;
Boillat et al. 2015). For example, the visual detection
of a red-colored abdomen on stickleback fish, typical
of breeding males, directly elicits aggression from
potential competitors (Tinbergen 1951). Similar sensory cues are employed for social behaviors in diverse species, but the cues and sensory modalities
are unique for every species. The most essential
cues known for guiding reproductive, parental, and
aggressive behaviors in rodents are chemosensory
signals (Chamero et al. 2007; Nodari et al. 2008;
Haga et al. 2010; Roberts et al. 2010), and a mechanistic dissection of social behavior in rodents begins
with the chemical senses (Dulac and Wagner 2006;
Martinez-Marcos 2009).
Multiple chemosensory systems, including the
main olfactory and vomeronasal systems, work in
concert to detect salient chemical stimuli and guide
adaptive behavioral responses in rodents. The vomeronasal system is classically associated with pheromones, a term that indicates secreted chemicals that
‘‘release’’ or ‘‘prime’’ a specific reaction in another
individual of the same species (Karlson and Luscher
1959). Indeed, mice with a genetically silenced vomeronasal organ (VNO) display dramatic changes in
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mating, aggressive, and parental behaviors (Leypold
et al. 2002; Stowers et al. 2002; Kimchi et al. 2007;
Wu et al. 2014). Changes in social behavior associated with dysfunction of the VNO generally represent a loss of specificity for the behavior itself as
opposed to a failure to display social behaviors in
general (Stowers et al. 2002). Indeed, volatile odors
detected through the main olfactory system can
maintain social preferences even in the absence of
VNO function (Keller et al. 2009). Recent evidence
indicates that genetic strategies for silencing VNO
sensory function (Leypold et al. 2002; Stowers et al.
2002; Kimchi et al. 2007; Wu et al. 2014) also silence
a small fraction of MOE sensory neurons (Omura
and Mombaerts 2014). Taken together, these studies
indicate that VNO-mediated sensory cues act in coordinated fashion with other sensory signals to facilitate appropriate behavioral outputs dependent on
multiple sensory modalities. The integration of internal and external signals guiding social behavior is a
complex process that is achieved through successive
stages of neural processing.
The cooperative action of VNO and main olfactory epithelium (MOE)-mediated sensory cues represents the clearest source of sensory integration
underlying social behavior in rodents. As was observed for the VNO, experiments disrupting main
olfactory function demonstrate an essential role in
social behavior (Mandiyan et al. 2005). The overlap
between specific social behaviors influenced by the
VNO versus MOE is extensive (Stowers et al. 2002;
Mandiyan et al. 2005; Kang et al. 2009; Korzan et al.
2013), but each system contributes uniquely to social
behavior. On a mechanistic level, the sensory cues
that activate VNO sensory neurons tend to be
larger non-volatile chemicals (Chamero et al. 2007;
Nodari et al. 2008), while the MOE responds more
strongly to volatile cues (Kay and Laurent 1999;
Albeanu et al. 2008). However, this distinction is
not absolute as many volatile chemicals can be solubilized and are therefore candidates to be detected
by either the VNO or MOE.
Behavioral differences resulting from dysfunction
of VNO versus MOE support a more significant difference in the respective contribution of each sensory
system to social behavior. The main olfactory system
exerts wide-ranging influences on virtually all behaviors (social and nonsocial; Kaupp 2010) of rodents.
In contrast, the VNO appears specialized for social
and defensive behavior (Luo et al. 2003; Nodari et al.
2008; Samuelsen and Meredith 2009; Isogai et al.
2011). Within the domain of social behavior the
MOE is more often required for initiating social behavior (Mandiyan et al. 2005), while the VNO
J. F. Bergan
provides individual specificity by detecting sensory
cues required for the discrimination of sex, health,
and social status (Stowers et al. 2002; Ben-Shaul
et al. 2010; Roberts et al. 2010; Boillat et al. 2015).
Detection of chemosensory stimuli both by the
olfactory and the vomeronasal systems begins with
binding between specific chemicals and receptors expressed on the surface of sensory neurons. A given
sensory neuron in the MOE expresses only a single
type of receptor from a large family of olfactory sensory receptors (Buck and Axel 1991). This ‘‘one
receptor’’-to-‘‘one neuron’’ relationship also characterizes the VNO, in which each sensory neuron
expresses a single member of the hundreds of possible vomeronasal receptors (VRs; Dulac and Axel
1995). Accordingly, the activity of each sensory
neuron conveys the information provided by a
single sensory receptor. While there is limited evidence for variability in the second-order mitral
cells of the main olfactory bulb (Dhawale et al.
