PREPRINT – ARTICLE ACCPETED AT TRENDS IN COGNITIVE NEUROSCIENCES

An Allostatic Theory of

Daniel S. Quintana Adam J. Guastella University of Oslo University of Sydney

Oxytocin has garnered considerable interest for its role in social behavior, as well as for the potential of intranasal administration to treat social difficulties. However, current theoretical models for under- standing oxytocin’s role in social behavior have little consideration for evolutionary and developmental histories. This article aims to broaden our understanding of oxytocin’s role in social behavior by adopt- ing an ethological approach through the of Niko Tinbergen’s “four questions”: How does oxytocin work? How does the role of oxytocin change during development? How does oxytocin enhance sur- vival? How did the oxytocin system evolve? We argue that oxytocin is most accurately described as an allostatic hormone that modulates both social and non-social behavior by maintaining stability through changing environments. Keywords: oxytocin, social behavior, social cognition, neuroendocrinology

What is Oxytocin’s Role in Human Behavior? However, this “social” description has been more re- cently disputed, with research demonstrating that oxy- Oxytocin is an evolutionarily ancient [1] neuromodula- tocin modulates both social and non-social cognition tor and hormone. It is primarily produced in the hypo- [13,14]. from which it is secreted both within the brain and into the circulatory system [2]. Oxytocin has cap- Poor replication rates in oxytocin research, similar to tured the most interest of any neuromodulatory system what has been seen in many other areas of the behav- [3] due to its role in social behavior and cognition [4]. ioural sciences [15], has been largely attributed to In light of reports that intranasally administered oxyto- methodological issues and a poor understanding of cin improves social behaviour and communication mechanisms. While there have been efforts to address [5,6], it has been nominated as a potential therapeutic these limitations—in terms of better understanding in- agent to help remedy social impairments (see Glos- tranasal oxytocin administration [16–18], identifying sary) [7], which is a key characteristic of several psy- the dose-response of intranasal oxytocin [19–21], and chiatric disorders. However, more recent results have improving study design [22,23]—the lack of an over- not matched early expectations regarding oxytocin’s arching theory that accounts for oxytocin’s function effects on social behaviour in psychiatric illnesses [8], across a range of contexts has also hindered conceptual with some studies reporting that null effects [e.g., 9]. replication and generalizability [24]. As mentioned Historically, oxytocin has also been associated with above, it was originally hypothesised that oxytocin fa- terms like the “moral molecule” [10] and the “cuddle cilitates prosocial behaviour. While the original study chemical” [11]. Such terms are now typically disre- [25] that popularised this theory has been the subject of garded in the scientific literature [12], with oxytocin or- fierce methodological critiques [e.g., 26], the concept dinarily considered a hormone involved in prosocial of a neuromodulator than influences positive, but not and non-prosocial cognitive processes and behaviour. negative, social behavior is difficult to reconcile with the broader existing literature that was available at the time, such as oxytocin’s effects on maternal aggression Daniel S. Quintana, Norwegian Center for Mental Disorders Re- search (NORMENT), University of Oslo; Adam J. Guastella, Brain and [27]. Moreover, instead of being based on a broader Mind Center, Sydney Children’s Hospital Westmead Clinical School, theoretical framework that could be applicable to gen- Faculty of Medicine and Health, University of Sydney. This research eral human behavior (e.g., evolutionary theory), this was supported by an Excellence Grant from the Novo Nordisk Founda- theory was primarily based on a limited set of past re- tion to D.S.Q. (NNF16OC0019856). The authors would like to thank Nicholas M. Grebe, Peder Isager, and Nathan Brouwer who provided sults. Such an approach can hinder the abductive scien- feedback on an earlier version of this manuscript. Correspondence con- tific process (i.e., drawing conclusions from an incom- cerning this paper should be addressed to Daniel S. Quintana, Norwe- plete set of possible observations) and consequently gian Center for Mental Disorders Research (NORMENT). Email: dan- conceptual replication [24]. Thus, to accelerate pro- [email protected] gress there is a critical need for oxytocin research to

QUINTANA AND GUASTELLA

Prior learning

Response to Prediction of changes in the future events environment

Sensing changes Vital in the physiological environment parameter

Physiological adjustment Behavioral/cognitive process

Physiological process

Figure 1. An allostatic model of oxytocin. This account recognizes both the physiological and psychological actions of oxytocin. It contains four cognitive and behavioral components (green rectangles): oxytocin-mediated sensing, learning, prediction, and response. Two key phys- iological components are also represented in this model (yellow ellipses): vital physiological parameters and physiological adjustments. The oxytocin system facilitates both the adjustment of sensing and response set-points and assists learning and prediction to better adapt to changing environments. apply a general theoretical framework that has the ca- can help uncover a rich synergistic understanding of pacity connect findings across domains of human be- oxytocin that would not be possible by asking answer- haviour and physiological regulation, which will allow ing each of these questions alone [29]. A classic etho- for more informed predictions about oxytocin. Conse- logical approach to generate a deeper understanding of quently, such integrated models may result in more re- phenotypes is Niko Tinbergen’s "four questions" liable predicted effects of intranasally administered ox- framework [30]. These reciprocal questions are: (1) ytocin. How did this phenotype evolve? (2) How does this phe- notype help survival? (3) What is the physiological Reconceptualizing Oxytocin’s Role Using an Etho- cause of this phenotype? (4) How does this phenotype logical Approach develop in the individual? The first two questions ad- dress evolutionary explanations whereas the second One example of a general framework that is emerging two address proximate explanations. Notably, these in the medical sciences is the use of an evolutionary four questions consider phenotype expression both at a perspective [28]. But while evolutionary perspectives given moment, along with the sequence of moments can help uncover why a phenotype evolved, they can- that give rise to the phenotype. Tinbergen originally not easily answer how a phenotype operates. Answer- formulated these questions for behavioral phenotypes ing these two interrelated “how” and “why” questions in animal behavior, however they have more recently

QUINTANA AND GUASTELLA

Box 1. The difference between allostasis and homeostasis

While both allostasis and homeostasis provide accounts for the regulation of physiological systems, there are two crucial differences between Walter Cannon’s original homeostasis proposal [33] and allostasis [34]. First, allostasis suggests that organisms can anticipate future changes in the environment and make adjustments accordingly before they occur. Second, physiological set-points can be adjusted to better suit the environmental conditions within an allostatic system. To illustrate this, let’s use energy metabolism as an example. A classical homeostatic system makes post-hoc adjustments to return a system to a static set-point, such as eating in response to the detection of energy deficits to reach a pre-determined metabolic activity level. In contrast, an allostatic system anticipates future environmental changes (e.g., associating an environment with low energy opportunities) and adjusts metabolic activity via behavior and physiology to better cope with predicted change. Allostasis and homeostasis are not exclusive processes, as they can operate complementarily [86]. While predicting future conditions is efficient over the long term, prediction errors are bound to occur on occasion, especially when conditions rapidly change unpredictably. Thus, homeostasis is necessary to perform post-hoc corrections to address prediction errors. However, the sensitivity of this correction is dependent on prior predictions.

