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The motivation to engage in social behaviors is influenced by past experience and internal state, but also depends on the behavior of other animals. Across species, the oxytocin (Oxt) and vasopressin (Avp) systems have consistently been linked to the modulation of motivated social behaviors. However, how they interact with other systems, such as the mesolimbic dopamine system, remains understudied. Further, while the neurobiological mechanisms that regulate prosocial/cooperative behaviors have been extensively examined, far less is understood about competitive behaviors, particularly in females. In this chapter, we highlight the specific contributions of Oxt and Avp to several cooperative and competitive behaviors and discuss their relevance to the concept of social motivation across species, including humans. Further, we discuss the implications for neuropsychiatric diseases and suggest future areas of investigation.
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Book Title
Series Title
Chapter Title Oxytocin, Vasopressin, and the Motivational Forces that Drive Social Behaviors
Copyright Year 2015
Copyright HolderName Springer International Publishing Switzerland
Author Family Name Caldwell
Given Name Heather K.
Division Laboratory of Neuroendocrinology and Behavior, Department of Biological
Organization Kent State University
Address Kent, OH, USA
Division School of Biomedical Sciences
Organization Kent State University
Address Kent, OH, 44242, USA
Corresponding Author Family Name Elliott Albers
Given Name H.
Division Center for Behavioral Neuroscience, Neuroscience Institute
Organization Georgia State University
Address Atlanta, GA, 30302, USA
Abstract The motivation to engage in social behaviors is influenced by past experience and internal state, but also
depends on the behavior of other animals. Across species, the oxytocin (Oxt) and vasopressin (Avp)
systems have consistently been linked to the modulation of motivated social behaviors. However, how they
interact with other systems, such as the mesolimbic dopamine system, remains understudied. Further,
while the neurobiological mechanisms that regulate prosocial/cooperative behaviors have been extensively
examined, far less is understood about competitive behaviors, particularly in females. In this chapter, we
highlight the specific contributions of Oxt and Avp to several cooperative and competitive behaviors and
discuss their relevance to the concept of social motivation across species, including humans. Further, we
discuss the implications for neuropsychiatric diseases and suggest future areas of investigation.
Keywords (separated by '-') Aggression - Competitive behavior - Cooperative behavior - Dopamine - Epigenetics - Neuropsychiatric
disorders - Oxytocin receptor - Pair bonding - Social behavior network - Social communication - Social
recognition memory - Vasopressin 1a receptor - Vasopressin 1b receptor
1Oxytocin, Vasopressin,
2and the Motivational Forces that Drive
3Social Behaviors
4Heather K. Caldwell and H. Elliott Albers
5Abstract The motivation to engage in social behaviors is inuenced by past
6experience and internal state, but also depends on the behavior of other animals.
7Across species, the oxytocin (Oxt) and vasopressin (Avp) systems have consistently
8been linked to the modulation of motivated social behaviors. However, how they
9interact with other systems, such as the mesolimbic dopamine system, remains
10 understudied. Further, while the neurobiological mechanisms that regulate
11 prosocial/cooperative behaviors have been extensively examined, far less is
12 understood about competitive behaviors, particularly in females. In this chapter, we
13 highlight the specic contributions of Oxt and Avp to several cooperative and
14 competitive behaviors and discuss their relevance to the concept of social moti-
15 vation across species, including humans. Further, we discuss the implications for
16 neuropsychiatric diseases and suggest future areas of investigation.
17 Keywords Aggression Competitive behavior Cooperative behavior
18 Dopamine Epigenetics Neuropsychiatric disorders Oxytocin receptor Pair
19 bonding Social behavior network Social communication Social recognition
20 memory Vasopressin 1a receptor Vasopressin 1b receptor
H.K. Caldwell
Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences,
Kent State University, Kent, OH, USA
H.K. Caldwell
School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
H. Elliott Albers (&)
Center for Behavioral Neuroscience, Neuroscience Institute, Georgia State University,
Atlanta, GA 30302, USA
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Curr Topics Behav Neurosci
DOI 10.1007/7854_2015_390
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21 Contents
22 1 Overview..................................................................................................................................
23 2 Origins and Mechanisms of Motivated Social Behaviors ......................................................
24 2.1 Cooperative and Competitive Behaviors........................................................................
25 2.2 Brain Areas that Regulate Cooperative and Competitive Behaviors.............................
26 3 Neuroendocrine Modulation of Social Behaviors...................................................................
27 3.1 The Oxytocin System .....................................................................................................
28 3.2 The Vasopressin System.................................................................................................
29 3.3 Signaling by Oxytocin and Vasopressin in the Brain....................................................
30 3.4 Epigenetics ......................................................................................................................
31 4 Oxytocin/Vasopressin and Cooperative and Competitive Behaviors:
32 Social Memory, Social Interactions, and Aggression.............................................................
33 4.1 Social Recognition Memory ...........................................................................................
34 4.2 Cooperative Behavior......................................................................................................
35 4.3 Competitive Behavior .....................................................................................................
36 4.4 Social Communication ....................................................................................................
37 4.5 Interactions Between Oxytocin, Vasopressin, and Dopamine
38 in the Regulation of Cooperation/Competition ..............................................................
39 5 Cooperativity and Competitiveness in Humans ......................................................................
40 5.1 Nonapeptides and Social Cognition in Healthy Humans...............................................
41 5.2 Oxytocin, Vasopressin, and the Mesolimbic Dopamine System...................................
42 6 Implications for Neuropsychiatric Disorders...........................................................................
43 6.1 Autism Spectrum Disorder .............................................................................................
44 6.2 Personality Disorder........................................................................................................
45 6.3 Schizophrenia..................................................................................................................
46 6.4 Posttraumatic Stress Disorder .........................................................................................
47 7 Conclusions and Future Directions .........................................................................................
48 References ......................................................................................................................................
50 1 Overview
51 Motivation is a dominant construct in psychology, psychiatry, and neuroscience, as
52 trying to understand why animals, including humans, do what they do is at the core
53 of these disciplines. Although motivation can be dened in a variety of ways, a key
54 component is that motivated behaviors are directed toward (approach) or away
55 (avoidance) from a stimulus. Motivation also contains emotional elements with
56 approach linked to positive hedonic valence and avoidance linked to negative
57 valence. This review focuses on social motivation, which, like other forms of
58 motivation, is inuenced by past experience and an individuals internal state.
59 Social motivation is, however, intrinsically more dynamic and less predictable
60 because the drive to approach or avoid another individual(s) depends in large
61 measure on how that individual behaves.
62 Recent studies of the neurobiology of social behavior have often characterized
63 social behavior as having a positive valence, often described as prosocial or af-
64 liative interactions (e.g., pair bonding, maternal behavior), or as having a negative
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65 valence, described as negative social interactions (e.g., aggression, territoriality).
66 Although such a dichotomy is convenient and can have descriptive value, a closer
67 look at these behaviors suggests that social motivation is more complex. For
68 example, while the formation of a pair bond in a species such as prairie voles has
69 positive behavioral elements, such as highly afliative behaviors directed toward a
70 partner, it is also associated with mating guarding, in which males display selective
71 aggression toward other voles. Thus, in the context of a pair bond, simply ascribing
72 positive valence to the afliative behaviors and negative valence to aggression is an
73 oversimplication. Further, all aggressive behaviors are not the same, nor are the
74 effects on the players. The fact is that winning is rewarding (Martinez et al. 1995;
75 Meisel and Joppa 1994), and there is even the possibility that losing can be
76 rewarding as long as the defeat is not too severe (Gil et al. 2013). Therefore,
77 assigning hedonic valence to social behaviors (e.g., aggressive behavior) or to
78 mating strategies (e.g., pair bonding) must be done with great care, particularly
79 when linking approach or avoidance with the neural mechanisms underlying
80 motivation.
81 Historically, investigations into the neurobiology of motivation have focused
82 primarily on the mesolimbic dopamine (DA) system where DA neurons were
83 thought of as rewardneurons. It has now been recognized that the role of the
84 mesolimbic DA system in hedonic mechanisms is far more complex. Understanding
85 social motivation requires us to expand our studies of the neural mechanisms of
86 motivation beyond this system into the networks that control the expression of
87 social behavior in response to social stimuli. Of the myriad of neurochemical
88 signals that are known to be involved in the modulation of social behaviors, two
89 neuropeptides, oxytocin (Oxt) and vasopressin (Avp), stand out as being critical
90 across species. Because of the vast literature on the role of these two nine-amino
91 acid neuropeptides, or nonapeptides, in regulating social behavior, this chapter will
92 focus on mammalian social behavior and provide examples of the powerful con-
93 tributions of these two neuropeptide systems to cooperative and competitive
94 behaviors.
95 2 Origins and Mechanisms of Motivated Social Behaviors
96 When considering the evolutionary origins of motivated behaviors, most simply
97 put, it all comes down to tness. Animals engage in species-specic behaviors
98 because over evolutionary time these behaviors were either selected for via natural
99 or sexual selection, or occurred through some other mechanism of evolution. In the
100 context of sexual behavior, males are described as ardentand females as
101 choosy,which is reected in their physiology. Males make a lot of sperm and
102 often display behaviors that that will result in the fertilization of as many eggs as
103 possible over their reproductive lifetime. Female mammals on the other hand
104 typically have to invest in the gestation and the care of offspring, so they tend to be
105 more selective about their mates. These differences in selective pressures result in
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106 vastly different behavioral displays between males and females. However, these
107 behavioral differences are not limited to sexual behaviors. For instance, in mam-
108 mals, biparental behavior is scarce, occurring in fewer than 6 % of rodent species
109 and 10 % of all mammals (Kleiman 1977). Thus, a male that engages in parental
110 care does so because the costof not being paternal is too high; for instance,
111 reproductive success may be compromised, but his proximity to the female
112 increases the likelihood that he is the sire of the offspring. There are also sex
113 differences in displays of cooperative and competitive behaviors, with females
114 typically displaying more cooperative behaviors across the lifetime and males
115 displaying more competitive behaviors, particularly during the breeding season.
116 In nature, the diversity in cooperativity and competitiveness observed across
117 animal species is striking. Some animals have social structures that are character-
118 ized by high levels of cooperativity, such as that observed in species that form
119 long-term social bonds such as pair bonds. In other species, high levels of com-
120 petitive behaviors serve to establish and maintain social dominance relationships.
121 Overlaid on the complexity of social life for a given species is a lack of stability, as
122 social behaviors often change over the seasons and over the lifetime. Further, the
123 different behavioral strategies employed by an animal have their particular costs and
124 benets. To explore these costs and benets, we can take a closer look at coop-
125 erative and competitive behaviors.
126 2.1 Cooperative and Competitive Behaviors
127 Cooperative behaviors, associated with afliative behaviors, are thought to have
128 evolved from reproductive and parental behaviors, in turn being permissive for the
129 development of longer-term social bonds (Crews 1997). Competitive behaviors too
130 are important in the formation of social bonds, as intraspecic interactions are
131 universal and often governed by dominance relationships. Some evolutionary
132 advantages to forming social bonds include localization of resources, lower pre-
133 dation due to group aggression, and increased reproductive opportunities
134 (Alexander 1974). Social bonds have been extensively studied in primates and in
135 some instances have been shown to increase evolutionary tness (Silk 2007). In
136 free-ranging baboons, females that have strong social bonds with one another live
137 longer than those who have weaker social bonds (Silk et al. 2009). Even in humans
138 social relationships can have profound effects on an individuals health, including
139 improved mood and a longer life (House et al. 1988; Rodriguez-Laso et al. 2007;
140 Baumeister and Leary 1995).
141 However, being social does have its cost, such as increased susceptibility to dis-
142 ease, parasites, or injury (Alexander 1974; Crews 1997). In order for animals to live in
143 groups, they must be able to tolerate close proximity; thus, keeping levels of
144 aggression in check becomes particularly important. It also requires a memory of the
145 members of the social group, as this allows animals to identify familiar stimuli, which
146 in turn is permissive for adaptive behavioral responses. While many mammalian
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147 species live in groups, some species show shiftsin the nature of their social inter-
148 actions depending on where they are in their breeding cycle. Some species display
149 high levels of afliative behaviors in the non-breeding season, while others increase
150 their intraspecic aggression when resources are scarce (Anacker and Beery 2013).