2010), the principle feature of the activity of the
main olfactory bulb is uniform activation of distinct
glomeruli (Bozza et al. 2004; Soucy et al. 2009).
Unlike the main olfactory system, dendrites of
mitral cells of the accessory olfactory bulb (AOB)
receive feed-forward information regarding social
and defensive stimuli likely derived from multiple
VRs (Wagner et al. 2006; Ben-Shaul et al. 2010).
This difference in coding logic suggests that AOB
neurons integrate complementary sensory information from multiple receptors (Wagner et al. 2006).
Recordings from AOB projection neurons exhibit
both specific sensory responses and sensory responses
to divergent sensory cues, the latter of which has
been taken as evidence for functional integration of
multiple receptor channels occurring immediately in
the AOB (Ben-Shaul et al. 2010; Bergan et al. 2014).
Another possible interpretation of complex AOB sensory responses is that they are inherited from VNO
sensory neurons that respond to multiple sensory
stimuli (Del Punta et al. 2002; Meeks et al. 2010).
Regardless, a deeper understanding of the role for
integration between sensory receptors requires first
knowing what information is conveyed by individual
receptors.
Chemical cues mediating social behavior in rodents include complex chemical mixtures emitted
in sweat, urine, and tears. Cognate ligands have
only been established for a small fraction of chemosensory receptors at present; however, the relationships between chemosensory receptors and socially
relevant ligands are rapidly becoming clear
(Novotny 2003; Benton et al. 2007; Chamero et al.
2007; Nodari et al. 2008; Haga et al. 2010; Isogai
Neural computation and neuromodulation
et al. 2011). A variety of active chemosensory compounds were identified by separating stimuli into
their constitutive parts and assaying the capacity of
each component to activate sensory neurons (Lin
et al. 2005; Nodari et al. 2008; Leinders-Zufall
et al. 2009; Isogai et al. 2011). The discovered ligands
are heterogeneous in their chemical properties, size,
and function. For example, a small protein cleverly
named ‘‘darcin’’ after the irresistible protagonist of
Jane Austen’s ‘‘Pride and Prejudice’’ is innately
attractive to female mice causing them to carefully
investigate darcin when presented alone, and to
prefer stimuli with added darcin (Roberts et al.
2010). In addition, an array of sulfated steroids
with diverse physiological functions was identified
as primary contributors to vomeronasal activation
by stimuli from females (Nodari et al. 2008). These
identified ligands join the likes of volatile urinary
compounds, major urinary proteins, MHC peptides,
and exocrine gland-secreting peptides as early components in a long process of elucidating the molecular players required for social behavior in rodents
(Lin et al. 2005; Chamero et al. 2007; Leinders-Zufall
et al. 2009; Haga et al. 2010).
The continued de-orphaning of chemosensory receptors provides a foundation for understanding the
neural logic behind social behavior. However, discerning the chemical messengers mediating social behavior
represents only the first step in understanding chemosensory-guided behavior, and it is equally important
to understand how neural circuits integrate the sensory responses that these chemicals induce.
Chemosensory stimuli are typically detected by multiple receptors and receptors are typically activated by
multiple stimuli (Soucy et al. 2009; Meeks et al. 2010).
Therefore, the combinatorial pattern of activation of
multiple sensory neurons is almost certainly required
to perceive, identify, and react to chemosensory stimuli in both the main olfactory and vomeronasal systems (Laurent 1997; Meeks et al. 2010). Multiple
senses and sensory signals are required to reliably
elicit social behaviors, and these channels of information must be integrated within the context of a fluctuating internal environment. In the case of
chemosensory systems the integration of these diverse
signals occurs through projections to an extensive network of regions of the brain often referred to as the
‘‘social behavior network’’ (SBN) (Newman 1999).
Central control and integration of
social behavior
Utilizing techniques ranging from focal lesions
(Dicks et al. 1969), to reversible inactivation
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(Pereira and Morrell 2011), to analyses of the expression of immediate early genes (Baum and Everitt
1992; Samuelsen and Meredith 2009), researchers
have consistently identified regions of the brain
that are of central importance for social behaviors
(Kruk et al. 1983; Ferris et al. 1990; Lonstein and
Stern 1997; Lin et al. 2011). These experiments consistently identify a network of sub-cortical regions
required for social behavior, including behavioral
centers of the hypothalamus, the medial amygdala,
the lateral septum, and the bed nucleus of the stria
terminalis (Newman 1999; Fig. 1). Patterned neural
activity distributed across many brain regions in this
‘‘SBN’’, in accord with diverse input from cortical
regions such as the prefrontal cortex, is essential
for an animal’s ability to respond to social stimuli
with suitable behaviors (Newman 1999; Petrovich
et al. 2001; Brecht and Freiwald 2012). The remarkable conservation of gene-expression profiles in SBN
nuclei suggests that core SBN functions are conserved across species and throughout the course of
evolution (O’Connell and Hofmann 2012).