Of course, descriptions of homeostasis have been updated since Walter Cannon’s original proposal to include anticipatory responses and adjustable set-points [34]. In light of more modern interpretations it would be technically correct to use the term “homeostasis” to describe a system that includes anticipatory responses and adjustable set-points, however, here we use the term “allostasis” to avoid potential confusion between the classic and more recent interpretations of homeostasis. been applied to several human characteristics, such as oxytocin in human social behavior, it is instructive to hormonal phenotypes [31], psychiatric conditions [32], characterize its evolutionary history (i.e., phylogeny). and social behaviors [29]. Oxytocin-like peptides are at least 600 million years old [36], with the precursor to mammalian oxytocin In this article, we review oxytocin through the lens of arising before vertebrates diverged from invertebrates Tinbergen’s four questions. In light of the two proxi- [37]. shares its ancestry with this precur- mate and two evolutionary explanations for oxytocin's sor, which is reflected by its structural similarity to ox- role in behavior and physiology, we argue that oxyto- ytocin and oxytocin’s affinity with the V1A vasopres- cin’s role in behavior and cognition is best character- sin receptor [38]. Oxytocin-like signaling influences ized as allostatic, as it facilitates adaptation, consolida- behavioral responses to changing environments in or- tion, and stability through changing environments. Un- ganisms with relatively unsophisticated nervous sys- like Cannon’s original description of homeostasis [33], tems, who shared ancient common ancestors with hu- which refers to moment-to-moment post hoc physio- mans. For instance, straightforward associative learn- logical adjustments to the environment and static phys- ing paradigms demonstrate that wild-type roundworms iological set-points, allostasis accounts for anticipated (C. elegans) can learn to associate certain environments changes in the environment to help ensure systems sta- with aversive properties. However, roundworms lack- bility, by integrating prior knowledge with current in- ing an oxytocin homologue (nematocin) and its recep- formation to modulate behavior and adjusting physio- tor fail to demonstrate the same degree of avoidance logical set-points based on environmental demands after pre-exposure to the aversive stimulus [39]. This (Box 1) [34]. Our allostatic model of oxytocin, which points to an error in the allostatic loop as mutant round- recognizes both its physiological and psychological ac- worms could not integrate current sensory information tions, contains four key cognitive and behavioral allo- with prior knowledge due to a deficit in associative static components: oxytocin-mediated sensing, learn- learning. Oxytocin’s role in adjusting to changes in en- ing, prediction, and response (Fig. 1). Oxytocin system vironmental conditions, based on prior learning, seems impairments can influence any of these four cognitive to be conserved in humans [40]. and behavioral allostatic components, which has impli- cations for several psychiatric disorders. Rapidly learning the behaviors that best suit a new environment is integral to an organism’s success. This How Did the Oxytocin System Evolve? has been demonstrated in neurally unsophisticated in- vertebrate organisms such the roundworm, as described Identifying oxytocin’s physiological and behavioral ef- above [39], in which nematocin is expressed in sensory fects that are highly conserved across species can help that detect thermal or mechanical changes in clarify its purpose. Novel regulatory circuits develop the environment [39,41]. Oxytocin also influences from older circuits [35], so it follows that unravelling a memory and learning processes in a range of verte- circuit’s origins can provide a better understanding of brates [42,43]. For instance, compared to wild-type its present role. Therefore, to help decipher the role of

QUINTANA AND GUASTELLA mice, oxytocin receptor (OXTR) knockout mice are de- ficient in reversal learning, which requires behavioral Glossary flexibility along with the ability to learn new behavioral strategies to quickly adapt to changes in the environ- Allostasis: The process of maintaining stability through ment [44]. In humans, intranasal oxytocin administra- change via the anticipation of future changes in environmen- tion facilitates rapid adaptation to social fear signals, tal conditions and adjusting response set-points. For exam- ple, recognizing anger in others can help avoid future pain which has survival value in rapidly changing environ- and injury by motivating an individual to either leave a situa- ments [45]. But while the effects of oxytocin admin- tion or prepare for conflict. The threshold for detecting anger istration on memory and learning in humans have been in others decreases when offspring are potentially threat- less consistent than animal research [42,46], these find- ened. This is contrast to homeostasis, which is the process of ings have been corroborated by analysis of oxytocin maintaining stability through change in relation to current conditions using a static response set-point. pathway gene expression in the , which re- ported that regions of increased OXTR gene expression Conceptual replication: Replication studies improve the are associated with brain regions networks underlying credibility of prior results. Broadly speaking, there are two learning processes [47], perhaps pointing to the need to approaches for replication. In a direct replication, research- ers attempt to replicate a previous finding using the same (or improve intranasal administration methods. Behavioral a very similar) protocol. In contrast, a conceptual replication flexibility is a critical element of an allostatic system, uses a different protocol in an attempt to find results con- as this facilitates adaptive behavioural strategies to bet- sistent with the original paper. ter suit a change in environmental conditions. Conserved: When a system or phenotype has remained un- changed, or relatively unchanged, over evolutionary history. Oxytocin-like mediation of tissue contraction can For instance, oxytocin only differs by one amino acid to its be observed in invertebrates, such as earthworms (Ei- ancestral forms (i.e., isotocin, mesotocin, inotocin, and nem- senia foetida) and leeches (Whitmania pigra), with the atocin). injection of an oxytocin-like peptide (anetocin) regulat- Ethology: A scientific discipline investigating animal be- ing contraction of the gut and the earthworm’s uterus havior under natural conditions, sometimes referred to as homologue [48,49]. A similar physiological response “behavioral biology”. has also been observed in sea squirts, with an oxytocin- like peptide shown to influence osmoregulation via sy- Evolutionary explanations: How a system evolved and the phon contraction [50]. Oxytocin’s role in osmoregula- current utility of a system (i.e., what is its current purpose?). tion is conserved in humans, via action on oxytocin re- Knockout: A laboratory organism (typically mice) that has ceptors in the cardiovascular system and the kidneys had had one or more genes inactivated or “knocked out”. By [51]. The effects of oxytocin on smooth muscle con- inactivating one or more genes, researchers can investigate traction is also conserved in humans, with oxytocin- the role of specific genes by comparing outcome measures of interest against wild-type (i.e., genetically unmodified) mediated smooth muscle contractions playing a role in conspecifics. human parturition, copulation, reproduction, gastric emptying, and cardiovascular regulation [2]. Therefore, Oxytocin homologue: A nonapeptide that closely related to while oxytocin seems to have first assisted basic tissue oxytocin, which can be traced back to a common precursor contraction, evolutionary pressures appear to have co- nonapeptide. Oxytocin homologues are found in a wide range of invertebrate (e.g., annepressin, inotocin, nematocin) opted oxytocin’s contractile effects to a broad range of and vertebrate (e.g., isotocin, mesotocin) species [2]. physiological systems in mammals that underlie allo- stasis. Crucially, oxytocin’s effects on smooth muscle Phenotype: An observable characteristic or trait of an or- contraction seems to operate with adjustable set-points ganism. This can include physical characteristics, physiolog- ical systems, and behavior. depending on situational demands (e.g., digestion, birth, lactation) [52–55], which is a key attribute of an Proximate explanations: A system’s underlying mecha- allostatic system. nisms and how the system develops over the lifespan.

Long-range axonal projections from oxytocin and oxy- Social impairments: Dysfunction in reciprocal social com- munication and interaction. Social impairment is associated tocin-like neurons to other regions of the brain are only with poor functional outcomes in relation to relationships, consistently found in complex vertebrates such as employment, and educational outcomes. mammals [56] and reptiles [57]. Less complex basal vertebrates, who only show stereotypic reproductive behaviors, demonstrate unspecific central release into

QUINTANA AND GUASTELLA

Prefrontal cortex Parvocellular Dorsal vagal complex Hippocampus neuronal axon Spinal cord

Sensory cortices PVN

Arcuate nucleus Magnocellular neuronal axon SON Amygdala Magnocellular neuronal axon Axonal release Dendritic release Endogenous oxytocin