151 Over the last several decades, investigation of the neural mechanisms underlying
152 social behavior has focused primarily on prosocialbehaviors, rather than com-
153 petitive behaviors. The tremendous progress that has been made in understanding
154 the neural mechanisms underlying phenomena such as maternal behavior and pair
155 bonding has likely contributed to this imbalance. Unfortunately, investigation of
156 more competitive behaviors, such as aggression, has been on the decline for a
157 variety of reasons (see Blanchard et al. 2003). Within studies of competitive
158 behavior, males have been the main experimental subjects, perhaps because of
159 Darwins emphasis on malemale competition and female mate choice in the
160 context of sexual selection (Darwin 1871). More recently, however, the importance
161 of competitive behaviors in females has been recognized. Not only do female
162 mammals compete for resources and mates to achieve reproductive benets, but
163 female competition is widespread in the animal kingdom (Rosvall 2011; Stockley
164 and Bro-Jorgensen 2011; Huchard and Cowlishaw 2011). Females compete for
165 resources such as food, nest sites, and protection using a variety of strategies
166 including intergroup aggression, dominance relationships and territoriality as well
167 as through the inhibition of the reproductive capacity of other females. In many
168 primate species, female aggression is associated with rank and ultimately repro-
169 ductive goals (for review, see Stanyon and Bigoni 2014). As a result, investigation
170 of female competitive behavior is essential to understanding social behavior as a
171 whole as well as its translational implications.
172 In rodents, one reason that there are few data on female competitive behavior is
173 that in commonly studied laboratory species, i.e., rats and mice, females display little
174 or no competitive behavior (Blanchard and Blanchard 2003). This contrasts with
175 what is observed in another laboratory rodent, whose utility as an experimental
176 model continues to increase, Syrian hamsters (Mesoscricetus auratus). Female
177 Syrian hamsters display a range of competitive strategies including the expression of
178 high levels of spontaneous offensive aggression, the rapid formation of robust
179 dominance relationships, and the ability to inhibit the reproductive capacity of other
180 females (Albers et al. 2002; Huck et al. 1988). While there is very little known about
181 the neural mechanisms controlling female offensive aggression in any mammalian
182 species, studies in hamsters have provided a good deal of information about how
183 gonadal hormones inuence female offensive aggression (Albers et al. 2002).
184 High levels of aggressive behaviors, intermale and territorial in particular, are
185 often at their peak with the onset of breeding. Other forms of aggression are closely
186 linked to parental behaviors, thus allowing for the defense of young, mates, food, or
187 territories. Seasonal shifts from high cooperativity/afliative behaviors to compet-
188 itive behaviors are mediated primarily by changes in gonadal steroids, which are
189 often linked to changes in photoperiod, though numerous neurotransmitter/
190 neuropeptides are also involved. In many mammalian species, androgen concen-
191 trations are very high during the breeding season, as they are needed to support
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192 reproductive behaviors as well as the physiology of the gonads. During the
193 non-breeding season, seasonal breeders will often undergo a period of gonadal
194 quiescence, whereby the testes shrink in size and levels of circulating androgens
195 plummet. However, it should be noted that in some species, such as hamsters (also
196 seen in birds), androgens, specically dehydroepiandrosterone (DHEA), produced
197 by the adrenal glands may help to support aggressive behavior during the
198 non-breeding season by serving as a prohormone or neurosteroid for the brain when
199 gonadally derived androgen levels are low (for review, see Soma et al. 2015).
200 2.2 Brain Areas that Regulate Cooperative and Competitive
201 Behaviors
202 The social behavior neural network (SBNN) hypothesis by Newman (1999) pro-
203 poses that a network composed of neural groups or nodesincluding, but not
204 limited to, the extended amygdala, the bed nucleus of the stria terminalis (BNST),
205 lateral septum (LS), periaqueductal gray (PAG), medial preoptic area (MPOA),
206 ventromedial hypothalamus (VMH), and anterior hypothalamus (AH) controls
207 social behavior. Each node within the SBNN meets several criteria: reciprocal
208 connectivity, neurons with gonadal steroid hormone receptors, and having been
209 identied as being important to more than one social behavior. The SBNN
210 hypothesis has gained traction in the eld in recent years (reviewed by Albers 2012,
211 2015; Crews 1997; Goodson and Kingsbury 2013). It represents a more nuanced,
212 and complicated, approach to the understanding of social behavior as it takes the
213 regulation of these behaviors beyond the examination of just a single neuroana-
214 tomical area and supposes that the output of the network is an emergent property.
215 The identication of SBNN for different species is an important next step in
216 understanding the complexity of behavior. While previous approaches have been
217 more simplistic, examining specic neural anatomical areas, single
218 neurotransmitter/neuropeptides, and behaviors, the foundation has now been laid
219 for impactful studies focused on how social behavior emerges from complex neural
220 networks. A large number of different types of motivated social behaviors are
221 thought to be controlled by the SBNN, including offensive and defensive aggres-
222 sion, social recognition memory, parental behavior, and social communication.
223 Importantly, Oxt/Avp and their receptors are found throughout the SBNN and are
224 ideally suited to regulate the expression of social behavior because of their plasticity
225 in response to factors that inuence social behavior (Fig. 1) (reviewed in Kelly and
226 Goodson 2014; Goodson and Kingsbury 2013; Albers 2012,2015; Caldwell et al.
227 2008a; Adkins-Regan 2009; Bosch and Neumann 2012).
228 Motivated behaviors also arise from a network of reciprocally connected brain
229 regions that determine the salience of stimuli, assign motivational value, and initiate
230 appropriate action (reviewed by Love 2014). The ventral tegmental area (VTA) is a
231 key region in this network in that VTA neurons producing DA project to a large
232 number of cortical and limbic structures, forming the foundation underlying the
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233 motivational circuitry. This network plays a critical role in social as well as
234 nonsocial behavior and appears to provide an alerting signal for unexpected stimuli.
235 Within this network, there are distinct groups of DA neurons that determine
236 motivational value, being excited by appetitive stimuli and inhibited by aversive
237 stimuli. Other groups of DA neurons appear to encode motivational salience, but
238 not valence, in that they are excited by the intensity of the stimulus, regardless of
239 whether it is appetitive or aversive (reviewed by Love 2014). See chapters by
240 Bissonette and Roesch, Robinson et al., Redish et al., and Salamone et al. for
241 detailed discussions of these issues.
242 While the SBNN and the mesolimbic DA system are distinct from one another,
243 they are thought to dynamically interact and support decision making in the context
244 of motivated social behaviors (OConnell and Hofmann 2011a,b). OConnell and
245 Hofmann (2011b) have proposed that these two systems should be considered as
Fig. 1 Oxytocin and vasopressin signaling in brain areas important to social motivation. Oxytocin
(Oxtr) and vasopressin receptors (Avprs) are found throughout the structures of the social behavior
neural network (SBNN) and the mesocorticolimbic dopamine (DA) system. Their localization in
these nuclei is critical for oxytocins and vasopressins modulation of socially motivated behaviors
and may serve as the functional connection between the SBNN and DA systems, particularly by
their action in the lateral septum (LS) and extended amygdala, including the bed nucleus of the
stria terminalis (BNST). Other abbreviations: AH anterior hypothalamus; BLA basolateral
amygdala; HIPP hippocampus; MeA medial amygdala; NAcc nucleus accumbens; OB olfactory
bulb; PAG periaqueductal gray; PFC prefrontal cortex; POA preoptic area; VP ventral pallidum;
VTA ventral tegmental area; VMH ventromedial hypothalamus
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246 part of a larger social decision-making network (SDM) that is relatively conserved
247 across species. Across these two systems, there are two neuroanatomical areas, or
248 nodes, of overlapthe LS and the extended amygdalaincluding the BNST.
249 These areas provide the functional connection between the two systems by acting as
250 relays, providing the SBNN with information from the motivational network about
251 the salience of a social stimulus in turn allowing for an appropriate behavioral
252 response. With these concepts in mind, in the following sections, we will discuss
253 the possibility that Oxt and Avp provide critical links between specic elements
254 within the SBNN and the motivational network that contribute to the motivational
255 forces driving social behaviors.
256 3 Neuroendocrine Modulation of Social Behaviors
257 The rst hormones implicated in the regulation of social behaviors were the gonadal
258 steroids (Berthold 1849), since changes in social behaviors are observed following
259 gonadectomy. While the gonadal steroids are important, so too are the evolution-
260 arily ancient Oxt and Avp neuropeptide systems, as well as their non-mammalian
261 homologues. Oxt and Avp are both primarily synthesized in the paraventricular
262 nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Their genes sit
263 in opposite transcriptional direction on the chromosome as the result of the
264 duplication of an ancestral vasotocin gene (Acher and Chauvet 1995; Acher et al.
265 1995) and they are synthesized as part of a larger precursor preprohormone (Hara
266 et al. 1990). Since they are so structurally similar, Oxt and Avp are considered
267 sisterhormones though their actions both peripherally and centrally can differ
268 signicantly from one another. Interestingly, across mammalian species, the roles of
269 Oxt and Avp with regard to cooperative and competitive behaviors tend to be fairly
270 conserved (Caldwell et al. 2008a; Caldwell and Young 3rd 2006; Lee et al. 2009a;
271 Adkins-Regan 2009; Neumann 2008; Veenema and Neumann 2008; Carter et al.
272 2008; Albers 2012,2015).
273 3.1 The Oxytocin System
274 Oxytocin literally meaning sharp childbirthis known for its peripheral actions on
275 the regulation of uterine contraction as well as the facilitation of milk ejection (Dale
276 1906; Ott and Scott 1910). In rats, Oxt is synthesized in larger, magnocellular
277 neurons, of the PVN and SON that project to the posterior pituitary and mediate the
278 aforementioned actions. However, it is Oxt that is synthesized in the smaller,
279 parvocellular neurons of the PVN that project centrally and mediate many of the
280 central actions of Oxt. It should be noted, however, that this compartmentalization
281 of function by magnocellular versus parvocellular neurons is not found in all
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282 species. In Syrian hamsters, magnocellular neurons do not exclusively project to the
283 posterior pituitary and seem to project centrally (Ferris et al. 1992b). Also, in mice
284 and several vole species, there are reports of parvocellular Oxt neurons outside of
285 the PVN (Castel and Morris 1988; Jirikowski et al. 1990; Wang et al. 1996) as well
286 as reports of Oxt collaterals from the SON/PVN to the nucleus accumbens (NAcc)
287 (Ross et al. 2009a).
288 Thus far, only a single Oxt receptor (Oxtr) has been identied, and it is thought
289 to be the primary mechanism for the transduction of the Oxt signal (Kimura et al.
290 1992; Kubota et al. 1996); however, see the section titled Signaling by Oxytocin
291 and Vasopressin in the Brain.The Oxtr is a member of the seven-transmembrane
292 G-protein-coupled receptor family and signals through G
GTP-binding proteins
293 and G
(Ku et al. 1995; Gimpl and Fahrenholz 2001; Zingg and Laporte 2003),
294 which results in the hydrolysis of phosphatidylinositol. The structure and sequence
295 of the Oxtr is similar to the Avp receptors (Gimpl and Fahrenholz 2001). In rats and
296 mice, the Oxtr is most often visualized with receptor autoradiography through the
297 use of a potent and specic
I-labeled antagonist (Kremarik et al. 1993; Veinante
298 and Freund-Mercier 1997). The Oxtr is observed in several areas of the brain,
299 including the hippocampal formation, LS, central amygdala (CeA), olfactory
300 tubercle, NAcc shell, dorsal caudateputamen, BNST, medial amygdala (MeA),
301 and VMH (Kremarik et al. 1993; Veinante and Freund-Mercier 1997; Insel et al.
302 1991), but there are seasonal as well as species- and sex-specic differences.
303 3.2 The Vasopressin System
304 Avp is named for its involvement in the constriction of blood vessels, but is also
305 important to salt and water balance. The peripheral actions of Avp are primarily
306 mediated by the magnocellular neurons of the PVN and SON, which result in Avp
307 release from the posterior pituitary. Centrally, Avp is more widely expressed than
308 Oxt, and its distribution can vary substantially between species. Avp immunore-
309 active (ir) cell bodies are consistently found in several hypothalamic nuclei
310 including the suprachiasmatic nucleus (SCN), PVN, SON as well as in groups of
311 accessary nuclei (Sofroniew 1983). Outside of the hypothalamus, Avp-ir neuronal
312 cell bodies in the BNST and MeA in most rodents so far examined (Sofroniew
313 1985). Interestingly, in Syrian hamsters, neuronal cell bodies containing Avp are
314 absent in the BNST and MeA (Albers et al. 1991). Projections from Avp-producing
315 neurons form a dense vasopressinergic network throughout the brain (Buijs et al.