Organization of circuits in the SBN indicates that
neurons active in the context of one social behavior
are frequently coupled both by anatomy and by
function to neurons important for vastly different
behaviors (Choi et al. 2005). For example, the posterior dorsal nucleus of the medial amygdala
(MeApd) responds strongly to reproductive stimuli
and the posterior ventral nucleus (MeApv) responds
strongly to defensive stimuli (Kang et al. 2006;
Samuelsen and Meredith 2009; Bergan et al. 2014).
Despite clear differences in sensory responses and
behavioral impact, MeApd and MeApv neurons are
heavily interconnected (Petrovich et al. 2001).
Moreover, the distinction of sensory function between MeApd and MeApv is not clear-cut, but
rather, is characterized by quantitative differences
in the frequency of neural responses to defensive
versus reproductive stimuli (Choi et al. 2005;
Samuelsen and Meredith 2009; Bergan et al. 2014).
Therefore, it is possible that specific behaviors rely
on a population of neurons with diverse sensory responses for their execution or that neurons controlling specific behaviors are distributed across multiple
regions of the brain. Of course, these options are not
mutually exclusive as diverse neurons in multiple regions are very likely to contribute to overlapping
behaviors.
The connection between reproductive and aggression-inducing neurons in MeA is consistent with
behavioral studies demonstrating the close
relationship between territorial aggression and reproductive behavior (Tinbergen 1951; Anderson 2012).
272
J. F. Bergan
Fig. 1 Cell-type specific circuitry of the SBN. (A) Schematic of SBN regions and anatomical connections highlighting the interconnected
nature of neural circuits mediating social behavior (AOB: accessory olfactory bulb; MOB: main olfactory bulb; MeA: medial amygdala;
BNST: bed nucleus of the stria terminalis; PMCo: posteromedial cortical amygdala; LS: lateral septum; Hyp: hypothalamus). Major
anatomical connections are indicated by arrows, although many additional connections exist. (B) Five hypothetical populations of
genetically defined neurons (A–D) are illustrated for a single node in the SBN. The genetic heterogeneity is undoubtedly greater than
this for any SBN region. In this diagram, population A has been infected with viral tracers, allowing identification of neural populations
immediately presynaptic to population A. Inputs to populations B–D will not be labeled in such experiments unless these neurons also
project to population A.
For example, a defining component of maternal behavior in mammals is increased aggressive behavior
of mothers toward intruding animals (Erskine et al.
1978; Numan and Insel 2003). Additionally, heavy
predation suppresses breeding in mammals, thereby
demonstrating an additional link between defensive
and reproductive behaviors (Ruxton and Lima 1997).
In these cases, coordination of multiple social behaviors provides an apparent survival benefit: increased
aggression in mothers protects pups from potential
threats and suppressing reproduction during times of
extreme predation conserves resources for future reproduction when natural predator/prey cycles are
more favorable. Such flexibility in social behavior
allows animals to adapt to requirements in the immediate environment, and likely represents a powerful selective pressure toward the development of
heavily integrated neural circuits for social behavior.
Classical anatomical tracing techniques beautifully
defined the connectivity of the SBN in broad strokes
(Petrovich et al. 2001). However, the diversity of
neurons and neural connections in the mammalian
brain, distinguished separately by geometry, anatomy, connectivity, function, or genetics, impart it
with unequaled complexity. Given this complexity,
a wiring diagram that incorporates synaptic connectivity from defined populations of neurons is
necessary to further our understanding of the circuits
mediating social behavior. Genetically specific strategies for the tracing of circuits offer sensitive and reliable techniques for identifying brain-wide inputs to
defined populations of cells (Watabe-Uchida et al.