Oxytocin secretion Posterior to the periphery pituitary

Figure 2. Oxytocin production and secretion within the brain and to the periphery: Oxytocin is mainly synthesized in by magno- cellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei within the hypothalamus. These nuclei have axons projecting to the , where oxytocin is stored for peripheral release. Magnocellular axonal neurons also project to the prefrontal cortex, hippocampus, arcuate nucleus, and amygdala for direct axonal release (solid arrows). Dendritically released oxytocin (dashed arrows) targets the amygdala and sensory cortices. Oxytocin is also synthesized in the parvocellular neurons of paraventricular nucleus, with axonal projections to the spinal cord and dorsal vagal complex (DVC). Image created with BioRender.com the cerebrospinal fluid [58]. Together, this has led to is its regulatory role. Our allostatic model proposes that speculation that long range axonal projections to vari- the oxytocin system supports the processing of stimuli ous brain regions, which facilitate the precise regula- that promotes survival and future acclimations to envi- tion of complex and sequential behaviors that are espe- ronmental shifts (Fig. 1). Such stimuli are often, but not cially apparent in mammals, appeared more recently in always, socially-relevant. The high conservation of the our evolutionary history [59]. Altogether, oxytocin’s oxytocin system points to its important function in be- modulatory effects on complex mammalian social be- havior and physiology. While the oxytocin system haviors has come an extraordinarily long way from the plays a role in energy regulation via thermoregulation, relatively basic functions, such as the osmotic response appetite, and metabolic homeostasis [60], this system in the sea squirt and gustatory learning in the round- has also evolved to influence learning and behavior, worm. Despite this wide gamut of complexity, a com- which is an efficient means of regulating energy by an- mon thread throughout oxytocin’s evolutionary history

QUINTANA AND GUASTELLA

Figure 3. Oxytocin pathway expression in the human brain. Oxytocin expression in the human brain (a) is associated with brain activations patterns underlying the processing of social cognition (b), and oxytocin pathway genes (OXTR and CD38) are highly coex- pressed with dopaminergic and muscarinic acetylcholine genes (c). These expression patterns were also significantly associated with several anticipatory, appetitive, and aversive mental states patterns, which were derived from a meta-analysis from a pool over 14,000 fMRI studies (d). Adapted from Quintana and colleagues [47]. ticipating and influencing the future via behavioral re- them. There is evidence for an ancient role of the oxy- sponses. To use a food foraging example, it is more ef- tocin system, with an oxytocin-like peptide (conopres- ficient over the long run for an organism to predict lo- sin) in the great pond snail (Lymnaea stagnalis), play- cations with abundant food sources by integrating past ing a key role in stereotypic mating behaviors, such as experience, than to use a trial-and-error strategy or a male copulation via gonadal contraction [61], mirroring random selection process. oxytocin’s role in human ejaculation [62]. Similarly, nematocin in the roundworm modulates mating behav- How Does the Oxytocin System Promote Reproduc- iors, including mate search and mate recognition [41]. tion and Survival? The role of oxytocin on mating-related behaviors has been conserved humans, as oxytocin facilitates com- Observational methods, such comparative analyses be- plex romantic bonds. For instance, intranasal oxytocin tween species and understanding how the oxytocin sys- increases perceived attractiveness in romantic female tem enhances present reproduction and survival, can partners in heterosexual men [63], and modulates social provide important clues for how the oxytocin system distance between heterosexual males and females [64]. evolved in humans. In this section, we discuss how ox- ytocin’s role in improving prediction and shifting phys- The most striking example of oxytocin’s role in off- iological set-points enhances present-day survival and spring care is that oxytocin knockout female mice can- reproduction. not eject milk and feed their offspring [65]. But despite the well-known role of the oxytocin system in parturi- Mating behaviors play an instrumental role in species tion, oxytocin knockout mice can still give birth to via- propagation, so they are a prime candidate for the rapid ble young [66], suggesting other systems work redun- selection of traits and the signaling systems that support dantly. Oxytocin has been shown to play an important

QUINTANA AND GUASTELLA role in mammalian mother-offspring behavior in sev- stress dysregulation later in life. This analgesic effect eral non-human species, such as mice [67], prairie may have translational value, with research demon- voles [68], and sheep [69]. In fact, the role of oxytocin strating that oxytocin treatment shortly after trauma in in social behavior was first suggested in 1968 by humans is protective against the later development of Klopfer & Klopfer in relation to goat maternal behav- post-traumatic stress disorder [87]. Altogether, by me- ior. The physiological role of oxytocin in parturition diating senses that contribute to learning, future predic- was well-known at the time. However, in what was an tion, and response processes (Fig. 1), the oxytocin sig- unorthodox idea at the time, the Klopfers speculated naling system is well-suited to facilitate survival. that “…this hormone [oxytocin], which apparently brings on the final uterine spasms which deliver the kid, How Does Oxytocin Exert its Effects? is also implicated in the induction of maternal behav- ior.” [70, pg. 865]. This prescient conclusion regarding In mammals, oxytocin is predominately synthesized by the role of oxytocin in mammalian social behavior was magnocellular neurons in the supraoptic and para- confirmed by research decades later. On first glance, ventricular nuclei within the hypothalamus [88] (Fig. oxytocin’s ‘classic’ reproductive functions appear to be 2). The supraoptic and paraventricular nuclei have reflexive and homeostatic, rather than allostatic. How- magnocellular neuronal axons that project to the poste- ever, the oxytocin system adapts to support the adjust- rior pituitary, where oxytocin is stored for peripheral ment physiological set-points (e.g., blood volume, na- release, modulating the activity of several peripheral triuresis) to better cope with the situational demands of systems. Magnocellular long-range axonal neurons pregnancy, parturition and lactation [71]. also project to several regions for central re- lease, such as the prefrontal cortex, arcuate nucleus, Oxytocin also plays an important role in appetite and and hippocampus [89,90], to facilitate local delivery of feeding, which are crucial survival processes. For in- oxytocin to several specific sites in the brain to modu- stance, antagonism of the OXTR increases meal sizes in late a diverse range of behaviors [88,89,91,92]. rodents [72] and OXTR oxytocin knockout mice are heavier than wild-type mice [73]. Moreover, oxytocin Given the relatively large amount of oxytocin that can is produced in the magnocellular neurons of the para- be released dendritically [93] and the long half-life of ventricular nucleus of the hypothalamus, a region of the oxytocin in the central nervous system of about 20 brain also involved in food intake regulation [74]. Ox- minutes [94], compared to the 2-minute half-life in ytocin administration has been found to reduce food in- blood, it is possible that centrally released oxytocin can take [75] and improve gastric motility [76] in humans, diffuse to forebrain areas not directly reached by axonal an effect that is most likely driven by oxytocin recep- projections [95–97]. Dendritically-released oxytocin tors on gastrointestinal tract smooth muscle [77]. While from the paraventricular nucleus has also been shown a relatively recent meta-analysis [78] concluded that to travel to the sensory cortices either via diffusion or oxytocin administration reduces feeding in animals, cerebrospinal fluid (CSF) [98,99]. However, there has there was no significant effect in humans, which may been more recent dispute regarding the effectiveness of reflect study heterogeneity or issues with intranasal ox- diffusion via dendritic release for meaningful quantities ytocin administration methods. Relatedly, a recent pro- of oxytocin delivery for sites that are distant from the posal using a life history theory framework suggests hypothalamus and axonal projections [100]. This sug- that oxytocin is central to the allocation of limited re- gests that delivery to these distant sites might be largely sources, including energy [79]. carried out by axonal release via long-range projec- tions. Oxytocin is also synthesized in parvocellular The need to monitor the environment and adapt to neurons of the paraventricular nucleus, with projections changes is critical for survival. Converging evidence to the midbrain, spinal cord, dorsal vagal complex [92], suggests that oxytocin facilitates the processing of sen- and magnocellular neurons in the sory cues, such as temperature [80], hunger [81], pain [56]. Central release is mediated by both parvocellular [82,83], and thirst [81,84]. The altered processing of in- and magnocellular neuronal axon release, with the abil- ternal states are likely due to shifting physiological set- ity for oxytocin to prime its own release [101] explain- points [82,83,85], which is an important element of al- ing the long-lasting behavioral effects of oxytocin. lostatic systems [86]. For instance, increases in circu- lating oxytocin enhances pain sensation tolerance in The location of oxytocin receptors, the combination of newborn mammals, which may be protective against axonal and dendritic oxytocin release, and the timing

QUINTANA AND GUASTELLA

Response Sensing Learning Prediction Conserved learning processing [39, 40, 42-45, 47] Conserved sensory functions [39, 41, 80-85] Tissue contraction across species [48-50, 52-55, 77]