316 1983,1987; De Vries and Buijs 1983; Sawchenko and Swanson 1982).
317 Avp receptors can be divided into two classes: Avp1 and Avp2 receptors (Avpr1
318 and Avpr2, respectively), both of which are seven-transmembrane
319 G-protein-coupled receptors that are similar in structure to the Oxtr. There are
320 two subtypes of the Avpr1: the Avpr1a and the Avpr1b. Peripherally, the Avpr1a
321 mediates the effects of Avp on vasoconstriction and can be found in the liver,
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322 kidney, platelets, and smooth muscle (Ostrowski et al. 1992; Watters et al. 1998).
323 Centrally, the Avpr1a is found in a variety of brain nuclei (Johnson et al. 1995;
324 Tribollet et al. 1997; Ostrowski et al. 1994; Szot et al. 1994). The Avpr1a is
325 modulated by gonadal hormones and photoperiod in some brain regions, but not
326 others (Johnson et al. 1995; Young et al. 2000; Caldwell and Albers 2004b;
327 Caldwell et al. 2008b). The Avpr1b was originally described in the anterior pitu-
328 itary, where it is prominent on the corticotrophs; however, it can also be found in
329 the brain (Antoni 1984; Lolait et al. 1995). In rats, there is a lack of consensus about
330 the central distribution of the Avpr1b, with some groups reporting Avpr1b in the
331 olfactory bulb, piriform cortical layer II, LS, cerebral cortex, hippocampus, PVN,
332 SCN, cerebellum, and red nucleus (Lolait et al. 1995; Saito et al. 1995; Vaccari
333 et al. 1998; Hernando et al. 2001; Stemmelin et al. 2005). However, a later study by
334 Young and colleagues, which used more stringent conditions for in situ hybrid-
335 ization histochemistry (ISHH), determined that the Avpr1b in rats and mice is more
336 discretely localized with prominent expression in hippocampal eld CA2 pyramidal
337 neurons (Young et al. 2006). The Avpr2 is found in the periphery and is primarily
338 expressed in the kidney; it has not been localized to the brain. Its role in the kidney
339 is to transduce the antidiuretic effects of Avp within the renal collecting ducts
340 (Bankir 2001).
341 3.3 Signaling by Oxytocin and Vasopressin in the Brain
342 Neuropeptides can act in a highly localized manner, similar to classic neurotrans-
343 mitter release at the synapse. However, neuropeptides can also be released in a
344 much more diffuse manner, potentially impacting large numbers of neurons at
345 multiple sites (Engelmann et al. 2000; Landgraf and Neumann 2004; Ludwig 1998;
346 Ludwig and Leng 2006). This diversity of action has long been recognized,
347 although the role of these different types of signaling mechanisms in the control of
348 social behavior is not well understood. Neuropeptides such as Oxt and Avp are
349 usually packaged in large dense-core vesicles (LDCV) that can be found in all areas
350 of neurons including the presynaptic terminal (Jakab et al. 1991; Buijs and Swaab
351 1979; van Leeuwen et al. 1978). Because of the broad distribution of LDCV
352 throughout the cell, neuropeptides can act locally at the synapse or much more
353 broadly when released from non-synaptic regions (e.g., dendrites) in what is called
354 volume transmission. Many factors affect the proles of neuropeptide release such
355 as the size of the neurons from which they are released, the spread of peptide after
356 release, and the timing and intensity of its degradation by peptidases. While the
357 spatial and temporal proles of peptide release via volume transmission are not well
358 understood (Leng and Ludwig 2008), estimates suggest that they may travel as far
359 as 45 mm from their site of release (Engelmann et al. 2000). Magnocellular
360 neurons in the hypothalamus represent the largest pool of nonapeptides in the brain,
361 and there is evidence that they are activated by a variety of stimuli related to social
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362 behavior (Delville et al. 2000). As a result, it seems likely that volume transmission
363 of nonapeptides from these neurons plays an important role in regulating social
364 behavior by acting on nonapeptide receptors throughout the SBNN.
365 Another consideration is that neuropeptides are commonly found in neurons that
366 also produce small molecular weight classical neurotransmitters(e.g., amino
367 acids) (for review, see van den Pol 2012; Albers 2015), thus allowing for their
368 co-release. In most cases, classical neurotransmitters are packaged in small synaptic
369 vesicles (SSVs) in presynaptic terminals. The exocytosis of both SSVs and LDCVs
370 at synapses is Ca
dependent. Because SSVs are usually in closer proximity to the
371 membrane than LDCV, less activity is required for amino acid neurotransmitter
372 release than for neuropeptide release. Therefore, synaptic release of neuropeptides
373 is thought to lag behind that of neurotransmitter release and to require more elec-
374 trical activity. The functional signicance of synaptic co-release of classical neu-
375 rotransmitters and neuropeptides is not known, but dynamic interactions of these
376 signals will likely be important in understanding neuropeptide regulation of
377 behavior (Bamshad et al. 1996). In summary, the ways that Oxt and Avp contribute
378 to neurochemical signaling within the brain are varied and complex. As a result,
379 researchers are left to untangle very intricate pharmacological interactions when
380 they consider the effects of these neuropeptides on behavior.
381 In addition to the diversity seen in the ways that Oxt and Avp can signal, Oxt
382 and Avp also have a high degree of similarity in their structure as well as in the
383 structure of their canonical receptors (Maybauer et al. 2008; Gimpl and Fahrenholz
384 2001; Manning et al. 2012; Song et al. 2014b). Due to these structural similarities,
385 there is a substantial amount of cross talk between these systems (Schorscher-Petcu
386 et al. 2010;Salaetal.2011), with Oxt and Avp having similar afnities for the
387 Oxtr, Avpr1a, and Avpr1b in rats and mice (Manning et al. 2008,2012). For
388 example, both Oxt and Avp can induce communicative behavior in hamsters when
389 injected into the AH by activating Avpr1a rather than the Oxtr (Song et al. 2014b).
390 Similarly, both Oxt and Avp can enhance social recognition and social reward by
391 activating the Oxtr and not the Avpr1a (Song et al. 2014a,b,2015; Ragnauth et al.
392 2004). These data indicate that the effects of Oxt and Avp on different social
393 behaviors can result from their activation of the Avpr1a, the Oxtr, or both.
394 Oxt and Avp receptors are distributed within structures of the mesolimbic DA
395 system, providing a means by which these systems may interact. These areas
396 include the amygdala, the hippocampus, the VTA, the prefrontal cortex (PFC), the
397 NAcc, and the ventral pallidum (VP) (Vaccari et al. 1998; Baskerville and Douglas
398 2010; Curtis et al. 2008). It is also important to remember that there is a great deal
399 of interspecies and interindividual variability in the distribution of Oxt and Avp
400 receptors and that these differences play a major role in producing differences in the
401 expression of social behavior.
402 Recent work in primates has shed some light on the complexity of these systems
403 in a broader evolutionary context, as there are some signicant evolutionary
404 changes in the Oxt and Avp systems. As discussed above, in rats and mice, the Oxtr
405 and Avprs are relatively non-selective for Oxt and Avp; however, in humans, the
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406 OXTR has signicant selectivity for Oxt over Avp. The functional signicance of
407 these differences in receptor selectivity is not known but is likely to be important.
408 Aside from cross talk, there are also sequence differences in Oxt across primate
409 species. Specically, work by Lee et al. (2011) challenged the idea that Oxt is an
410 invariant nine-amino acid sequence by determining that some New World primates
411 have an amino acid substitution in the 8th position, a leucine rather than a proline.
412 The implications of these ndings are still being explored (Cavanaugh et al. 2014),
413 but this coupled with variations in the Avpr1a gene suggests that there has been,
414 and perhaps continues to be, an evolutionary shift in these systems and reinforces
415 the importance of studying these systems together rather than in isolation (for
416 review, see Ragen and Bales 2013). These ndings are likely to impact work in
417 preclinical models and may help to resolve some of the conicting ndings in the
418 literature between primates and other mammalian species.
419 3.4 Epigenetics
420 The advent of epigenetics has also challenged our understanding of how these
421 systems are regulated and potentially how they regulate other systems. Epigenetics
422 refers to changes in gene transcription that are not due to changes in nucleotide
423 sequence, but rather are abovethe genome. Epigenetic mechanisms include
424 histone modication and gene methylation, both of which alter the ability of the
425 transcriptional machinery to access promoter regions. While much of this work
426 originally centered on Oxt and maternal behavior in animal models, it has now been
427 expanded to human studies.
428 Elegant work from Dr. Michael Meaneys laboratory found that in rats, the
429 quality of motherinfant interactions affected DNA methylation and histone acet-
430 ylation patterns in the offspring (e.g., Champagne et al. 2001,2004; Fish et al.
431 2004; Francis et al. 1999; Weaver et al. 2004). During the rst postpartum week,
432 low licking-and-grooming (LG) dams have reduced Oxtr binding in the MPOA
433 compared to high LG dams (Champagne et al. 2001; Francis et al. 2000). Further,
434 microinjection of an Oxtr antagonist reduces licking and grooming in high LG
435 dams, with essentially no effect in low LG dams (Champagne et al. 2001). For more
436 complete reviews of this work, see (Champagne 2008; Bridges 2015).
437 More recently, work in humans suggests that changes in the methylation of the
438 OXTR are associated with a variety of diseases/disorders, including anorexia
439 nervosa (Kim et al. 2014), the perception of fear and anxiety (Puglia et al. 2015;
440 Ziegler et al. 2015), psychopathy (Dadds et al. 2014), and autism (Gregory et al.
441 2009). However, a direct causal relationship between methylation patterns and
442 behavior has yet to be made; however, given the animal literature, it seems likely
443 that this is an important means by which early life experience may be able to
444 directly impact behavior.
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445 4 Oxytocin/Vasopressin and Cooperative and Competitive
446 Behaviors: Social Memory, Social Interactions,
447 and Aggression
448 Within mammals, social structures can vary widely. Take for instance naked mole
449 rats and their large insect-like colony structure, prairie voles and their pair bonding
450 that results in a lifetime social dyad, or more solitary species such as Syrian
451 hamsters. With this diversity, it might be assumed that there are vast differences in
452 the types of behaviors that these species are capable of displaying and in the
453 neurotransmitters and/or brain areas that are important to their regulation. This,
454 however, does not seem to be the case. While the details may differ, there are, in
455 fact, a limited number of social behaviors common to most species and they include
456 the ability to remember others of the same species (social memory) as well as the
457 social behaviors that determine the nature of their relationships with conspecics
458 (e.g., afliation/dominance). Furthermore, the roles of Oxt and Avp in the modu-
459 lation of social behaviors have been evolutionarily conserved across species. For
460 example, aggression is modulated by social experience-induced changes in the
461 expression of Avpr1a in the hypothalamus in both male prairie voles and hamsters.
462 Since 90 % of mammals are not biparental, it is common for them to live in large
463 social groups and display both cooperativity and competitiveness, depending on the
464 context. Even in species that are more solitary and highly competitive, individuals
465 have the capacity for social recognition, social communication, as well as the
466 potential to form stable long-standing social relationships. There are also sex
467 differences as well as environmental effects, such as photoperiod, which can cause
468 shifts in social behaviors from the breeding to the non-breading season. In this
469 section, we will explore the role of Oxt and Avp in selected forms of cooperative
470 and competitive behavior in these differing and complex social contexts.