2012; Rothermel et al. 2013). Therefore, it is now
possible to separately identify the inputs arriving at
genetically and/or anatomically distinct neural populations. Given the remarkable diversity of cell types
throughout the SBN, the development of conditional
rabies variants capable of fluorescently labeling presynaptic neurons from genetically targeted populations of ‘‘starter’’ cells is particularly exciting
(Wickersham et al. 2007). Techniques such as these
enable the creation of a brain-wide catalog of neural
circuits that incorporates cell-type specific connectivity at the level of a single neuron. When combined
with advances in histology and rapid imaging, a
complete cell-specific map of the SBN connectivity
is within reach in the near future (Chung et al. 2013;
Kim et al. 2013).
Permanent sexual dimorphisms in social
behavior and in neural circuits
The single defining feature of social behavior is likely
the fact that the same sensory stimulus can elicit
diametrically opposed behaviors when presented to
different animals.
Several pioneering studies independently discovered the central role of sex-steroids for social behavior, and revealed a critical period during perinatal
development during which sex steroids pattern sexually dimorphic behaviors (Steinach et al. 1936;
Phoenix et al. 1959; McCarthy 2008; Arnold 2009).
These studies formed the foundation of the ‘‘organization/activation’’ hypothesis which states that sexsteroids act near the time of birth to organize
Neural computation and neuromodulation
sexually dimorphic neural circuits (McCarthy 2008).
The reciprocal interaction between endocrine secretions in non-neural tissue and the function of neural
circuits mediating behavior remains a central theme
of behavioral neuroscience to this day.
The organization/activation hypothesis correctly
stresses the essential contribution of biology to the
development of complex individual patterns of social
behavior (Colapinto 2000) Thus, sexually dimorphic
social behaviors can be attributed to sex-specific patterns of neural apoptosis and arborization during
development (Goy and McEwen 1980; MacLusky
and Naftolin 1981; Roselli and Resko 1993; Morris
et al. 2004; Gotsiridz et al. 2007; Wu et al. 2009;
Cooke 2011). While the relative contribution of
nature and nurture are certain to be complex and
interwoven in humans, the sexual dimorphisms in
behavior and neural function uncovered using
model systems are now becoming appreciated as essential considerations for neuroscience and health
research (McCarthy et al. 2012).
The receptors and enzymes associated with sex
steroids are expressed prominently in regions of the
brain important for social behavior (Simerly et al.
1990; Quadros et al. 2002; Wu et al. 2009). In regions such as the medial amygdala, testosterone promotes cell-survival via its conversion to estrogen by
aromatase (Morris et al. 2008). The same hormonal
spike induces apoptosis in the anteroventral periventricular nucleus, thereby generating a nucleus that is
significantly larger in females than in males (Bodo
et al. 2006). Importantly, sexual dimorphisms in cell
number and morphology lead to dramatic differences
in function such that the representation of sensory
stimuli within SBN nuclei is fundamentally different
in males versus females (Samuelsen and Meredith
2009; Bergan et al. 2014) and young versus old animals (Bergan et al. 2014). For example, responses to
conspecific sensory cues are comparable in medial
amygdala neurons of juvenile animals regardless of
gender, but become biased toward opposite-sex stimuli in adult mice (Bergan et al. 2014). Similarly, the
behavioral changes resulting from sexually dimorphic
neural circuit development are often not noticed
while levels of sex steroids remain low during adolescence (Phoenix et al. 1959).
Rapid modulation of neural activity by
hormones and neuropeptides
Dramatic changes in number, morphology, and connectivity of neurons are typically restricted to early
developmental periods; however, neural circuits
remain responsive to steroids throughout life.
273
Starting at puberty, the increased levels of circulating
sex steroids reversibly ‘‘activate’’ functions of neural
circuits that drive social behavior. For example, estradiol directly modulates sensory responses in the
vomeronasal sensory epithelium, suggesting that the
earliest stages of sensory coding of social cues may be
dependent on the endocrine status of the animal
(Cherian et al. 2014). At the molecular level, actions
routed through nuclear steroid receptors can dramatically alter transcriptional regulation and lead to significant changes in cellular function. Howeer, since
traditional nuclear signaling pathways of steroids require new protein synthesis, the effects mediated by
these mechanisms require hours to days for action
(Blaustein 2012).
Sex steroid signaling is concentrated in regions of
the brains of mammals and birds essential for social
behavior, suggesting that locally synthesized estrogens may rapidly influence circuits mediating social
behavior (Balthazart 1991; Blaustein et al. 1992;
Lauber and Lichtensteiger 1994; Naftolin et al.
1996; Wagner and Morrell 1997; Saldanha et al.
2000; Bakker et al. 2002; Balthazart and Ball 2006;
Remage-Healey and Bass 2006; Ishii et al. 2007;
Wooley 2007; Remage-Healey et al. 2008; Wu et al.