Phylogeny Coordinated and planned behaviors across species [56, 57, 61, 63] Water, metabolic, and feeding regulation [60, 72-76, 114] Reproductive behaviors and reflexes [41, 61-64, 67-71] Milk let down reflex [65, 71]

Purpose Parturition [2, 83, 111] Sensory modalities (e.g., thirst, pain, temperature) [80-85] explinations Evolutionary Central dendritic release [93, 95-99] Central axonal release [56, 59, 89-92, 100] Location of oxytocin receptors in the brain [47, 102]

Mechanism Peripheral and central release mechanisms [92, 104] Changes in oxytocin signalling over the lifetime [109, 117-119] Learning in early development [115, 116, 119, 121, 122] Oxytocin's protective role during parturition for the newborn [83,111,112] Proximate explinations Proximate Ontogeny Oxytocin's role in cortical development [98] Set-point Anticipation adjustment

Figure 4. Integrating Tinbergen’s four questions with an allostatic theory of oxytocin. Important research results described in this article are organized by Tinbergen’s four questions: How did the oxytocin system evolve (phylogeny), how does oxytocin enhance sur- vival (purpose), how does oxytocin work (mechanism), and how does the role of oxytocin change during development (ontogeny). In addition, these results are categorized by how they are primarily related to the four key elements of our proposed allostatic model (re- sponse, sensing, learning, and prediction; Fig, 1), within the two main characteristics of an allostatic system: set-point adjustment and anticipation. and coordination of oxytocin secretion contributes to the brain and periphery has important implications for the diverse, allostatic effects of oxytocin. While the site the coordination of physiology and behavior. Varied of oxytocin synthesis and axonal pathway destinations axonal projection destinations also help regulate a di- are similar across mammalian species, but what differs verse range of behaviors [92]. For instance, opto- is the site of oxytocin receptors [102]. The site of re- gentetically-mediated stimulation of hypothalamic ceptors can evolve faster than axonal pathways—high- neurons in rats induces specific oxytocin release in the lighting the role of extrasynaptic release—allowing rel- central amygdala via axonal projections [89]. Recent atively rapid behavioral acclimations to changes in the human evidence derived from two post-mortem da- environment [103]. Only small variations in oxytocin tasets indicates considerable diversity for oxytocin’s receptor gene promotor elements are needed to modify role in psychological processes, with the associations expression patterns, which can facilitate rapid behav- between OXTR expression patterns in the human brain ioral acclimations. The capacity to independently regu- and brain circuits underlying anticipatory, appetitive, late central and peripheral secretion [104], a means of and aversive mental states (Fig. 3). The OXTR expres- varying peripheral effects simply by adjusting the re- sion pattern had among the top 0.5% strongest correla- lease schedule of oxytocin (e.g., pulsatile secretion dur- tions with these mental state patterns, out of over ing lactation [105] vs. continuous secretion for natriu- 20,000 protein coding genes [47]. resis [106]), and the widespread delivery of oxytocin in

QUINTANA AND GUASTELLA

Box 2. Verifying oxytocin’s allostatic role in cognition and behavior In this article we outline evidence for the involvement of the oxytocin system in allostatic regulation, using both evolutionary and prox- imate explanations. However, future research is required to verify this theory. Here, we offer some suggestions on how this theory can be corroborated. In terms of cognition, research can verify how oxytocin influences learning and decision making under shifting condi- tions (e.g., a probabilistic reversal learning task), using both social and non-social cues. An allostatic theory would predict that intranasal oxytocin administration improves learning speed and decision making compared to placebo, regardless of whether the stimuli is social or non-social. Future research can also assess the role of oxytocin on the allostatic regulation of physiological processes. Body fluid regulation is an appealing candidate for investigation, as humans tend to feel thirsty before appreciable changes in body fluid composition [84]. Intriguingly, oxytocin’s association with thirst in the anticipation of fluid loss has been reported in breastfeeding mothers, inde- pendent of vasopressin activity and plasma osmolality [85]. Thus, future research could manipulate oxytocin levels using intranasal administration to examine how this system influences allostatic thirst behavior and cognition.

To assess the role of oxytocin signaling on human development, future work can also investigate genetic variants of the oxytocin signaling pathway (e.g., the oxytocin receptor). Research can examine whether there are oxytocin pathway gene variants that are protective against early life stressors due to the promotion of behavioral and cognitive flexibility, which is needed to cope with changing environments. Most gene-environment studies have extremely low statistical power, increasing the chances of false-positive findings, which highlights the need for large population-level investigations. In terms of evolutionary processes, research can assess the conservation of oxytocin’s role in associative learning and planned behaviors across a wide range of species with oxytocin-like signaling, using both social and non- social tasks. Indeed, the experimental tasks described above can be easily adapted for animal research.

How Does the Role of Oxytocin Change Across De- development. Unlike oxytocin receptor expression lev- velopment? els in the brain, which vary across the lifespan, the number of oxytocin neurons is fairly similar between For our ancestors, each stage of development would gestation to adulthood [109]. have been associated with unique behavioral chal- lenges related to survival and reproduction. For new- Research supports an analgesic and hypoxia buffering borns and children, surviving the high risks of birth, role of oxytocin in early life during parturition bonding with parents, and social learning would have [83,111], providing a possible explanation for fetal de- been crucial. Later in development, bonding with allies velopment of the oxytocin system—to help cope with and potential mates would have been paramount. And the stresses associated with childbirth. Relatedly, oxy- of course, later in life, bonding with children would tocin may also assist with the expulsion of fluid from help ensure that offspring survive long enough for their the lungs after birth [112], which assists in the fetal genes to be passed on to the next generation. In this transition to independent respiration outside the womb. section, we discuss how and why oxytocin signaling In terms of oxytocin release, the characteristic pulsatile changes across development and the implications of release of oxytocin appears from birth in humans [113]. these shifts. For newborns, oxytocin has been shown to trigger feed- ing behaviors, at least in mice [114]. In toddlers, evi- The expression of an oxytocin-like peptide in early in- dence is emerging for oxytocin’s role in social behavior vertebrate development points to the use of peptide sig- [115] and its stress buffering effect [116], which has naling in the early ontogenesis of this evolutionary an- been more thoroughly investigated in adults. Scholars cient group of organisms. The central nervous system have identified specific “infant”, “pubertal”, and of sea squirt larvae, which is made up of only approxi- “adult”, patterns of oxytocin receptor expression in the mately 100 neurons, expresses oxytocin-like genes brain across mammalian development, with both the in- [107]. Oxytocin-related peptides are also expressed in fant and pubertal patterns characterized by transient ox- the larval form of roundworms [41] and red flour bee- ytocin receptor expression during these developmental tles (Tribolium castaneum), with the latter demonstrat- periods [109,117,118]. These oxytocin binding patterns ing increased expression compared to adults [108]. Ox- across development seems to vary between species ytocin development is highly conserved in ver- [119], which is consistent with species-specific evolu- tebrates, as they are generated early in embryonic de- tionary pressures. velopment from the third ventricle prenatally in several mammalian and non-mammalian species, such as hu- There are several lines of evidence indicating that en- mans, rodents, fish, and chickens [109]. Oxytocin is vironmental pressures on oxytocinergic signaling early first synthesized in the human brain prenatally and de- in life impacts later physiology and behavior. It has tected around 14-weeks gestation [110], suggesting that been remarkably demonstrated that oxytocin facilitates this neuropeptide plays a role in fetal physiology and