471 4.1 Social Recognition Memory
472 Displays of social behaviors often depend on whether the interaction is with an
473 individual that is familiar or unknown. Thus, the ability to recognize individuals
474 and remember them, i.e., social recognition memory, plays an important role in the
475 decision to approach or avoid. There are considerable data that both Oxt and Avp
476 contribute to social recognition memory. Essentially, Oxt facilitates social memory
477 by altering the processing of socially salient olfactory information (for review, see
478 Lee et al. 2009a; Gabor et al. 2012; Wacker and Ludwig 2012). In males, Oxt
479 infused into the olfactory bulb (OB), lateral ventricles, and MPOA facilitates social
480 recognition memory (Dluzen et al. 1998; Benelli et al. 1995; Popik and Van Ree
481 1991). Some of the particulars of the circuit have been worked out with the
482 assistance of genetic knockouts of the Oxt system, with Oxt knockout (Oxtr /)
483 mice and forebrain-specic Oxtr knockout (Oxtr FB/FB, where CRE recombinase
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484 is driven by a CaMKIIαpromoter) mice having decits in social recognition
485 memory (Lee et al. 2008a,b; Takayanagi et al. 2005; Macbeth et al. 2009; Ferguson
486 et al. 2000; Hattori et al. 2015). Based on this work, a four-gene micronet involving
487 Oxt, the Oxtr, estrogen receptor α, and estrogen receptor βhas been proposed as
488 being critical to the regulation of social recognition memory in both males and
489 females (Choleris et al. 2003). In particular, estrogen-dependent Oxt signaling in
490 the MeA appears to be key for normal social recognition memory. Infusion of Oxt
491 into the MeA of Oxt /mice can rescue decits in social recognition memory
492 (Ferguson et al. 2001), and infusion of an Oxtr antisense DNA or an Oxtr antagonist
493 into control mice can block social recognition memory (Choleris et al. 2007;
494 Ferguson et al. 2001). Female Oxt /mice also have a disrupted Bruce effect
495 (Bruce 1959), whereby they terminate their pregnancy when exposed to their mate,
496 which suggests that they do not remember him (Wersinger et al. 2008).
497 Recent work suggests that Oxt may also play a role in human social recognition.
498 Generally speaking, exogenous Oxt enhances the memory for faces (Savaskan et al.
499 2008; Guastella et al. 2008; Rimmele et al. 2009). Further, a common
500 single-nucleotide polymorphism (SNP) (rs237887) in the OXTR is moderately
501 associated with face recognition memory in families from the UK and Finland that
502 have a child with an autism spectrum disorder (ASD) (Skuse et al. 2014). Taken
503 together, these data suggest that Oxt and the Oxtr have a conserved role in the
504 modulation of social memory across species.
505 Avp also appears to be important for social memory. Androgen-dependent Avp
506 projections from the MeA and BNST to the LS, all parts of the SBNN, are important
507 for individual recognition (De Vries et al. 1984; Mayes et al. 1988; Bluthe et al.
508 1990,1993). Microinjections of Avp into the LS of control or AVP-decient
509 Brattleboro rats facilitate social memory, whereas microinjections of Avpr1a
510 antagonists or infusions of antisense Avpr1a oligonucleotides into the LS of control
511 rats impair social recognition memory (Engelmann and Landgraf 1994; Landgraf
512 et al. 1995). The use of Avpr1a /and Avpr1b /mice has also provided some
513 insight into the contributions of Avp to social memory. However, in the NIMH line
514 of Avpr1a /mice, the ndings have been mixed (Hu et al. 2003), with one group
515 reporting that males have impaired social recognition that can be rescued by the
516 overexpression of Avpr1a in the LS (Bielsky et al. 2003,2005; Bielsky and Young
517 2004) and another group reporting no decits in social recognition, but rather in
518 olfaction (Wersinger et al. 2007b). While the reason for the discrepancy remains
519 unknown, it is obvious from previous reports that Avpr1a in the LS is important for
520 normal social recognition memory. Interestingly, Avpr1b /mice have mild
521 impairments in social recognition memory (Wersinger et al. 2002) and lesions, and
522 genetic silencing of the CA2 region of the hippocampus, where the Avpr1b is
523 prominently expressed, also results in impaired social recognition memory
524 (Stevenson and Caldwell 2012; Hitti and Siegelbaum 2014).
525 While the aforementioned data provide strong support for a role of Avp in social
526 recognition, how or if Avp modulates social recognition has really only been
527 studied in a small number of species. Further, the data are limited by the fact that
528 the vast majority of studies have only examined social recognition for very short
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529 intervals (<2 h). However, there are some studies that suggest that Avp may be
530 important for long-term social recognition. Specically, injection of an Avpr1a
531 antagonist into the LS can block the formation of a mating-induced pair bond in
532 male prairie voles, while injection of Avp into the LS institutes a pair bond in the
533 absence of mating (Liu et al. 2001). Since social recognition is a necessary part of
534 pair bonding and pair bonds can last for a lifetime, these data suggest that Avp
535 signaling via the Avpr1a can induce long-term changes in social recognition. There
536 are also data to suggest that Avpr1a antagonists administered into the MeA can alter
537 maternal memories in rats. Normally, after a ten-day separation from their pups,
538 mothers display full maternal behavior within about 12 h of re-exposure. However,
539 in peripartum mothers, in which an Avpr1a antagonist is infused into the MeA, the
540 latency to display full maternal behavior does not occur for approximately 60 h; the
541 antagonist had no effect on the initial expression of maternal behavior on the day of
542 parturition (Nephew and Bridges 2008).
543 More recently, we have found that male Syrian hamsters can recognize social
544 odors of other male Syrian hamsters for 24 h. Injection of Oxt or Avp intracere-
545 broventricular (i.c.v) extends their social memory to 48 h. Interestingly, these
546 effects are mediated by the Oxtr and not the Avpr1a (Song et al. 2015). In the
547 broader context of animal behavior, it will also be important to determine whether
548 Avp mediates some of the more complex forms of social recognition found by
549 rodents such as kin recognition and the true recognition of specic individuals
550 (e.g., Mateo and Johnston 2003; Johnston and Peng 2008; Petrulis 2009).
551 4.2 Cooperative Behavior
552 Although cooperative behavior is certainly not limited to species that pair bond, pair
553 bonding species do provide an important model system in which to investigate the
554 neurobiology of cooperation. That said, it remains important to recognize that these
555 bonds are formed by mating and are limited to the cooperation of a male and a
556 female. Pair bonding, formed by mating, represents one form of cooperative
557 behavior. Pair bonds are somewhat unique among mammals in that they are only
558 seen in 35 % of mammalian species (Kleiman 1977). Dened as a preference for
559 contact with a familiar sexual partner, selective aggression toward unfamiliar
560 conspecics, biparental care, socially regulated reproduction, and incest avoidance
561 (Carter et al. 1995; Carter and Getz 1993), pair bonding can be found in titi
562 monkeys (Callicebus cupreus), marmosets (Callithrix penicillata and Callithrix
563 jacchus jacchus), California mice (Peromyscus californicus), and prairie voles
564 (Microtus ochrogaster). Humans too can have strong selective bonds between
565 mates, but also show cooperative behaviors in many other contexts as well. The
566 extent to which human pair bonds and other forms of human cooperative behavior
567 are regulated by Oxt and Avp remains to be determined.
568 Our understanding of the mechanisms by which Oxt and Avp contribute to pair
569 bonding comes primarily from work in prairie voles. Prairie voles live in extended
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570 family groups and are considered a socially monogamous species (Carter et al.
571 1995) (social monogamy is distinct from sexual monogamy as most individuals
572 have extra-pair copulations). The formation of a pair bond is experimentally tested
573 in the laboratory using a partner preference test (Williams et al. 1992), whereby the
574 preference of a male or female for an animal in which they have previously
575 cohabitated, i.e., the partner, versus a stranger,is assessed. If the experimental
576 subject spends twice as much time with the partneranimal, then it is said to have
577 formed a pair bond with that individual (Insel and Hulihan 1995; Carter and Getz
578 1993; Williams et al. 1994; Carter et al. 1995).
579 Due to the diversity in social structures within the genus Microtus, comparative
580 studies between vole species have provided signicant insight into the neural
581 regulation of social bonding. By comparing the neurochemistry of monogamous
582 vole species, such as the prairie or pine vole (Microtus pinetorum), to
583 non-monogamous voles, such as the montane (Microtus montanus) or meadow
584 (Microtus pennsylvanicus) voles, scientists have explored how variations in Oxt and
585 Avp neurochemistry between highly related species can result in signicant dif-
586 ferences in social behavior (Young et al. 2008,2011; Adkins-Regan 2009). While
587 there are differences in Oxt- and Avp-ir cells or their projections between species,
588 most profound are the changes in the neuroanatomical distribution of the Oxtr and
589 the Avpr1a. Relative to non-monogamous voles, monogamous voles have higher
590 densities of Oxtr, as measured using Oxtr autoradiography and ISHH, in the NAcc,
591 the PFC, and the BNST. In contrast, promiscuous voles have higher Oxtr density in
592 the LS, VMH, and the cortical nucleus of the amygdala (Insel and Shapiro 1992;
593 Young et al. 1996; Smeltzer et al. 2006). Evidence that the differences in the
594 distribution of the Oxtr between species might be behaviorally meaningful comes
595 primarily from pharmacological studies.
596 In female prairie voles, central infusion of an Oxtr antagonist blocks the for-
597 mation of the pair bond, but has no effect on sexual behavior, whereas central
598 infusion of Oxt facilitates the pair bond in the absence of mating (Insel et al. 1995;
599 Williams et al. 1994; Cho et al. 1999) and can decrease male-directed aggression
600 (Bales and Carter 2003). In the aforementioned studies, the infusions were i.c.v.;
601 however, manipulation of Oxtr signaling, using Oxtr antagonists and RNAi
602 knockdown of the Oxtr within the NAcc, inhibits formation of a partner preference
603 (Liu and Wang 2003; Young et al. 2001; Keebaugh et al. 2015), and overexpression
604 of the Oxtr in the NAcc of adult female prairie voles accelerates the formation of
605 partner preference (Ross et al. 2009b). However, overexpression of the Oxtr in the
606 NAcc of non-monogamous meadow voles is not sufcient to promote pair bond
607 formation (Ross et al. 2009b), which suggests that all of the required neurocircuitry
608 is not in place for this species.
609 There are also differences in the distribution of the Avpr1a between vole species.
610 Prairie voles have a higher density of Avpr1a, as measured using receptor autora-
611 diography and ISHH, within the MeA, accessory olfactory bulb, diagonal band,
612 thalamus, VP, and BNST compared to montane voles (Young et al. 1997; Insel et al.
613 1994). Montane voles, on the other hand, have a higher density of Avpr1a in the
614 medial PFC and the LS (Smeltzer et al. 2006; Insel et al. 1994). These differences in
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615 Avpr1a distribution are thought to contribute to differences in social organization
616 between monogamous and non-monogamous vole species. This hypothesis is sup-
617 ported by data in pine voles and meadow voles, which suggest similar social
618 structure-specic distributions of Avpr1a between these species (Insel et al. 1994).
619 Further support for this hypothesis comes from pharmacological manipulations of
620 the Avpr1a in prairie voles. When an Avp antagonist is injected i.c.v. prior to mating,
621 the formation of a partner preference is inhibited. Conversely, Avp infusion facili-
622 tates the formation of the partner preference (Winslow et al. 1993; Cho et al. 1999).
623 Some of the more interesting data that support a role for the differential distribution
624 of the Avpr1a in the formation of social bonds come from a study in which the prairie
625 vole Avpr1a gene was overexpressed in the ventral forebrain of meadow voles,
626 resulting in increases in the amount of time meadow voles spent huddled with their
627 partners compared to controls (Lim et al. 2004).
628 4.3 Competitive Behavior
629 The most conspicuous form of competitive behavior is aggression. Offensive and
630 defensive aggressions have been studied most intensely and almost exclusively in
631 male mammals. Further, the neural circuits that overlap much of the SBNN have
632 been proposed for each of these forms of aggression (Delville et al. 2000; Choi
633 et al. 2005). Although frequently characterized as a negative social interaction,
634 aggression plays a highly constructive role in the formation of social relationships.
635 In the vast majority of mammals that do not form pair bonds, dominance rela-
636 tionships provide social bonds that serve many adaptive functions (e.g., resource
637 distribution) and that ultimately reduce social conict. Typically, dominance rela-
638 tionships are rapidly determined through aggressive interactions but are primarily
639 maintained through social communication (e.g., scent marking, vocalization),
640 thereby reducing the dangers of intense ghting (Albers et al. 2002; Fernald 2014).