2009). Recent evidence from songbirds demonstrates
that estrogens can be produced locally in the brain
and that the concentration of estrogens in the brain
fluctuates during social behavior (Remage-Healey
et al. 2008; Saldanha et al. 2011). This raises the
exciting possibility that aromatase activity and estrogen signaling are controlled by neural activity.
Synaptic release of estrogens provides potential for
rapid modulation of neural activity by steroids with
spatial precision at the level of neurons (Balthazart
and Ball 2006; Remage-Healey et al. 2008, 2011;
Cornil et al. 2006, 2012; Nomoto and Lima 2015).
The importance of rapid modulation of estrogens is
now well established in birds. While there is clear
precedent for rapid action of estrogens in the mammalian brain (Wooley 1999; Cherian et al. 2014), the
role of brain-derived estrogens for social behavior in
mammals remains poorly understood and should be
explored further.
Neuromodulation is a defining characteristic of
SBN function in mammals with estradiol, oxytocin,
vasopressin, dopamine, serotonin, glucocorticoids,
kisspeptin, gonadotropin-releasing hormone, and
many more neuromodulators exerting profound effects on behavior through actions in the SBN
(Fig. 2). Neuroactive peptides act rapidly on multiple
spatial scales (McCann et al. 2002; Stoop 2012) and
regulate the translation of sensory information into
behavior through these actions, more often than not
274
J. F. Bergan
Fig. 2 Mechanisms of short-term and long-term modulation of social behavior. Neural computations in the SBN of a female (left) and a
male (right) guide adaptive social behaviors and endocrine responses based on sensory input. Genetically defined populations of distinct
neuromodulatory neurons provide valuable access points for the genetic dissection of circuit function. SBN nuclei are hubs both of
neuromodulation and of the action of steroid hormones (which are easily accessible using traditional techniques in endocrinology).
Neuromodulation and the actions of steroid hormones in the SBD are effective means of producing multiple behavioral outputs in
either sex. However, the patterns of social behavior in male and female mice (arrows) remain distinctive.
arriving on a variant of circuit function sensitively
tuned for an animal’s current environment, experience, and neuroendocrinal state. Of course, the influence of neuromodulators on SBN function also
depends on sexual dimorphisms in the architecture
of the circuit, as organizational effects on sites of
SBN neuromodulation are clear (Bodo et al. 2006;
Wu et al. 2009).
Two of the most well-studied neuromodulators
influencing SBN function are the evolutionarily conserved neurohypophysial hormones oxytocin and vasopressin, first isolated in 1953 (du Vigneaud et al.
1953). Oxytocin and vasopressin differ in only two
amino acids, but have profoundly different influences
on behavior and circuit function (Huber et al. 2005).
These small peptides have now been associated with
a tremendous range of behavioral, physiological, and
neuroendocrine functions. For example, oxytocin
rapidly activates MeA neurons (Terenzi and Ingram
2005), promotes social behavior (Nishimori et al.
1996; Macbeth et al. 2010; see Stoop 2012), and reduces fear-induced behaviors (Knobloch et al. 2012).
One recent study demonstrated that social rewards
mediated by oxytocin required the oxytocindependent enhancement of long-term depression at
serotonergic synapses in the nucleus accumbens
(Dölen et al. 2013). Yet, we still know relatively
little regarding the broad actions that vasopressin
or oxytocin exert on the moment-to-moment function of social circuits (Terenzi and Ingram 2005;
Owen et al. 2013).
The central position of the SBN offers an effective
site for neuromodulation to sculpt social behavior
(Ferguson et al. 2001; Binns and Brennan 2005
Veenema et al. 2010; Martinez et al. 2013). Indeed,
oxytocin knockout mice exhibit striking deficits in
social recognition that are rescued by local infusion
of oxytocin in the MeA (Ferguson et al. 2001). This
remarkable finding simultaneously illustrates the
impact of oxytocin on MeA function and the
275
Neural computation and neuromodulation
importance of MeA activity in social recognition.
The diversity of neurotransmitters and neuromodulators that act in the SBN is remarkable (Lein et al.
2007), and this complexity of neurotransmission suggests SBN circuits are capable of diverse functions
that depend on internal hormonal and neuromodulatory states. The profound behavioral influences of
these neuromodulators have been studied extensively
and in many cases their influence is exerted through
the SBN; however, we know comparatively little regarding the changes in circuit function imparted by
these neuromodulators.