QUINTANA AND GUASTELLA cortical development in response to sensory experi- namely, that the oxytocin system facilitates allostasis ences in neonatal non-human mammals [98]. Specifi- by anticipating change in the future and adjusting phys- cally, it was shown that early-life sensory deprivation iological set-points to better cope with change (Fig. 4). reduced oxytocin neuron firing in the paraventricular In terms of evolutionary explanations, several physio- nuclei (PVN) as well as oxytocin release from the PVN, logical and behavioral functions of oxytocin that sup- which is indicative of the crucial role of sensory expe- port allostasis, particularly features that improve the riences in early life and how oxytocin signaling plays a anticipation of future needs, are highly conserved role in this process. Moreover, oxytocin administration across vertebrate and invertebrate species rescued the detrimental effects of sensory deprivation. [39,40,44,45,50,51]. The oxytocin system also sup- In another example, nursery-reared rhesus monkeys ports reproductive and survival functions by helping demonstrate lower concentrations of oxytocin in CSF adjust physiological set-points to better suit current compared to mother-reared rhesus monkeys [120]. Ox- needs [52–55]. In terms of proximate explanations, the ytocin also plays an instrumental role in learning during location of oxytocin receptors in the brain [47,118] and development, for both social [121] and non-social cues the combination of axonal and dendritic oxytocin re- [119], which impacts the future prediction of condi- lease in the brain [88,92], supports varied behaviors un- tions and behavioral responses (Fig. 1). Moreover, CSF derlying sensation, reaction, learning, and prediction. levels of oxytocin in human neonates are positively as- Additionally, oxytocin’s role in early life learning sociated with social engagement behaviors at three [70,98,115,119] and its changing function over the life- months of age [116], which is a critical early period for time [83,109,111,117,118] reflects how this neuropep- learning social communication. While causation cannot tide supports flexible behaviors and shifting demands, be inferred from these results, subsequent work in ma- depending on the life-period. caque neonates demonstrated that oxytocin administra- tion increases affiliative communicative gestures com- Concluding Remarks pared to placebo [122]. The highest levels of oxytocin binding in the prenatal and postnatal mouse around the A close examination of the proximate and evolutionary period of parturition are also found in tissues regions explanations for oxytocin suggests that it has evolved regulating physiological regulation and stress re- as a hormone that promotes allostasis, which is the abil- sponses [123]. ity to maintain stability through change [127]. This is consistent with oxytocin’s popularized role in social Why would evolution select certain biological systems behavior, as these behaviors can be used to maintain to be especially susceptible to the environment and oth- allostasis, but also recognizes broader roles of oxyto- ers to be largely innate during critical periods of devel- cin, beyond social behavior, and also for situations opment? Systems that can be shaped by the environ- where survival and adaptation may be in conflict with ment require flexibility. Success for our ancestors was pro-social responses (Box 2). Although the concept of dependent on the ability to quickly adapt to changing allostasis shares many similarities with homeostasis, al- environments, which is thought to have been largely lostasis recognizes that organisms can anticipate future driven by cumulative learning from others [124]. The changes in the environment and respond accordingly susceptibility of the oxytocin system to early life stress- using both physiological and behavioral strategies (Box ors may be a trade-off for its benefits on learning, pre- 1; Fig. 1). Indeed, preliminary research has shown that diction, and response. In other words, the extraordinary intranasally administered oxytocin may improve the ability for humans to adapt to changing environments ability to anticipate the actions of others [128] and fa- may come at the cost of psychiatric disorders that cilitate cooperative behavior [129], which could occur emerge when the biological systems that support learn- through improved theory of mind capability and neuro- ing, such as the oxytocin system, are impaired [125]. biological synchrony [130]. While it has been proposed that oxytocin circuits contribute to learning and predic- An integrative interpretation of oxytocin’s role via tion based impairments in autism [125], prior theories a Tinbergian approach tend not to account for the role of non-social effects of oxytocin. Answering Tinbergen’s four interrelated questions re- veals a deep synergistic conception of behaviors and But how does one neuropeptide influence such a di- biological processes that is difficult to achieve by ad- verse range of behaviors centered on the singular goal dressing each of these questions in isolation [126],

QUINTANA AND GUASTELLA

Outstanding questions

• What are the dose-dependent effects of intranasally administered oxytocin on allostatic processes? The commonly administered dose is 24 international units, but there is little evidence that this dose is the most efficacious.

• Central oxytocin receptor (OXTR) patterns in human adults have been recently identified, helping clarify the functional signifi- cance of oxytocin signaling. But do OXTR expression patterns change across the lifespan? And if so, what is the functional sig- nificance of these changes and are these related to allostatic processes?

• Where does intranasally administered oxytocin travel after administration? Preliminary evidence using a novel oxytocin receptor positron emission tomography tracer suggests that intranasally administered oxytocin in rodents reaches the olfactory bulb of rodents, however, an OXTR radiotracer is yet to be developed for human use. Identifying the destination of intranasally adminis- tered oxytocin can help clarify its effects and confirm that intranasally administered oxytocin reaches the brain via a nose-to- brain route.

• How does oxytocin signaling interact with other signaling systems to exert its effects on allostatic processes? For instance, OXTR is highly coexpressed with dopamine D2 and D5 receptors in the human brain. This suggests that dopamine signaling is likely to play an important role on oxytocin signaling via the reward of accurate allostatic prediction.

• Despite the documented sex-specific roles of oxytocin across various domains (e.g., empathic accuracy, stress response, neural activity) the majority of oxytocin research has been conducted in males. Are oxytocin’s effects on allostatic processes sexually dimorphic? Do these sexually dimorphic effects change over the lifespan?

of allostasis? By the unique properties of oxytocin sig- some aspects of our theoretical framework are specula- naling. Oxytocin is a relatively unique messaging sys- tive, particularly those drawn from a relatively small tem in that it is almost exclusively produced in the hy- pool of human oxytocin studies, whose outcomes are pothalamus but has a wide variety of actions both pe- sometimes inconsistent. However, the main goal for ripherally and centrally, which can occur simultane- our proposal is to stimulate these emerging lines of re- ously. So rather than evolving a new messenger system, search. A greater research focus is required on under- evolution seems to have co-opted the ancestral oxyto- standing the nuanced effects of oxytocin using various cin system by adjusting its release schedule and engi- research approaches investigating the varied role this neering receptors that are sensitive to specific release messaging system has on different peripheral and cen- schedules. Put another way, instead of developing a tral processes (see Outstanding Questions). Such novel radiofrequency bands for new sets of broadcasts, work will extend our understanding of how this ancient evolution uncovered a way to communicate using neuropeptide modulates our response to both current Morse code. Given that oxytocin exerts its effects both and anticipated changes in the environment. peripherally and centrally, this system is well-placed to coordinate diverse physiological and psychological ac- References tions that center on specific goals [131]. Allostasis also requires the coordination of several parallel processes, 1 Feldman, R. et al. (2016) Oxytocin pathway genes: evolution- as allostatic systems need to anticipate future changes ary ancient system impacting on human affiliation, sociality, in environmental conditions and to make the required and psychopathology. Biol. Psychiatry 79, 174–184 2 Jurek, B. and Neumann, I.D. (2018) The oxytocin receptor: adjustments, which are often behavioral. Our allostatic from intracellular signaling to behavior. Physiol. Rev. 98, model highlights the crucial role that oxytocin plays in 1805–1908 learning and plasticity, which has implications for the 3 Kenkel, W.M. (2019) Corpus Colossal: A Bibliometric Anal- treatment of social difficulty. The manipulation of the ysis of Neuroscience Abstracts and Impact Factor. Front. In- oxytocin system via intranasal administration could tegr. Neurosci. 13, 4 Guastella, A.J. and MacLeod, C. (2012) A critical review of modulate the core features of learning, interoception, the influence of oxytocin nasal spray on social cognition in and prediction to improve social outcomes. humans: Evidence and future directions. Horm. Behav. 61, 410–418 In this paper, we propose that oxytocin’s primary role 5 Yatawara, C.J. et al. (2016) The effect of oxytocin nasal spray on social interaction deficits observed in young children with in behavior is to facilitate stability in changing environ- autism: a randomized clinical crossover trial. Mol. Psychiatry ments, which rooted in its evolutionary significance to 21, 1225–1231 promote survival and operationalized through circuits guiding learning, prediction, and response. At present,