641 4.3.1 Oxytocin and Competitive Behavior
642 Some of the earliest evidence that Oxt is involved in both aggression and social
643 communication came from studies in squirrel monkeys. In male squirrel monkeys,
644 with established dominantsubordinate relationships, i.c.v. administration of Oxt
645 increases aggression in dominant males, while having no effect in subordinate
646 males (Winslow and Insel 1991b). In contrast, Oxt stimulates scent marking in
647 subordinate males but does not alter marking in dominant males (Winslow and Insel
648 1991b), thus demonstrating that social experience can determine the behavioral
649 response to Oxt acting in the brain. Studies in rats suggest one mechanism that
650 might contribute to the effects of social experience on the behavioral response to
651 Oxt. Dominant male rats have signicantly higher levels of Oxtr mRNA in the MeA
652 3 h after the social encounter that dened their relationship. Further, infusion of an
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653 Oxtr antagonist immediately after the establishment of subordinate status increases
654 the duration of the dominantsubordinate relationship (Timmer et al. 2011). Social
655 status also signicantly impacts the circulating levels of serum Oxt in primates. In
656 rhesus monkeys, dominant females have signicantly higher levels of serum Oxt
657 than subordinates (Michopoulos et al. 2011,2012). The importance of social
658 experience in determining the behavioral response to Oxt/Avp is a theme we will
659 see repeatedly in this chapter.
660 Historically, there have been little data supporting a role for Oxt in the regulation
661 of intermale aggression in laboratory species of rodents. However, some recent
662 work suggests that pharmacological treatment with Oxt may have antiaggressive
663 effects in adult males. Work from Jaap Koolhaaslaboratory has found that phar-
664 macological enhancement of Oxt in rats, by intranasal treatment or i.c.v. infusion,
665 reduces offensive aggression and promotes prosocial exploratory behaviors
666 (Calcagnoli et al. 2013,2014,2015a). Furthermore, these inhibitory effects seem to
667 be mediated by Oxt acting via the Oxtr in the CeA; however, it should be noted that
668 blocking endogenous Oxt signaling in the CeA has no effect (Calcagnoli et al.
669 2015b). Thus, it is proposed that these ndings should be considered in the context
670 of pharmacological effects rather than being directly regulated by the local
671 endogenous Oxt system (Calcagnoli et al. 2015b).
672 The role of Oxt in the neural regulation of female offensive aggression is sparse;
673 as mentioned previously, females of the most commonly studied laboratory rodents,
674 unlike many other mammalian species, rarely display aggressive behaviors outside
675 of the peripartum period. However, there is evidence in female Syrian hamsters that
676 Oxt can inuence competitive behaviors. Specically, microinjection of Oxt into
677 the MPOA-AH reduces offensive aggression, and injection of an Oxtr antagonist
678 increases offensive aggression directed toward a female intruder (Harmon et al.
679 2002a). Traditionally, Oxt in female rodents has focused on maternal aggression.
680 This is a unique, and transient, hormonal/physiological time in a females life and is
681 characterized by high levels of nurturing behaviors directed toward pups and
682 aggressive behaviors directed toward intruders. During the peripartum period, Oxt
683 has anxiolytic effects (Bosch and Neumann 2008), specically via its actions in the
684 PVN and CeA (Blume et al. 2008; Jurek et al. 2012; Windle et al. 1997; Huber et al.
685 2005; Viviani et al. 2011; Knobloch et al. 2012). These decreases in anxiety permit
686 females to attend to their pups. But even with lower levels of anxiety and strong
687 bonds with her offspring, dams can display high levels of maternal aggression.
688 Depending on the brain area and the behavioral state of the animal, Oxt and/or Oxtr
689 antagonists can either increase or decrease maternal aggression (for review, please
690 see Bosch 2013). For instance, in rats bred for low-anxiety rats, Oxt in the PVN
691 increases maternal aggression (Bosch et al. 2005), but when microinjected into the
692 BNST of Wistar rats decreases maternal aggression (Consiglio et al. 2005). In
693 hamsters, injection of Oxt into the amygdala facilitates maternal aggression (Ferris
694 et al. 1992a). So, while Oxt is important to aggression in females, its effects are
695 context and brain site specic. There are also numerous studies that support the
696 assertion that developmental exposure to Oxt is important for the proper devel-
697 opment of motivated social behaviors, including aggression, but those studies will
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698 not be reviewed in this chapter (recently reviewed in Miller and Caldwell 2015;
699 Hammock 2015).
700 4.3.2 Vasopressin and Competitive Behavior
701 Most of what we know about the role of nonapeptides in competitive behavior
702 comes from studies of Avp and aggressive behavior. Further, much of the work has
703 focused on the Avpr1a, as this was the rst centrally identied receptor, and as
704 such, there are a number of pharmacological tools. However, the Avpr1b appears
705 also to be important for displays of aggressive behavior. Because of the differences
706 in the distribution of these two receptor subtypes, this section will be divided by
707 receptor subtype.
708 4.3.3 The Vasopressin 1a Receptor and Competitive Behavior
709 The rst evidence for a role for Avp in aggression came from studies in male
710 hamsters in which the injection of Avpr1a antagonists into the AH signicantly
711 inhibited offensive aggression (Ferris and Potegal 1988; Potegal and Ferris 1990).
712 Subsequent studies have replicated these results and shown that Avp injected into
713 the AH stimulates offensive aggression (Caldwell and Albers 2004a; Ferris et al.
714 1997). However, the ability of Avp to stimulate aggression by its action in the AH
715 appears to depend on an individuals prior social experience. Avp injected into the
716 AH increases aggression in male hamsters previously trained to ght other hamsters
717 and in hamsters socially isolated for at least four weeks, but not in hamsters housed
718 in social groups. The ability of social experience to enhance the response of the AH
719 to Avp appears to be mediated by experience-dependent increases in the number of
720 Avpr1a in the AH (Albers et al. 2006; Cooper et al. 2005). In summary, Avp has
721 powerful effects on offensive aggression in male hamsters but only if social
722 experience has upregulated Avpr1a receptors in the AH.
723 Avp can also have potent effects on aggression in male prairie voles through a
724 similar mechanism. Sexually, naïve male voles are essentially non-aggressive,
725 choosing to explore intruder males as opposed to attacking them (Winslow et al.
726 1993). Following mating-induced pair bonding, males display high levels of
727 aggression toward conspecics other than their mate and have increases in the
728 density of Avpr1a receptors in the AH (Gobrogge et al. 2009). Further, overex-
729 pression of the Avpr1a in the AH using viral vector gene transfer increases
730 aggression in non-pair-bonded males. Thus, in male hamsters and prairie voles,
731 species with very different types of social organization, an individuals social
732 experience can modulate the number of Avpr1a in the AH and thereby regulate the
733 intensity of aggression that is expressed.
734 Another hypothalamic region where Avp inuences aggression is the ventro-
735 lateral hypothalamus (VLH). Avp injected into the VLH facilitates aggression in
736 gonadally intact males and castrated males given testosterone but does not facilitate
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737 aggression in castrated controls (Delville et al. 1996). Avpr binding is also reduced
738 in the VLH following that castration and precastration levels of binding can be
739 restored by testosterone. In contrast, it is not known whether testosterone inuences
740 the ability of Avp to alter aggression when injected into the AH. However, since
741 castration reduces Avpr binding within this region (Delville et al. 1996), it seems
742 possible that castration could reduce aggression stimulated by Avp. It should be
743 noted that the relationship between gonadal hormones and aggression is complex;
744 however, it is clear that testosterone does not simply induce aggression in males
745 (for review, see Johnson et al. 1995; Young et al. 2000; Demas et al. 2007).
746 In females, while there is evidence that gonadal hormones can affect Avpr1a
747 binding within the VLH (Delville and Ferris 1995), the specic effects on
748 aggression are unknown.
749 There are also extra-hypothalamic regions where aggression and Avp activity
750 have been linked. In both male rats and mice selected for varying levels of
751 aggression, a negative correlation has been observed between Avp ber density in
752 the LS and the amount of intermale aggression (Compaan et al. 1993; Everts et al.
753 1997). Interestingly, these differences in Avp and aggression are not related to
754 differences in circulating levels of testosterone (Elkabir et al. 1990). The role of
755 septal Avp in aggression has also been studied in male rats bred for low or high
756 anxiety. Release of Avp into the LS is signicantly lower in the much more
757 aggressive low-anxiety rats than in the high-anxiety rats that exhibit lower levels of
758 aggression. In addition, septal administration of Avp to the highly aggressive group
759 and administration of the Avpr1a antagonist to the low aggressive group did not alter
760 the levels of aggression expressed (Beiderbeck et al. 2007). The level of aggres-
761 siveness and the pattern of Avp expression in the LS and BNST are also correlated in
762 mice. The monogamous California mice (Peromyscus californicus) have shorter
763 attack latencies and increased Avp-ir in the BNST and LS compared to the polyg-
764 amous, white-footed mice (Peromyscus leuopus) (Bester-Meredith et al. 1999).
765 Interestingly, when California mice pups are cross-fostered to white-footed mice
766 dams, they are less aggressive in adulthood than those reared by the same species,
767 and they have less Avp-ir in the BNST and SON compared to controls
768 (Bester-Meredith and Marler 2001). These data in mice, like those from hamsters,
769 suggest that changes in the social environment are able to alter Avp neurocircuitry
770 and the behavior driven by that circuitry. In addition, although relationships between
771 aggressiveness and Avp expression and release within the LS have been found, Avp
772 may not have any direct effects on male aggression by its actions in the LS.
773 Despite the powerful effects of Avp on aggression in the hypothalamus, not all
774 central manipulations of Avp have been found to inuence offensive aggression.
775 Although i.c.v. injections of an Avpr1a antagonist increase the latency to the onset
776 of aggression in highly aggressive California mice, i.c.v. injections of Avp or
777 Avpr1a antagonists have no effect on aggression in white-footed mice
778 (Bester-Meredith and Marler 2001). In non-pair-bonded male prairie voles with
779 extensive experience with aggression, i.c.v. administration of an Avpr1a antagonist
780 does not inhibit aggression (Winslow et al. 1993). There is other evidence from rats
781 that i.c.v. administration of Avp does not alter the expression of aggression nor does
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782 deletion of the Avpr1a receptor in mice (Elkabir et al. 1990; Wersinger et al.
783 2007b). While it is clear that Avp can stimulate aggression by its action in some
784 brain sites, it remains possible that Avp might act to reduce aggression by its action
785 in other brain regions or by its action on other receptors (e.g., the Oxtr) to
786 reduce/inhibit aggression. It is also important to recognize that aggression is a
787 complex behavior and may be facilitated by neurochemical systems other than Avp,
788 at least in some cases.
789 In females, Avp has very different effects on offensive aggression than it does in
790 males. As described above, in male hamsters, injection of Avpr1a antagonists into
791 the AH inhibits offensive aggression and injection of Avp stimulates aggression
792 (Ferris and Potegal 1988; Potegal and Ferris 1990; Caldwell and Albers 2004a;
793 Ferris et al. 1997). In contrast, in female hamsters, an Avpr1a antagonist injected
794 into the AH stimulates offensive aggression and injection of Avp inhibits aggres-
795 sion in the residentintruder test (Gutzler et al. 2010). More recently, similar sex
796 differences have been seen in the effects of Avp and Avpr1a antagonists on social
797 play behavior in rats (Bredewold et al. 2014; Veenema et al. 2013). For example,
798 injection of Avpr1a antagonists in the LS increases social play in juvenile males and
799 reduces social play in juvenile females. In a related study, a negative correlation
800 was found between Avp mRNA levels in the BNST and social play in male juvenile
801 rats (Paul et al. 2014). As social play is a precursor to aggressive behavior, these
802 data are consistent with AVP-related sex differences in the regulation of competi-
803 tive behaviors.
804 4.3.4 The Vasopressin 1A Receptor and Maternal Aggression
805 Maternal aggression is an intense form of aggression displayed by lactating mothers
806 confronted by intruders (Lonstein and Gammie 2002). Studies using Avpr1a /
807 mice found that maternal aggression does not differ from that seen in wild-type
808 mice (Wersinger et al. 2007b). In contrast, i.c.v. administration of Avp in lactating
809 rats reduces and an Avpr1a antagonist increases aggression toward male intruders
810 (Nephew and Bridges 2008; Nephew et al. 2010). The effects of i.c.v. adminis-
811 tration of Avp and an Avpr1a antagonist on maternal aggression were also exam-
812 ined in rat strains that had been selectively bred for high (HAB) or low
813 (LAB) anxiety (Bosch and Neumann 2010). In both strains, Avp was found to
814 increase and an Avpr1a antagonist to decrease maternal aggression, respectively.
