Integrative and Comparative Biology Advance Access published June 18, 2015

Integrative and Comparative Biology Integrative and Comparative Biology, pp. 1–13 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

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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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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.

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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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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

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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

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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

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Central control and integration of social behavior Utilizing techniques ranging from focal lesions (Dicks et al. 1969), to reversible inactivation

(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).

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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).

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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

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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.

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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.

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

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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).

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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 (Do¨len 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

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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.

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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

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

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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

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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

Funding J.F.B. was supported by Massachusetts at Amherst.

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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-Rodrı´guez and C. Saldanha for organizing this symposium and extending the opportunity for me to take part in it.

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