QUINTANA AND GUASTELLA

6 Parker, K.J. et al. (2017) Intranasal oxytocin treatment for so- 27 Ferris, C.F. et al. (1992) Oxytocin in the amygdala facilitates cial deficits and biomarkers of response in children with au- maternal aggression. Ann. N. Y. Acad. Sci. 652, 456–457 tism. Proc. Natl. Acad. Sci. DOI: 28 Wells, J.C. et al. (2017) Evolutionary public health: introduc- https://doi.org/10.1073/pnas.1705521114 ing the concept. The Lancet 390, 500–509 7 Guastella, A.J. and Hickie, I.B. (2016) Oxytocin treatment, 29 Hofmann, H.A. et al. (2014) An evolutionary framework for circuitry and autism: a critical review of the literature placing studying mechanisms of social behavior. Trends Ecol. Evol. oxytocin into the autism context. Biol. Psychiatry 79, 234– 29, 581–589 242 30 Tinbergen, N. (1963) On aims and methods of ethology. 8 Alvares, G.A. et al. (2017) Beyond the hype and hope: critical Ethology 20, 410–433 considerations for intranasal oxytocin research in autism 31 Calisi, R.M. (2014) An integrative overview of the role of spectrum disorder. Autism Res. 10, 25–41 gonadotropin-inhibitory hormone in behavior: Applying Tin- 9 Dadds, M.R. et al. (2014) Nasal oxytocin for social deficits in bergen’s four questions. Gen. Comp. Endocrinol. 203, 95– childhood autism: A randomized controlled trial. J. Autism 105 Dev. Disord. 44, 521–531 32 Brüne, M. et al. (2012) The crisis of psychiatry—insights and 10 Zak, P.J. (2012) The moral molecule: The source of love and prospects from evolutionary theory. World Psychiatry 11, 55– prosperity, Random House. 57 11 Coghlan, A. (2010) ‘Cuddle chemical’eases symptoms of 33 Cannon, W.B. (1929) Organization for physiological homeo- schizophrenia. New Sci. 207, 10 stasis. Physiol. Rev. 9, 399–431 12 Shamay-Tsoory, S.G. and Abu-Akel, A. (2016) The social sa- 34 Ramsay, D.S. and Woods, S.C. (2014) Clarifying the roles of lience hypothesis of oxytocin. Biol. Psychiatry 79, 194–202 homeostasis and allostasis in physiological regulation. Psy- 13 Eckstein, M. et al. (2019) Oxytocin increases -gaze to- chol. Rev. 121, 225 wards novel social and non-social stimuli. Soc. Neurosci. 14, 35 Carter, C.S. (2014) Oxytocin pathways and the evolution of 594–607 human behavior. Annu. Rev. Psychol. 65, 17–39 14 Harari-Dahan, O. and Bernstein, A. (2017) Oxytocin attenu- 36 Gwee, P.-C. et al. (2009) Characterization of the neurohypo- ates social and non-social avoidance: Re-thinking the social physial hormone gene loci in elephant shark and the Japanese specificity of Oxytocin. Psychoneuroendocrinology 81, 105– lamprey: origin of the vertebrate neurohypophysial hormone 112 genes. BMC Evol. Biol. 9, 47 15 Munafò, M.R. et al. (2017) A manifesto for reproducible sci- 37 Liutkeviciute, Z. et al. (2016) Global map of oxytocin/vaso- ence. Nat. Hum. Behav. 1, 0021 pressin-like neuropeptide signalling in insects. Sci. Rep. 6, 16 Lee, M.R. et al. (2018) Oxytocin by intranasal and intrave- 39177 nous routes reaches the cerebrospinal fluid in rhesus ma- 38 Manning, M. et al. (2012) Oxytocin and vasopressin agonists caques: determination using a novel oxytocin assay. Mol. and antagonists as research tools and potential therapeutics. J. Psychiatry 23, 115–122 Neuroendocrinol. 24, 609–628 17 Smith, A.S. et al. (2019) Oxytocin delivered nasally or intra- 39 Beets, I. et al. (2012) Vasopressin/oxytocin-related signaling peritoneally reaches the brain and plasma of normal and oxy- regulates gustatory associative learning in C. elegans. Science tocin knockout mice. Pharmacol. Res. 146, 104324 338, 543–545 18 Martins, D. et al. (2019) Do direct nose-to-brain pathways un- 40 Hurlemann, R. et al. (2010) Oxytocin enhances amygdala-de- derlie intranasal oxytocin-induced changes in regional cere- pendent, socially reinforced learning and emotional empathy bral blood flow in humans? bioRxiv in humans. J. Neurosci. 30, 4999–5007 19 Quintana, D.S. et al. (2017) Dose-dependent social-cognitive 41 Garrison, J.L. et al. (2012) Oxytocin/Vasopressin-Related effects of intranasal oxytocin delivered with novel Breath Peptides Have an Ancient Role in Reproductive Behavior. Powered device in adults with autism spectrum disorder: a Science 338, 540–543 randomized placebo-controlled double-blind crossover trial. 42 Chini, B. et al. (2014) Learning about oxytocin: pharmaco- Transl. Psychiatry 7, e1136 logic and behavioral issues. Biol. Psychiatry 76, 360–366 20 Quintana, D.S. et al. (2015) Low dose oxytocin delivered in- 43 Maroun, M. and Wagner, S. (2016) Oxytocin and Memory of tranasally with Breath Powered device affects social-cogni- Emotional Stimuli: Some Dance to Remember, Some Dance tive behavior: a randomized 4-way crossover trial with nasal to Forget. Biol. Psychiatry 79, 203–212 cavity dimension assessment. Transl. Psychiatry 5, e602 44 Sala, M. et al. (2011) Pharmacologic Rescue of Impaired 21 Spengler, F.B. et al. (2017) Kinetics and Dose Dependency Cognitive Flexibility, Social Deficits, Increased Aggression, of Intranasal Oxytocin Effects on Amygdala Reactivity. Biol. and Seizure Susceptibility in Oxytocin Receptor Null Mice: Psychiatry 82, 885–894 A Neurobehavioral Model of Autism. Biol. Psychiatry 69, 22 Walum, H. et al. (2016) Statistical and methodological con- 875–882 siderations for the interpretation of intranasal oxytocin stud- 45 Eckstein, M. et al. (2016) Oxytocin Facilitates Pavlovian Fear ies. Biol. Psychiatry 79, 251–257 Learning in Males. Neuropsychopharmacology 41, 932–939 23 Quintana, D.S. (2018) Revisiting non-significant effects of 46 Brambilla, M. et al. (2016) Effects of Intranasal Oxytocin on intranasal oxytocin using equivalence testing. Psychoneuro- Long-Term Memory in Healthy Humans: A Systematic Re- endocrinology 87, 127–130 view. Drug Dev. Res. 77, 479–488 24 Muthukrishna, M. and Henrich, J. (2019) A problem in the- 47 Quintana, D.S. et al. (2019) Oxytocin pathway gene networks ory. Nat. Hum. Behav. 3, 221–229 in the human brain. Nat. Commun. 10, 668 25 Kosfeld, M. et al. (2005) Oxytocin increases trust in humans. 48 Fujino, Y. et al. (1999) Possible functions of oxytocin/vaso- Nature 435, 673–676 pressin-superfamily peptides in annelids with special refer- 26 Calin-Jageman, R.J. and Cumming, G. (2019) The New Sta- ence to reproduction and osmoregulation. J. Exp. Zool. Part tistics for Better Science: Ask How Much, How Uncertain, Ecol. Genet. Physiol. 284, 401–406 and What Else Is Known. Am. Stat. 73, 271–280