815 Other studies have used microdialysis to examine the role of Avp in specic brain
816 regions in the regulation of maternal aggression in HAB and LAB rats (Bosch and
817 Neumann 2010). In HAB, but not LAB, rats, Avp is positively correlated with
818 maternal aggression in the CeA but not the PVN. In addition, administration of an
819 Avpr1a antagonist into the CeA reduces aggression in HAB rats, while adminis-
820 tration of Avp into the CeA increases aggression in LAB rats. The ability of Avp to
821 promote maternal aggression by acting in the CeA does not appear to be restricted
822 to HAB rat strains since similar results have been reported in Sprague-Dawley rats
823 (Meddle and Bosch, unpublished; cited in, Bosch 2011). In the future, it will be
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824 important to clarify the effects of Avp on maternal aggression, its site(s) of action,
825 and whether the effects of Avp on aggression are related to anxiety levels.
826 4.3.5 The Vasopressin 1b Receptor and Competitive Behavior
827 There is compelling evidence that the Avpr1b is essential for displays of aggressive
828 behavior directed toward a conspecic (for review, see Caldwell et al. 2008a,c;
829 Stevenson and Caldwell 2012). In residentintruder and neutral cage aggression
830 tests, Avpr1b /mice display fewer attacks and have longer attack latencies than
831 Avpr1b +/+ controls (Wersinger et al. 2002,2007a). Further, in a reversal of a
832 residentintruder test where the experimental mice are intruders rather than resi-
833 dents, Avpr1b /mice display normal defensive avoidance behaviors when
834 attacked by a stimulus animal, but are less likely to initiate retaliatory attacks
835 (Wersinger et al. 2007a). Pharmacological studies using the Avpr1b antagonist,
836 SSR149415, support the ndings of work in Avpr1b /mice. Syrian hamsters
837 orally administered SSR149415 have reductions in the frequency and duration of
838 offensive attacks, in chase behaviors, in ank marking, and in the olfactory
839 investigation that often precedes and accompanies an offensive attack (Blanchard
840 et al. 2005). Mice given SSR149415 display fewer defensive bites when forced to
841 encounter a threatening predator and reductions in the duration of offensive
842 aggression in a residentintruder test (Griebel et al. 2002).
843 The decits in aggressive behaviors observed in Avpr1b /mice are not
844 limited to males. Following parturition, female Avpr1b /mice have reductions in
845 maternal aggressive behaviors, compared to control mice, as measured by longer
846 attack latencies and fewer attacks, directed toward a male intruder (Wersinger et al.
847 2007a). Interestingly, the disruption of the Avpr1b does not affect all forms of
848 aggressive behavior. In a nonsocial context, such as the predation of a cricket,
849 Avpr1b /and Avpr1b +/+ mice have similar attack latencies (Wersinger et al.
850 2007a). Based on the genetic and pharmacological data, it has been hypothesized
851 that the disruption of the Avpr1b does not specically disrupt aggressive behavior,
852 but rather the ability to have the appropriate behavioral response within a given
853 social context (Caldwell et al. 2008c; Young et al. 2006; Stevenson and Caldwell
854 2012).
855 With prominent expression within the pyramidal neurons of the CA2 region of
856 the hippocampus, recent work has focused on what the Avpr1b may be doing here.
857 To this end, Pagani et al. 2015 have shown that replacement of the Avpr1b in the
858 dorsal CA2 region of Avpr1b /mice restores socially mediated attack behaviors.
859 Further, selective Avpr1b antagonists result in the production of
860 N-methyl-D-aspartic-acid-dependent excitatory postsynaptic responses specically
861 within the CA2 region of control mice, but not Avpr1b /mice (Pagani et al.
862 2015). While the hippocampus is not currently a recognized node in the SBNN, it is
863 a part of the motivational pathway. The CA2 region is structurally unique, as it does
864 not receive rich mossy ber input from the dentate gyrus (Tamamaki et al. 1988),
865 and is the only part of the hippocampus to receive input from the posterior
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866 hypothalamus and the perforant pathway (Bartesaghi et al. 2006; Borhegyi and
867 Leranth 1997; Vertes and McKenna 2000), which connects the entorhinal cortex to
868 the hippocampal formation (Bartesaghi and Gessi 2004). Further, there is a vaso-
869 pressinergic projection from the PVN to the CA2 region (Cui et al. 2013). Based on
870 the ndings described here, we, and others, have hypothesized that the CA2 region
871 of the hippocampus may aid in the formation and/or recall of accessory
872 olfactory-based memories (Caldwell et al. 2008c; Young et al. 2006). Thus, it
873 seems likely that this is a region that will need to be included in future discussions
874 of the SBNN and its interactions with the mesolimbic DA system.
875 4.4 Social Communication
876 While Avp plays a key role in the regulation of social communication in hamsters
877 (see below), Oxt also contributes to its regulation. Hamsters communicate using a
878 form of scent marking called ank marking, and the expression of ank marking is
879 essential for the maintenance of dominant/subordinate relationships (Johnston
880 1985). After the rapid establishment of dominance, aggressive behavior declines
881 and ank marking increases in the dominant hamsters and to a lesser extent in the
882 subordinate hamsters (Ferris et al. 1987). In the absence of ank marking,
883 aggression remains high and a stable relationship is not formed.
884 Oxt injected into the areas extending from the MPOA to the posterior medial and
885 lateral aspects of the AH (referred to from here on as the MPOA-AH) of dominant
886 female hamsters induces ank marking in a dose-dependent manner but only when
887 the dominant hamsters are tested with their subordinate partners (Harmon et al.
888 2002b). Oxt does not induce ank marking when injected into the MPOA-AH of
889 socially naive female hamsters tested with an opponent or alone. In males, by
890 contrast, Oxt induces ank marking in dominant hamsters when they are tested with
891 their subordinate partner or alone (Harmon et al. 2002b). These data indicate that
892 social experience, social context, and sex interact to regulate the ability of Oxt to
893 stimulate ank marking by its actions in the MPOA-AH in hamsters.
894 Although Oxt can stimulate ank marking, Avp plays the predominate role in
895 regulating its expression. Avp stimulates high levels of ank marking in male and
896 female hamsters by acting on the Avpr1a in the rostral hypothalamus (Ferris et al.
897 1984,1985; Albers et al. 1986). It is of note that the MPOA-AH is substantially
898 larger than the site where Avp can induce aggression (Ferris et al. 1986a). Avp can
899 also induce ank marking following its injection into the LS, BNST, and PAG (Irvin
900 et al. 1990; Hennessey et al. 1992). Gonadal hormones modulate the ability of Avp
901 to stimulate ank marking by regulating the number of hypothalamic Avpr1a
902 (Huhman and Albers 1993; Albers et al. 1988). In the LS, BNST, and PAG, gonadal
903 hormones have only small effects on the ability of Avp to stimulate ank marking,
904 suggesting that the MPOA-AH may be the primary site where gonadal hormones
905 inuence the ability of Avp to stimulate ank marking (Albers and Cooper 1995).
906 Interestingly, Avp seems to have the ability of inducing ank marking, regardless
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907 of the social context. For example, in hamsters with an established dominant/
908 subordinate relationship, injection of Avp produces high levels of ank marking in
909 either the dominant or subordinate hamster during social interactions (Ferris et al.
910 1986b). Similar results have been obtained in squirrel monkeys where AVP injected
911 i.c.v. induces scent marking in both dominant and subordinate males (Winslow and
912 Insel 1991a).
913 4.5 Interactions Between Oxytocin, Vasopressin,
914 and Dopamine in the Regulation
915 of Cooperation/Competition
916 As discussed in detail above, Oxt and Avp act within regions considered to be
917 components of the mesolimbic DA system to inuence cooperative and competitive
918 behaviors. There is also evidence that DA in the mesolimbic DA system plays
919 important roles in the regulation of both cooperative and competitive behaviors.
920 Non-selective DA antagonists block mating-induced partner preferences in both
921 male and female prairie voles, and treatment with the non-selective DA agonist
922 apomorphine facilitates partner preference in the absence of mating (Aragona et al.
923 2003; Wang et al. 1999). The NAcc shell, and not the core, appears to be the site of
924 action for these drugs since local administration into the NAcc shell, but not the
925 core, has the same effects as systemic administration. Increase in DA activity within
926 the NAcc that occurs following mating is necessary for the formation of pair bonds
927 in male prairie voles (Aragona et al. 2003). Activation of DA D2 receptors in the
928 NAcc can induce a pair bond in cohabiting voles in the absence of mating, while
929 activation of D1 receptors can block pair bonding (Aragona et al. 2006). In addi-
930 tion, D1 receptors are increased in the NAcc in male prairie voles following the
931 formation of a pair bond. Mating guarding aggression in males can also be inhibited
932 by D1 antagonists injected into the NAcc (Aragona and Wang 2009). Other regions
933 in the network also play a key role in the formation of cooperative behavior.
934 Pair-bonded voles have lower concentrations of D1 receptors and higher concen-
935 trations of D2 receptors in the medial prefrontal cortex than non-pair-bonded voles
936 (Smeltzer et al. 2006). Enhancement of DA release in the VTA via administration
937 of GABA or glutamate antagonists can also induce pair bonding in male voles
938 (Curtis and Wang 2005).
939 There is also considerable evidence that the mesolimbic DA system plays a
940 critical role in the regulation of competitive behavior and in particular aggression
941 (for review, see de Almeida et al. 2005). For instance, the non-selective DA
942 receptor agonist apomorphine stimulates aggression and ank marking in male
943 hamsters (Hyer et al. 2012). Social experience can regulate the expression of DA in
944 several nodes of the SBBN. The amount of the rate-limiting synthetic enzyme for
945 DA, tyrosine hydroxylase, increases signicantly in several regions of the SBNN
946 including the LS and BNST as well as within the shell of the NAcc in males trained
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947 to ght as compared to controls (Schwartzer et al. 2013). In addition, activation of
948 D1 and D2 receptors in the NAcc inuences the expression of aggression and its
949 rewarding properties (Couppis and Kennedy 2008; Miczek et al. 2002) although
950 selective aggression in male voles appears to require only the D1 receptor activation
951 (Aragona et al. 2006). While DA is involved in various aspects of the preparation,
952 expression, and consequences of aggression, its precise role remains elusive.
953 The importance of interactions between Oxt, Avp, and DA in social motivation
954 has been widely discussed, and yet there are few studies demonstrating a direct link
955 between these neuropeptides and DA in controlling social behavior. Partner pref-
956 erences induced by the activation of D2 receptors in the NAcc can be prevented by
957 administration of an Oxtr antagonist and partner preferences induced by i.c.v. Oxt
958 administration can be blocked by a D2 antagonist administered in the NAcc (Liu
959 and Wang 2003). In addition, overexpression of Avpr1a in the VP of the
960 non-pair-bonded meadow voles results in mating-induced partner preferences that
961 can be blocked by a D2 antagonist given prior to mating (Lim et al. 2004).
962 Despite the mounting empirical evidence suggesting that Oxt and Avp can
963 directly interact with DA to inuence social behavior, the majority of evidence for
964 this interaction comes from studies showing either that Oxt and/or Avp act within
965 structures that comprise the mesolimbic DA system, or that manipulations of DA
966 can inuence the same social behaviors that are inuenced by Oxt and Avp.