Circuit dissection of social behavior
The elegant work performed in small neural circuits
with countable numbers of neurons provides a useful
template for understanding how we might approach
the function of SBN circuits. The complex neural
dynamics found in highly streamlined nervous systems (e.g., the Caenorhabditis elegans nervous system
and the stomatagastric-ganglion of lobster) is remarkable (Marder and Goaillard 2006; Marder and
Bucher 2007; Bargmann 2012; Gordus et al. 2015).
Given the devotion required to understand these
small neural circuits, one might be inclined to give
up hope for a mechanistic understanding of mammalian social behavior. In fact, the larger number of
neurons in the SBN could provide some benefit to
researchers in that we are able to rely on statistical
descriptions for first-order questions. Still, deciphering how the SBN detects, processes, and responds to
sensory stimuli would be complex if the system were
static. In light of extensive and diverse neuromodulation, this problem is truly daunting.
Progress in research on C. elegans and Drosophila
demonstrates that the first priority in understanding
the function of circuits relies on elucidating a circuit
diagram with sufficient resolution to address functional questions (White et al. 1986; Kohl et al. 2013).
The coarse anatomy of the SBN, including an understanding of how circuits differ among individuals
(see Petrovich et al. 2001) is well established. Tools
for dramatically refining these maps, with attention
to specific cell types, long-range connectivity, and
synaptic contacts are now readily available
(Wickersham et al. 2007; Watabe-Uchida et al.
2012; Rothermel et al. 2013). Towards this goal,
the diversity of gene-expression profiles in SBN neurons provides tremendous genetic access to investigate circuit function (Xu et al. 2012). Experiments
like these will help elucidate the synaptic connections
and circuit mechanisms that enable neuromodulators
to transform sensorimotor processing of social information in the SBN throughout an animal’s life.
A refined map of SBN neuroanatomy will facilitate
our ability to causally relate genetically and anatomically defined neural populations to specific neural
computations underlying social behavior, a process
that is already well underway. For example, neurons
in the ventrolateral subdivision of the ventromedial
hypothalamus (VMHvl) of male mice are activated
by social interactions with another male and optogenetic activation of these neurons elicits aggressive
behavior even in the absence of another animal.
Activation and inactivation of VMHvl neurons
exert bidirectional control on attack behavior, demonstrating both the necessity and the sufficiency of
VMHvl neurons for producing inter-male aggression
(Lin et al. 2011). A separate hypothalamic nucleus,
the medial preoptic area (MPOA), is consistently implicated in the regulation of parental behavior
(Kuroda et al. 2011), and optogenetic and viral manipulation of the MPOA identified a specific subset
of galanin-expressing neurons essential for suppressing pup-directed aggression and promoting the
grooming of pups (Wu et al. 2014). Taken together,
these results highlight the capacity of discrete neural
populations to reliably produce specific social behaviors in mammals. At the same time, these experimental approaches provide a relatively straightforward
way to isolate the function of carefully defined
neural populations within the context of normal
functioning of circuits.
Conclusion
Strategies for causally relating neural activity to distinct behaviors require effective techniques to monitor and control the activity of genetically defined
populations of neurons, and to relate these findings
to changes in behavior (Lin et al. 2011; Wang et al.
2011; Cohen et al. 2012; Smear et al. 2013; Wu et al.
2014; Hong et al. 2014; Packer et al. 2015). Recent
technical advances demonstrate that a mechanistic
study of SBN function, with respect to individual
differences, hormonal effects, and rapid neuromodulation is rapidly becoming feasible. Deciphering the
neural computations performed by distinct neurons
at all levels of the SBN has clear implications for
understanding social behavior in both health and
dysfunction. Positive social interactions possess a remarkable capacity to promote health, and social isolation has disastrous consequences for health,
including learning deficits, immune dysfunction,
and even mortality (Holt-Lunstad et al. 2010;
Cacioppo and Cacioppo 2012). Given the important
276
J. F. Bergan
relationships between social behavior and health,
broadly defined, deciphering circuits’ processes that
refine adaptive social behavior this basic could provide considerable benefits for medicine.
Acknowledgments
The authors would like to thank E. Stewart, L.
Remage-Healey, and A. Farrar for help in preparing
this manuscript. I openly acknowledge that many
valuable lines of research were omitted due to the
narrow scope of this review in comparison to the
breadth of relevant research. Most of all, I thank R.
Calisi-Rodrı́guez and C. Saldanha for organizing this
symposium and extending the opportunity for me to
take part in it.
Funding
J.F.B. was supported by
Massachusetts at Amherst.
the
University
of
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