QUINTANA AND GUASTELLA

49 Oumi, T. et al. (1996) Annetocin, an annelid oxytocin-related 69 Da Costa, A.P. et al. (1996) The role of oxytocin release in peptide, induces egg-laying behavior in the earthworm, Ei- the paraventricular nucleus in the control of maternal behav- senia foetida. J. Exp. Zool. 276, 151–156 iour in the sheep. J. Neuroendocrinol. 8, 163–177 50 Ukena, K. et al. (2008) Unique form and osmoregulatory 70 Klopfer, P.H. and Klopfer, M.S. (1968) Maternal “imprint- function of a neurohypophysial hormone in a urochordate. ing” in goats: Fostering of alien young. Ethology 25, 862–866 Endocrinology 149, 5254–5261 71 Leng, G. and Russell, J.A. (2019) The osmoresponsiveness of 51 McCann, S.M. et al. (2002) Oxytocin, vasopressin and atrial oxytocin and vasopressin neurones: Mechanisms, allostasis natriuretic peptide control body fluid homeostasis by action and evolution. J. Neuroendocrinol. 31, e12662 on their receptors in brain, cardiovascular system and kidney. 72 Blouet, C. et al. (2009) Mediobasal hypothalamic leucine Prog. Brain Res. 139, 309–328 sensing regulates food intake through activation of a hypo- 52 Russell, J.A. et al. (2003) The magnocellular oxytocin sys- thalamus–brainstem circuit. J. Neurosci. 29, 8302–8311 tem, the fount of maternity: adaptations in pregnancy. Front. 73 Camerino, C. (2009) Low Sympathetic Tone and Obese Phe- Neuroendocrinol. 24, 27–61 notype in Oxytocin‐deficient Mice. Obesity 17, 980–984 53 Uvnäs-Moberg, K. et al. (2001) Oxytocin facilitates behav- 74 Leibowitz, S.F. et al. (1981) Hypothalamic paraventricular ioural, metabolic and physiological adaptations during lacta- nucleus lesions produce overeating and obesity in the rat. tion. Appl. Anim. Behav. Sci. 72, 225–234 Physiol. Behav. 27, 1031–1040 54 Welch, M.G. et al. (2014) Oxytocin regulates gastrointestinal 75 Blevins, J.E. and Baskin, D.G. (2015) Translational and ther- motility, inflammation, macromolecular permeability, and apeutic potential of oxytocin as an anti-obesity strategy: In- mucosal maintenance in mice. Am. J. Physiol.-Gastrointest. sights from rodents, nonhuman primates and humans. Phys- Liver Physiol. 307, G848–G862 iol. Behav. 152, 438–449 55 Wu, C.-L. et al. (2003) Pharmacological effects of oxytocin 76 Petring, O.U. (1989) The effect of oxytocin on basal and peth- on gastric emptying and intestinal transit of a non-nutritive idine‐induced delayed gastric emptying. Br. J. Clin. Pharma- liquid meal in female rats. Naunyn. Schmiedebergs Arch. col. 28, 329–332 Pharmacol. 367, 406–413 77 Qin, J. et al. (2009) Oxytocin receptor expressed on the 56 Eliava, M. et al. (2016) A New Population of Parvocellular smooth muscle mediates the excitatory effect of oxytocin on Oxytocin Neurons Controlling Magnocellular Neuron Activ- gastric motility in rats. Neurogastroenterol. Motil. 21, 430– ity and Inflammatory Pain Processing. Neuron 89, 1291–1304 438 57 Smeets, W.J.A.J. and González, A. (2001) Vasotocin and 78 Leslie, M. et al. (2018) A systematic review and quantitative mesotocin in the brains of amphibians: State of the art. Mi- meta-analysis of the effects of oxytocin on feeding. J. Neuro- crosc. Res. Tech. 54, 125–136 endocrinol. 30, e12584 58 Knobloch, H.S. and Grinevich, V. (2014) Evolution of oxyto- 79 Grebe, N.M. and Gangestad, S.W. (2019) Oxytocin: An Evo- cin pathways in the brain of vertebrates. Front. Behav. Neu- lutionary Framework. In The Oxford Handbook of Evolution- rosci. 8, 31 ary Psychology and Behavioral Endocrinology (Lisa L. M. 59 Grinevich, V. et al. (2016) Assembling the puzzle: pathways Welling and Shackelford, T. K., eds), Oxford University of oxytocin signaling in the brain. Biol. Psychiatry 79, 155– Press 164 80 Hicks, C. et al. (2014) Body temperature and cardiac changes 60 Chaves, V.E. et al. (2013) Role of oxytocin in energy metab- induced by peripherally administered oxytocin, vasopressin olism. Peptides 45, 9–14 and the non-peptide oxytocin receptor agonist WAY 267,464: 61 Van Kesteren, R.E. et al. (1995) Structural and functional a biotelemetry study in rats. Br. J. Pharmacol. 171, 2868– evolution of the vasopressin/oxytocin superfamily: vasopres- 2887 sin-related conopressin is the only member present in 81 Benelli, A. et al. (1991) Oxytocin-induced inhibition of feed- Lymnaea, and is involved in the control of sexual behavior. J. ing and drinking: No sexual dimorphism in rats. Neuropep- Neurosci. Off. J. Soc. Neurosci. 15, 5989–5998 tides 20, 57–62 62 Filippi, S. et al. (2003) Role of oxytocin in the ejaculatory 82 Rash, J.A. et al. (2014) Oxytocin and pain: a systematic re- process. J. Endocrinol. Invest. 26, 82–86 view and synthesis of findings. Clin. J. Pain 30, 453–462 63 Scheele, D. et al. (2013) Oxytocin enhances brain reward sys- 83 Mazzuca, M. et al. (2011) Newborn Analgesia Mediated by tem responses in men viewing the face of their female partner. Oxytocin during Delivery. Front. Cell. Neurosci. 5, Proc. Natl. Acad. Sci. 110, 20308–20313 84 Phillips, P.A. et al. (1984) Body fluid changes, thirst and 64 Scheele, D. et al. (2012) Oxytocin Modulates Social Distance drinking in man during free access to water. Physiol. Behav. between Males and Females. J. Neurosci. 32, 16074–16079 33, 357–363 65 Young, W.S. et al. (1996) Deficiency in mouse oxytocin pre- 85 James, R.J. et al. (1995) Thirst induced by a suckling episode vents milk ejection, but not fertility or parturition. J. Neuro- during breast feeding and relation with plasma vasopressin, endocrinol. 8, 847–853 oxytocin and osmoregulation. Clin. Endocrinol. (Oxf.) 43, 66 Nishimori, K. et al. (1996) Oxytocin is required for nursing 277–282 but is not essential for parturition or reproductive behavior. 86 Schulkin, J. and Sterling, P. (2019) Allostasis: A Brain-Cen- Proc. Natl. Acad. Sci. 93, 11699–11704 tered, Predictive Mode of Physiological Regulation. Trends 67 Ferguson, J.N. et al. (2001) Oxytocin in the medial amygdala Neurosci. 42, 740–752 is essential for social recognition in the mouse. J. Neurosci. 87 van Zuiden, M. et al. (2017) Intranasal oxytocin to prevent 21, 8278–8285 posttraumatic stress disorder symptoms: a randomized con- 68 Olazabal, D.E. and Young, L.J. (2006) Oxytocin receptors in trolled trial in emergency department patients. Biol. Psychia- the nucleus accumbens facilitate “spontaneous” maternal be- try 81, 1030–1040 havior in adult female prairie voles. Neuroscience 141, 559– 88 Busnelli, M. and Chini, B. (2018) Molecular Basis of Oxyto- 568 cin Receptor Signalling in the Brain: What We Know and