967 Interestingly, there are very little data on whether Oxt or Avp might contribute the
968 rewarding properties of social behavior. A limited amount of data suggest that Oxt
969 can induce a conditioned place preference (CPP) when given peripherally to male
970 rats or centrally to female mice (Liberzon et al. 1997; Kent et al. 2013). Recently,
971 we investigated whether injection of Oxt or Avp into the VTA could produce a
972 conditioned place preference in male hamsters (Song et al. 2014a). Both Oxt and
973 Avp increase CPP when injected into the VTA. The administration of selective Oxt
974 and Avpr1a agonists and antagonists revealed that the rewarding properties of both
975 Oxt and Avp in the VTA are mediated by the Oxtr and not the Avpr1a.
976 5 Cooperativity and Competitiveness in Humans
977 As we all know, cooperation and competition are a hallmark of nearly all human
978 endeavors. Successful cooperation and competition require a set of social skills
979 collectively termed social cognition, which allow an individual to engage in social
980 behaviors that are appropriate for a particular context. Since the emergence of the
981 social cognition eld in the late 1960s and early 1970s, there has been a concerted
982 scientic effort to understand the complicated cognitive processes that underlie
983 human social interactions. While social cognition and many disciplines that are
984 brought to bear in this eld are interesting, there is accumulating evidence that Oxt
985 and Avp in humans are important to social cognition. This section will highlight
986 what we know about Oxt and Avp in humans, in particular how exogenous
987 administration of these nonapeptides impacts measures of social cognition.
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988 As described throughout this chapter, there is considerable compelling evidence
989 that Oxt promotes social behaviors, at least in specic contexts. In humans, the
990 study of social behaviors includes testing procedures designed to measure trust, the
991 ability to read facial expressions, the memory for socially salient information, such
992 as faces, and more recently measures of empathy. In most human studies focused on
993 the therapeutic effects of Oxt and Avp, they are exogenously administered intra-
994 nasally. This delivery system is preferable as it is considered noninvasive and some
995 assert that Oxt and Avp are able to cross the bloodbrain barrier using this route of
996 delivery (Born et al. 2002); however, this latter assertion is debatable given their
997 size, hydrophilic nature, as well as numerous other issues.
998 5.1 Nonapeptides and Social Cognition in Healthy Humans
999 5.1.1 Oxytocin and Social Cognition in Humans
1000 Investigation into the role of Oxt in human cognition has dramatically increased
1001 over the last decade. More recently, attempts have been made to reconcile the
1002 existing data on the role of Oxt into a broader theory and understanding of human
1003 cognition. For example, De Dreu proposes that Oxt plays a critical role in the
1004 motivation of cooperation and competition in humans (De Dreu and Kret 2015;De
1005 Dreu 2012). This hypothesis stems from the idea that humans are social animals and
1006 are likely to cooperate with others, even with those genetically unrelated. It pro-
1007 poses that Oxt motivates humans to like and empathize with others in their group, to
1008 comply with group norms, and to reciprocate trust with other group members, while
1009 competing with out-group members. While De Dreus hypothesis is in reference to
1010 the endogenous Oxt system, this idea is supported by some recent work using
1011 intranasal Oxt. Essentially, intranasal Oxt increases in-groupfavoritism when
1012 individuals are asked to use intuitive decision making; however, Oxt has an
1013 opposite effect if individuals are asked to use reective decision making (Ma et al.
1014 2015). These data suggest that an individualscognitive stylemay contribute to
1015 the effects of Oxt, which has implications for both endogenous and exogenous Oxt.
1016 Given the literature in animal models, and the proposed prosocial effects of Oxt,
1017 in recent years, there has been a surge in the number of clinical studies that have
1018 administered exogenous Oxt to improve social interactions in healthy individuals.
1019 While the data do suggest that intranasal Oxt as a therapeutic agent has some
1020 efcacy, long-term and doseresponse studies have yet to be completed. In humans,
1021 intranasal Oxt may inuence the processing of social information in several ways,
1022 including selective attention, enhancement of the memory, and/or the appraisal of
1023 socially relevant information (Guastella and MacLeod 2012). Intranasal Oxt also
1024 increases trust, as measured by an individuals willingness to accept social risk
1025 during a social interaction (Zak et al. 2005; Kosfeld et al. 2005). However, similar
1026 to what is observed in other species, the effects of Oxt on trust are nuanced and
1027 often sex specic. For instance, if subjects are provided with information that
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1028 suggests that a trustee is untrustworthy, then intranasal Oxt does not facilitate trust,
1029 or as the authors state, Oxt makes people trusting, not gullible(Mikolajczak et al.
1030 2010). In females that have had their trust betrayed, intranasal Oxt results in less
1031 restoration of trust behavior compared to controls (Yao et al. 2014). However, in
1032 males, intranasal Oxt does not alter trust behavior in individuals that have had their
1033 trust betrayed, whereas placebo controls decrease their trust in response to betrayal
1034 (Baumgartner et al. 2008). Further, when intranasal Oxt treatment in males is
1035 coupled with functional magnetic resonance imaging (fMRI), there is a reduction in
1036 activity in areas of the brain associated with processing fearful stimuli, such as the
1037 amygdala and some areas of the midbrain, and reward feedback, such as the stri-
1038 atum (Baumgartner et al. 2008).
1039 Oxt also has sex-specic effects in the context of reciprocal altruism, as mea-
1040 sured using the prisoners dilemma game, which examines cooperative exchange
1041 (Chen et al. 2015b; Feng et al. 2014; Rilling et al. 2014). Specically, intranasal
1042 Oxt administered to females causes them to treat computer partners more like
1043 human partners; this same effect is not observed in males (Rilling et al. 2014). In
1044 this same context, there are also striking sex differences in neural activation, as
1045 measured by fMRI. In males, Oxt increases activation in the caudate/putamen while
1046 decreasing activation in females. The authors suggest that in this context, Oxt may
1047 increase the reward or salience of positive social interactions among males, while
1048 having the opposite effect in females (Feng et al. 2014; Rilling et al. 2014). Recent
1049 work also indicates that Oxt selectively improves kinship recognition in women but
1050 not men and that Oxt improves mens performance in competition recognition
1051 (Fischer-Shofty et al. 2013). Taken together, these data suggest that intranasal Oxt
1052 does not universally promote social interactions, but rather that the effects are subtle
1053 and dependent upon the social context and sex of the individuals. As mentioned
1054 previously, there has been a ood of clinical studies using intranasal Oxt, and with
1055 those studies, there is evidence that it can improve the ability to infer another
1056 individuals mental state, improves facial recognition memory, alters the processing
1057 of faces, and can facilitate empathy (Heinrichs et al. 2009; Rimmele et al. 2009;
1058 Domes et al. 2007; Guastella et al. 2008,2009; Zak et al. 2007; Hurlemann et al.
1059 2010; Unkelbach et al. 2008; Bos et al. 2015).
1060 While the intranasal administration of Oxt can denitely inuence aspects of
1061 social cognition, it is the individual differences in endogenous Oxt and their asso-
1062 ciation with social cognition that is equally, if not more, important. Not only are
1063 individual differences in Oxt genetically heritable (Rubin et al. 2014), but also they
1064 appear to be stable (Feldman et al. 2007) and can be modulated by social interactions
1065 (Feldman et al. 2010). Further, individual differences in Oxt and Oxt signaling may
1066 increase an individuals vulnerability to certain neuropsychiatric disorders charac-
1067 terized by altered social cognition; see the section titled Implications for
1068 Neuropsychiatric Disorders.Some recent work suggests that endogenous Oxt
1069 may underlie natural variations in social perception (Lancaster et al. 2015). Further,
1070 in a more recent study, plasma Oxt is associated with increases in activity in brain
1071 areas that are important to social cognition such as the superior temporal sulcus,
1072 inferior frontal gyrus, and medial prefrontal cortex (Lancaster et al. 2015).
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1073 Interpretation of some of the aforementioned data is muddled by our lack of
1074 understanding about the functional relationship between peripheral and central Oxt.
1075 But, it does follow that peripheral physiology and central physiology (behavioral
1076 output) are often going to be coupled, even if the systems are separate. However,
1077 while there is some evidence that they can be associated with one another (Landgraf
1078 and Neumann 2004), this does not always appear to be the case (Amico et al. 1990;
1079 Rosenblum et al. 2002; Winslow et al. 2003; Leng and Ludwig 2015).
1080 5.1.2 Vasopressin and Social Cognition in Humans
1081 The role of Avp in the regulation of social behavior in humans has not been studied
1082 as extensively as Oxt, though it is often associated with antisocial rather than
1083 prosocial behaviors. In males, intranasal Avp increases electromyogram
1084 (EMG) activity to socially neutral facial expressions (Thompson et al. 2004), as
1085 well as the memory for happy and angry faces (Guastella et al. 2010b). This
1086 suggests that Avp acts to bias an individual to perceive a neutral stimulus as an
1087 aggressive or threatening stimulus or enhances the encoding of negative social cues
1088 (Thompson et al. 2004; Guastella et al. 2010b). In females, Avp decreases EMG
1089 responses to happy and angry faces, suggesting that Avp acts to increase the per-
1090 ception of friendliness (Thompson et al. 2006). These sex-specic responses to Avp
1091 are supported by other studies as well (Feng et al. 2014; Rilling et al. 2014;
1092 Thompson et al. 2006) and may reect sex differences in Avp neurochemistry and
1093 in the types of behavioral strategies employed during social interactions. Other
1094 effects include decreases in emotional recognition in men (Uzefovsky et al. 2012)
1095 and increases in empathy concern in individuals who received more parental
1096 warmthin their early family life (Tabak et al. 2015). It should be noted that the
1097 same issues that plague intranasal Oxt studies, such as the separation of central and
1098 peripheral Avp, are issues with the aforementioned studies as well.
1099 5.2 Oxytocin, Vasopressin, and the Mesolimbic Dopamine
1100 System
1101 Studies employing nasally administered Oxt and Avp have found numerous
1102 examples where these peptides alter the activity in various structures of the
1103 mesolimbic DA system. For example, Oxt augments the ventral striatum response
1104 to viewing the faces of romantic partners and to reciprocated cooperation from
1105 human partners (Rilling et al. 2012; Scheele et al. 2013). In women, Oxt increases
1106 activity in the VTA in response to both positive and negative facial expressions, but
1107 reduces the VTA response to reciprocated cooperation (Groppe et al. 2013; Chen
1108 et al. 2015a). While it is clear that Oxt and Avp can signicantly alter activity in
1109 several structures in the mesolimbic DA system, the functional signicance of these
1110 responses is not known. It is also possible that these neuropeptides alter social
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1111 motivation without engaging DA neurons. For example, recent data indicate that
1112 Oxt enhances the attractiveness of female faces and is correlated with increased
1113 activity in the striatum, but no measureable differences in DA signaling (Striepens
1114 et al. 2014); however, more sensitive methods may be needed to detect subtle
1115 changes in behaviorally evoked DA release.
1116 6 Implications for Neuropsychiatric Disorders
1117 Oxt and Avp have also been implicated in a variety of neuropsychiatric disorders,
1118 particularly those that are characterized by aberrant social interactions and/or
1119 heightened aggression, such as ASD, personality disorder, schizophrenia, and
1120 PTSD. Further, many of these neuropsychiatric disorders are also characterized by
1121 dysfunctions of the mesolimbic DA system (for review, see Dichter et al. 2012). As
1122 many of these disorders are complex and have multiple etiologies, it becomes even
1123 more important not only to understand the potential contributions of Oxt and Avp,
1124 as well as their therapeutic effects, but also to determine how these systems interact
1125 with the DA system.
1126 6.1 Autism Spectrum Disorder
1127 ASD is characterized by repetitive behaviors, communication difculties, and
1128 abnormal sociability (Matson and Nebel-Schwalm 2007a,b). In preclinical models
1129 of ASD, specically Oxt /and Oxtr /mice, there are behavioral decits that
1130 are consistent with some of the symptoms of ASD (Crawley et al. 2007; Lee et al.
1131 2008a,b; Macbeth et al. 2009; Wersinger et al. 2008; Winslow and Insel 2002;
1132 Ferguson et al. 2000,2001). Evidence that Oxt may have a role in ASD comes from
1133 several sources. There are reports of reduced concentrations of Oxt in the cerebral
1134 spinal uid (CSF) of autistic children, and reduced CSF Oxt is correlated with
1135 impairments in social functioning (Modahl et al. 1998). There are also increases in
1136 the amount of the Oxt prohormone in the blood of autistic children, which is
1137 indicative of incomplete processing of Oxt into its biologically active form (Green
1138 et al. 2001). Oxt treatment in adults with ASD results in the reduction of repetitive
1139 behaviors and improvements in emotional recognition (Hollander et al. 2003,2007)
1140 and can increase eye gazing, a behavior important to social communication
1141 (Auyeung et al. 2015). In youth and adults with ASD, intranasal Oxt enhances
1142 emotion recognition (Domes et al. 2013,2014; Guastella et al. 2010a) and increases
1143 social interactions (Andari et al. 2010). Further, in adults with Aspergers syn-
1144 drome, Oxt-mediated increases in emotional recognition are associated with an
1145 increase in activity in the left amygdala (as measured in fMRI) (Domes et al. 2014).
