An Allostatic Theory of Oxytocin

PREPRINT – ARTICLE ACCPETED AT TRENDS IN COGNITIVE NEUROSCIENCES An Allostatic Theory of Oxytocin 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 understanding 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 lens of Niko Tinbergen’s “four questions”: How does oxytocin work? How does the role of oxytocin change during development? How does oxytocin enhance survival? 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 recently 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]. thalamus 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 physiological 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 phenotype 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 address 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

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