QUINTANA AND GUASTELLA

What We Need to Know. Curr. Top. Behav. Neurosci. 35, 3– 107 Hamada, M. et al. (2011) Expression of neuropeptide- and 29 hormone-encoding genes in the Ciona intestinalis larval 89 Knobloch, H.S. et al. (2012) Evoked axonal oxytocin release brain. Dev. Biol. 352, 202–214 in the central amygdala attenuates fear response. Neuron 73, 108 Stafflinger, E. et al. (2008) Cloning and identification of an 553–566 oxytocin/vasopressin-like receptor and its ligand from in- 90 Maejima, Y. et al. (2014) Oxytocinergic circuit from para- sects. Proc. Natl. Acad. Sci. 105, 3262–3267 ventricular and supraoptic nuclei to arcuate POMC neurons 109 Grinevich, V. et al. (2015) Ontogenesis of oxytocin pathways in hypothalamus. FEBS Lett. 588, 4404–4412 in the mammalian brain: late maturation and psychosocial 91 Zoicas, I. et al. (2014) Brain Oxytocin in Social Fear Condi- disorders. Front. Neuroanat. 8, 164 tioning and Its Extinction: Involvement of the Lateral Sep- 110 Swaab, D.F. et al. (1992) The human hypothalamo-neurohy- tum. Neuropsychopharmacology 39, 3027–3035 pophyseal system in relation to development, aging and Alz- 92 Althammer, F. and Grinevich, V. (2017) Diversity of oxyto- heimer’s disease. Hum. Hypothal. Health Dis. 93, 237 cin neurons: beyond magno- and parvocellular cell types? J. 111 Tyzio, R. et al. (2006) Maternal oxytocin triggers a transient Neuroendocrinol. DOI: 10.1111/jne.12549 inhibitory switch in GABA signaling in the fetal brain during 93 Pow, D.V. and Morris, J.F. (1989) Dendrites of hypothalamic delivery. Science 314, 1788–1792 magnocellular neurons release neurohypophysial peptides by 112 Nair, P.K. et al. (2005) Oxytocin-induced labor augments IL- exocytosis. Neuroscience 32, 435–439 1β-stimulated lung fluid absorption in fetal guinea pig lungs. 94 Mens, W.B. et al. (1983) Penetration of neurohypophyseal Am. J. Physiol.-Lung Cell. Mol. Physiol. 289, L1029–L1038 hormones from plasma into cerebrospinal fluid (CSF): half- 113 Marchini, G. and Stock, S. (1996) Pulsatile release of oxyto- times of disappearance of these neuropeptides from CSF. cin in newborn infants. Reprod. Fertil. Dev. 8, 163–165 Brain Res. 262, 143–149 114 Schaller, F. et al. (2010) A single postnatal injection of oxy- 95 Leng, G. and Ludwig, M. (2008) Neurotransmitters and pep- tocin rescues the lethal feeding behaviour in mouse newborns tides: whispered secrets and public announcements. J. Phys- deficient for the imprinted Magel2 gene. Hum. Mol. Genet. iol. 586, 5625–5632 19, 4895–4905 96 Coombes, J.E. et al. (1991) Release of oxytocin into blood 115 Feldman, R. (2012) Oxytocin and social affiliation in humans. and into cerebrospinal fluid induced by naloxone in anaesthe- Horm. Behav. 61, 380–391 tized morphine-dependent rats: the role of the paraventricular 116 Clark, C.L. et al. (2013) Neonatal CSF oxytocin levels are nucleus. J. Neuroendocrinol. 3, 551–561 associated with parent report of infant soothability and socia- 97 Fuxe, K. et al. (2012) On the role of volume transmission and bility. Psychoneuroendocrinology 38, 1208–1212 receptor-receptor interactions in social behaviour: focus on 117 Tribollet, E. et al. (1989) Appearance and transient expres- central catecholamine and oxytocin neurons. Brain Res. 1476, sion of oxytocin receptors in fetal, infant, and peripubertal rat 119–131 brain studied by autoradiography and electrophysiology. J. 98 Zheng, J.-J. et al. (2014) Oxytocin mediates early experi- Neurosci. 9, 1764–1773 ence–dependent cross-modal plasticity in the sensory corti- 118 Vaidyanathan, R. and Hammock, E.A. (2017) Oxytocin re- ces. Nat. Neurosci. 17, 391 ceptor dynamics in the brain across development and species. 99 Veening, J.G. and Olivier, B. (2013) Intranasal administration Dev. Neurobiol. 77, 143–157 of oxytocin: Behavioral and clinical effects, a review. Neuro- 119 Hammock, E. (2015) Developmental perspectives on oxyto- sci. Biobehav. Rev. 37, 1445–1465 cin and vasopressin. Neuropsychopharmacology 40, 24 100 Chini, B. et al. (2017) The Action Radius of Oxytocin Release 120 Winslow, J.T. et al. (2003) Rearing Effects on Cerebrospinal in the Mammalian CNS: From Single Vesicles to Behavior. Fluid Oxytocin Concentration and Social Buffering in Rhesus Trends Pharmacol. Sci. 38, 982–991 Monkeys. Neuropsychopharmacology 28, 910–918 101 Ludwig, M. et al. (2002) Intracellular calcium stores regulate 121 DeMayo, M.M. et al. (2019) Circuits for social learning: A activity-dependent neuropeptide release from dendrites. Na- unified model and application to Autism Spectrum Disorder. ture 418, 85–89 Neurosci. Biobehav. Rev. 107, 388–398 102 Freeman, S.M. and Young, L.J. (2016) Comparative Perspec- 122 Simpson, E.A. et al. (2014) Inhaled oxytocin increases posi- tives on Oxytocin and Vasopressin Receptor Research in Ro- tive social behaviors in newborn macaques. Proc. Natl. Acad. dents and Primates: Translational Implications. J. Neuroen- Sci. 111, 6922–6927 docrinol. 28, 123 Greenwood, M.A. and Hammock, E.A.D. (2017) Oxytocin 103 Campbell, P. et al. (2009) Central vasopressin and oxytocin receptor binding sites in the periphery of the neonatal mouse. receptor distributions in two species of singing mice. J. Comp. PLOS ONE 12, e0172904 Neurol. 516, 321–333 124 Boyd, R. et al. (2011) The cultural niche: Why social learning 104 Amico, J.A. et al. (1990) Pattern of Oxytocin Concentrations is essential for human adaptation. Proc. Natl. Acad. Sci. 108, in the Plasma and Cerebrospinal Fluid of Lactating Rhesus 10918–10925 Monkeys (Macaca mulatto,): Evidence for Functionally Inde- 125 Quattrocki, E. and Friston, K. (2014) Autism, oxytocin and pendent Oxytocinergic Pathways in Primates. J. Clin. Endo- interoception. Neurosci. Biobehav. Rev. 47, 410–430 crinol. Metab. 71, 1531–1535 126 Bateson, P. and Laland, K.N. (2013) Tinbergen’s four ques- 105 Wakerley, J.B. and Lincoln, D.W. (1973) The milk-ejection tions: an appreciation and an update. Trends Ecol. Evol. 28, reflex of the rat: a 20-to 40-fold acceleration in the firing of 712–718 paraventricular neurones during oxytocin release. J. Endo- 127 Sterling, P. and Eyer, J. (1988) Allostasis: A new paradigm to crinol. 57, 477–493 explain arousal pathology. In Handbook of life stress, cogni- 106 Verbalis, J.G. et al. (1991) Oxytocin produces natriuresis in tion and health pp. 629–649, John Wiley & Sons rats at physiological plasma concentrations. Endocrinology 128 Aydogan, G. et al. (2018) The effect of oxytocin on group 128, 1317–1322 formation and strategic thinking in men. Horm. Behav. 100, 100–106

QUINTANA AND GUASTELLA

129 Zhang, H. et al. (2019) Oxytocin promotes coordinated out- 131 Roney, J.R. (2016) Theoretical frameworks for human behav- group attack during intergroup conflict in humans. eLife 8, ioral endocrinology. Horm. Behav. 84, 97–110 e40698 130 Spengler, F.B. et al. (2017) Oxytocin facilitates reciprocity in social communication. Soc. Cogn. Affect. Neurosci. 12, 1325– 1333