1146 There are also some genetic and epigenetic links between the Oxt system
1147 and ASD. There are data in the Chinese Han population, in Finnish families,
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1148 in Caucasian children, and in individuals with high-functioningASD, suggesting
1149 that portions of the OXTR gene may contain susceptibility loci for ASD (Wu et al.
1150 2005; Ylisaukko-oja et al. 2006; Jacob et al. 2007; Wermter et al. 2010; Nyffeler
1151 et al. 2014). Epigenetic modications of the OXTR gene have also been reported,
1152 with hypermethylation of the OXTR promoter found in ASD subjects and sub-
1153 sequent reductions in OXTR mRNA (Gregory et al. 2009). A more recent study
1154 focused on whether the levels of DNA methylation of the OXTR could predict
1155 individual variability in social perception found that there are signicant associa-
1156 tions between the degree of OXTR methylation and social perception (Jack et al.
1157 2012). Though the sample sizes in these latter two epigenetic studies are small, the
1158 data are provocative and will likely facilitate more research in this area.
1159 Data implicating Avp in the etiology of ASD are sparse, but there have been
1160 studies suggesting that polymorphisms of the AVPR1A may contribute to ASD
1161 (Kim et al. 2002; Wassink et al. 2004; Yirmiya et al. 2006; Kantojarvi et al. 2015;
1162 Tansey et al. 2011). Further, two of the polymorphisms, RS3 and RS1, have been
1163 linked to differential activation of the amygdala (Meyer-Lindenberg et al. 2009),
1164 providing a possible neural substrate with which the Avp system may interact to
1165 mediate a genetic risk for ASD.
1166 6.2 Personality Disorder
1167 Personality disorder is characterized by disconnect between an individuals
1168 behavior and cultural norms. Those diagnosed with personality disorder have
1169 impairments in at least two of the following areas: (1) cognition, (2) affectivity,
1170 (3) interpersonal functioning, and (4) impulse control (American Psychiatric
1171 Association 2013). To date, only a handful of studies have examined how exoge-
1172 nous Oxt treatment affects individuals diagnosed with personality disorder, and they
1173 have been performed primarily in individuals diagnosed with borderline personality
1174 disorder (BPD). Females diagnosed with BPD and treated with intranasal Oxt have
1175 reductions in stress reactivity (Simeon et al. 2011), decreases in hypersensitivity to
1176 threat, and decreases in amygdala activation in response to angry faces compared to
1177 controls, suggesting that Oxt in these individuals may decrease their reaction to a
1178 perceived social threat (Bertsch et al. 2013; Brune et al. 2013). This same research
1179 group also reports that females with BPD have reduced plasma Oxt concentrations
1180 (Bertsch et al. 2012). There are also data that suggest that intranasal Oxt can worsen
1181 trust in BPD and that this worsening is correlated with the patientshistory of
1182 childhood trauma (Ebert et al. 2013). One issue with all of the aforementioned
1183 studies is that BPD patients were not used as controls, only healthy individuals,
1184 making it more difcult to parse out what is going on specically within BPD
1185 patients. However, these data do reinforce the importance of past history and social
1186 context.
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1187 One study has measured Oxt in the CSF of individuals with personality disorder,
1188 which includes individuals diagnosed with intermittent explosive disorder, as well
1189 as BPD. This study found that while CSF Oxt concentrations are not correlated with
1190 having a personality disorder, a life history of suicidal behavior is inversely cor-
1191 related with Oxt (Lee et al. 2009b). The authors suggest that these data are con-
1192 sistent with the previous work in animal models demonstrating that Oxt can reduce
1193 aggressive behaviors (Consiglio and Lucion 1996; Giovenardi et al. 1998; Harmon
1194 et al. 2002a; Bales and Carter 2003).
1195 Since individuals diagnosed with a personality disorder often have more
1196 impulsive behaviors, which can result in increased aggression, it is not surprising
1197 that Avp has been examined in these individuals. However, the data appear to be
1198 contradictory. A study by Coccaro et al. (1998) found a positive correlation
1199 between Avp in the CSF of personality-disordered individuals that have a life
1200 history of aggressive behavior. However, an earlier study found no differences in
1201 CSF Avp between violent offenders and controls (Virkkunen et al. 1994). It may be
1202 that differences in the populations studied account for the inconsistency in the
1203 ndings, but it seems that more work in this area is warranted.
1204 6.3 Schizophrenia
1205 There are three broad categories of symptoms that characterize schizophrenia:
1206 (1) positive (e.g., hallucinations and delusion), (2) negative (e.g., anhedonia,
1207 impaired social behavior), and (3) cognitive/attentional (e.g., impaired memory and
1208 executive function) (American Psychiatric Association 2013). However, in humans,
1209 while its role has remained controversial, Oxt has been linked to schizophrenia
1210 since the 1970s when it was used as an antipsychotic (Bujanow 1974,1972; for a
1211 recent review, see Rich and Caldwell 2015). Altered CSF concentrations of Oxt are
1212 reported in patients diagnosed with schizophrenia (Beckmann et al. 1985;
1213 Linkowski et al. 1984). However, the data are conicting with some studies
1214 reporting an increase in Oxt and the Oxt carrier protein neurophysin I (Linkowski
1215 et al. 1984; Beckmann et al. 1985) and another reporting no change in CSF Oxt
1216 concentrations (Glovinsky et al. 1994). However, patients with higher plasma levels
1217 of Oxt have less severe positive symptoms and exhibit fewer social decits (Rubin
1218 et al. 2010,2011).
1219 There are also reports of SNPs in the promotor regions of the OXT and OXTR
1220 genes that may contribute to symptom severity and treatment efcacy in schizo-
1221 phrenic patients (Teltsh et al. 2012; Watanabe et al. 2012; Montag et al. 2013).
1222 SNPs of the OXTR gene are associated with the severity of symptoms and the
1223 improvement of the positive symptoms of schizophrenia following treatment with
1224 antipsychotics (Souza et al. 2010a,b). Additionally, postmortem analysis of brain
1225 tissue from unmedicated schizophrenia patients has altered immunoreactivity of the
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1226 Oxt carrier protein, neurophysin I, in the PVN, internal palladium, and substantia
1227 nigra (Mai et al. 1993). Most recently, in patients with schizophrenia and poly-
1228 dipsia, decreases in plasma Oxt were found to correlate with the ability to correctly
1229 identify facial emotions (Goldman et al. 2008). Thus, it appears that alterations in
1230 the Oxt system underlie all three symptom domains. Given the dysregulation of the
1231 Oxt system in patients with schizophrenia, Oxt has been studied as a candidate for
1232 use as a therapeutic.
1233 Some studies suggest that Oxt may have antipsychotic properties (for review, see
1234 Macdonald and Feifel 2012; Bakermans-Kranenburg and van Jzendoorn 2013).
1235 Previous work found that injections of Oxt can reduce the symptoms of psychosis
1236 and anhedonia in patients with schizophrenia (McEwen 2004; Churchland and
1237 Winkielman 2012). In healthy patients, intranasal Oxt increases holistic processing,
1238 divergent thinking, and creative cognition (De Dreu et al. 2013), and studies in
1239 schizophrenic patients report that intranasal Oxt can be benecial. Specically,
1240 intranasal Oxt can facilitate social cognition (Davis et al. 2013; Feifel et al. 2010;
1241 Pedersen et al. 2011; Averbeck et al. 2012) and alleviate some of the cognitive
1242 decits and positive symptoms (Pedersen et al. 2011). Yet, intranasal Oxt may be
1243 most effective as an adjunctive therapy to already prescribed antipsychotics, where
1244 chronic Oxt treatment is able to ameliorate some of the negative symptoms and the
1245 cognitive decits, as well as the positive symptoms (Feifel et al. 2010,2012;
1246 Modabbernia et al. 2013). While this research suggests that Oxt treatment has the
1247 potential to improve symptoms in all three domains, where in the brain and how
1248 these effects are mediated remains unknown.
1249 Support for a potential role for Avp in schizophrenia comes from studies indi-
1250 cating that treatment with neuroleptics improves psychiatric symptoms and reduces
1251 (or normalizes) Avp in blood plasma (Peskind et al. 1987; Raskind et al. 1987). In
1252 studies using an animal model that lacks Avp, the Brattleboro rat, there are reports
1253 of decits in behaviors associated with schizophrenia, specically social discrimi-
1254 nation and prepulse inhibition of the startle reex; these decits can be rescued
1255 following treatment with antipsychotics (Feifel and Priebe 2001,2007; Feifel et al.
1256 2004,2007,2009). Given that schizophrenia is a complicated multiple etiology
1257 neuropsychiatric disorder, it may be that Oxt and Avp only contribute to certain
1258 types of schizophrenia. Further, it is likely that their action within specic parts of
1259 the brain is particularly important. Thus, the use of preclinical models continues to
1260 be critical to help improve our understanding of the specic neural substrates where
1261 these neuropeptides may act to contribute to the symptoms associated with
1262 schizophrenia as well as to determine their therapeutic efcacy (for review, see Rich
1263 and Caldwell 2015; Feifel 2011,2012; Rosenfeld et al. 2010).
1264 6.4 Posttraumatic Stress Disorder
1265 Work examining Oxt and Avp in the context of PTSD has only recently begun, but
1266 PTSD is characterized by some symptoms related to Oxt and Avp functions,
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1267 specically dysregulation of stress reactivity and problems with intimate relation-
1268 ship interactions, which relies on normal social cognition (American Psychiatric
1269 Association 2013; Monson et al. 2009). While there have been no clinical studies
1270 looking at Oxt, intranasal Oxt has been proposed to be used as an adjunctive
1271 treatment to help enhance psychotherapy, as it may help ultimately reduce the fear
1272 response at the level of the amygdala and diminish the hormonal stress response
1273 (Koch et al. 2014). In regard to Avp, there has been one clinical study. Intranasal
1274 Avp administered to men, but not women, diagnosed with PTSD results in
1275 improved social cognition with their heterosexual partner. Further, mens urinary
1276 Avp is negatively correlated with the severity of their PTSD (Marshall 2013). While
1277 these data are limited in scope, they do suggest that understanding the role of Avp
1278 in modulating social cognition may have clinical relevance in some psychiatric
1279 conditions.
1280 7 Conclusions and Future Directions
1281 Oxt and Avp are key neurochemical signals that act throughout the brain to
1282 inuence socially motivated behaviors, having powerful effects on both cooperative
1283 and competitive behaviors mediated by their actions within the SBNN. There is also
1284 a substantial body of evidence that the mesolimbic DA system is involved in
1285 regulating cooperative and competitive behaviors. More recently, these two net-
1286 works have been combined into a larger social decision-making network. However,
1287 there is a lack of understanding about the neurochemical linkages between the
1288 socialand motivationalelements within these networks. We propose that the
1289 Oxt and Avp systems represent a bridge between the social and motivational ele-
1290 ments. More specically, we propose that Oxt and Avp provide the critical links
1291 between specic elements of the SBNN and DA within the motivational network
1292 that produce the forces that drive social behaviors. While there is little direct
1293 support for this hypothesis, there is ample evidence that Oxt and Avp can act within
1294 structures comprising the mesolimbic DA system and that manipulations of DA can
1295 inuence the same social behaviors as Oxt and Avp.
1296 These interactions also have important implications for neuropsychiatric disor-
1297 ders characterized by aberrant social behaviors, particularly those with known
1298 disruptions in Oxt and Avp signaling. Rigorous testing of preclinical models
1299 continues to be the best way to uncover the specic mechanisms (i.e., neuro-
1300 chemistry, substrates, and circuits) that are important to socially motivated
1301 behaviors. Thus, it is crucial that a variety of species be studied to help determine
1302 both the conserved and unique mechanisms of Oxt and Avp actions across
1303 development, sexes, and behaviors. Overall, this is an exciting time in the eld of
1304 socially motivated behaviors, with the advent of new experimental tools and an
1305 improvement in our ability to examine entire circuits we are now on the brink of
1306 making signicant leaps in our understanding of these systems.
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