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An Allostatic Theory of Oxytocin

2020; Elsevier BV; Volume: 24; Issue: 7 Linguagem: Inglês

10.1016/j.tics.2020.03.008

1879-307X

Daniel Quintana, Adam J. Guastella,

Attachment and Relationship Dynamics

Several studies on oxytocin could not be replicated, and this has been attributed to methodological limitations. Although this is an important issue, the impact of the lack of an overarching theory has yet to be recognized.Oxytocin is conventionally considered to be a social hormone, but more recent work suggests that it also modulates non-social cognition and behavior.Oxytocin-like peptides in evolutionarily ancient organisms regulate allostatic processes, such as osmoregulation, that are conserved in humans.Oxytocin facilitates the processing of social and non-social sensory cues that are crucial for survival.Oxytocin receptor location and oxytocin release patterns govern the diverse but coordinated actions of oxytocin on physiology and behavior.Oxytocin signaling changes across development to support the different environmental pressures at each developmental stage. 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 the role of oxytocin in social behavior pay little consideration to its evolutionary and developmental history. This article aims to broaden our understanding of the role of oxytocin in social behavior by adopting an ethological approach through the lens of Nikolaas Tinbergen's 'four questions' – how does oxytocin work; how does the role of oxytocin change during development; how does oxytocin enhance survival; and 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. 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 the role of oxytocin in social behavior pay little consideration to its evolutionary and developmental history. This article aims to broaden our understanding of the role of oxytocin in social behavior by adopting an ethological approach through the lens of Nikolaas Tinbergen's 'four questions' – how does oxytocin work; how does the role of oxytocin change during development; how does oxytocin enhance survival; and 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. Oxytocin is an evolutionarily ancient [1.Feldman R. et al.Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology.Biol. Psychiatry. 2016; 79: 174-184Abstract Full Text Full Text PDF PubMed Google Scholar] neuromodulator and hormone. It is primarily produced in the hypothalamus from which it is secreted both within the brain and into the circulatory system [2.Jurek B. Neumann I.D. The oxytocin receptor: from intracellular signaling to behavior.Physiol. Rev. 2018; 98: 1805-1908Crossref PubMed Scopus (87) Google Scholar]. Oxytocin has captured the most interest of any neuromodulatory system [3.Kenkel W.M. Corpus colossal: a bibliometric analysis of neuroscience abstracts and impact factor.Front. Integr. Neurosci. 2019; 13: 18Crossref PubMed Scopus (1) Google Scholar] owing to its role in social behavior and cognition [4.Guastella A.J. MacLeod C. 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Oxytocin treatment, circuitry and autism: a critical review of the literature placing oxytocin into the autism context.Biol. Psychiatry. 2016; 79: 234-242Abstract Full Text Full Text PDF PubMed Google Scholar], which are a key characteristic of several psychiatric disorders. However, more recent results have not matched early expectations regarding the effects of oxytocin on social behavior in psychiatric illnesses [8.Alvares G.A. et al.Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder.Autism Res. 2017; 10: 25-41Crossref PubMed Scopus (23) Google Scholar], and some studies report null effects (e.g., [9.Dadds M.R. et al.Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial.J. Autism Dev. Disord. 2014; 44: 521-531Crossref PubMed Scopus (139) Google Scholar]). Historically, oxytocin has also been associated with terms such as the 'moral molecule' [10.Zak P.J. The Moral Molecule: The Source of Love and Prosperity. Random House, 2012Google Scholar] and the 'cuddle chemical' [11.Coghlan A. 'Cuddle chemical' eases symptoms of schizophrenia.New Sci. 2010; 207: 10Google Scholar]. These terms are now typically disregarded in the scientific literature [12.Shamay-Tsoory S.G. Abu-Akel A. The social salience hypothesis of oxytocin.Biol. Psychiatry. 2016; 79: 194-202Abstract Full Text Full Text PDF PubMed Google Scholar], and oxytocin is generally considered to be a hormone that is involved in both prosocial and non-prosocial cognitive processes and behavior. However, this 'social' description has been disputed, and research demonstrates that oxytocin also modulates non-social cognition [13.Eckstein M. et al.Oxytocin increases eye-gaze towards novel social and non-social stimuli.Soc. Neurosci. 2019; 14: 594-607Crossref PubMed Scopus (2) Google Scholar,14.Harari-Dahan O. Bernstein A. Oxytocin attenuates social and non-social avoidance: re-thinking the social specificity of oxytocin.Psychoneuroendocrinology. 2017; 81: 105-112Crossref PubMed Scopus (0) Google Scholar]. Poor replication rates in oxytocin research, paralleling many other areas of the behavioral sciences [15.Munafò M.R. et al.A manifesto for reproducible science.Nat. Hum. Behav. 2017; 1: 0021Crossref PubMed Scopus (679) Google Scholar], have been largely attributed to methodological issues and poor understanding of the mechanisms of oxytocin action. Although efforts have been made to address these limitations – in terms of better understanding of intranasal oxytocin administration [16.Lee M.R. et al.Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay.Mol. 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Revisiting non-significant effects of intranasal oxytocin using equivalence testing.Psychoneuroendocrinology. 2018; 87: 127-130Crossref PubMed Scopus (0) Google Scholar] – the lack of an overarching theory that accounts for the function of oxytocin across a range of contexts has hindered conceptual replication and generalizability [24.Muthukrishna M. Henrich J. A problem in theory.Nat. Hum. Behav. 2019; 3: 221-229Crossref PubMed Scopus (35) Google Scholar]. As mentioned above, it was originally hypothesized that oxytocin facilitates prosocial behavior. Although the original study [25.Kosfeld M. et al.Oxytocin increases trust in humans.Nature. 2005; 435: 673-676Crossref PubMed Scopus (2144) Google Scholar] that popularized this theory has been the subject of fierce methodological critiques (e.g., [26.Calin-Jageman R.J. Cumming G. The new statistics for better science: ask how much, how uncertain, and what else is known.Am. Stat. 2019; 73: 271-280Crossref PubMed Scopus (0) Google Scholar]), the concept of a neuromodulator than influences positive, but not negative, social behavior is difficult to reconcile with the broader literature, such as the effect of oxytocin on maternal aggression [27.Ferris C.F. et al.Oxytocin in the amygdala facilitates maternal aggression.Ann. N. Y. Acad. Sci. 1992; 652: 456-457Crossref PubMed Google Scholar]. Moreover, instead of being based on a broader theoretical framework that could be applicable to general human behavior (e.g., evolutionary theory), this theory was primarily based on a limited set of past results. Such an approach can hinder the abductive scientific process (i.e., drawing conclusions from an incomplete set of possible observations) and consequent conceptual replication [24.Muthukrishna M. Henrich J. A problem in theory.Nat. Hum. Behav. 2019; 3: 221-229Crossref PubMed Scopus (35) Google Scholar]. Thus, to accelerate progress there is a crucial need for oxytocin research to apply a general theoretical framework that can connect findings across domains of human behavior and physiological regulation, and which will allow more informed predictions to be made concerning the function of oxytocin. Consequently, such integrated models may result in more reliable understanding of the effects of intranasally administered oxytocin. One example of a general framework that is emerging in the medical sciences is the use of an evolutionary perspective [28.Wells J.C. et al.Evolutionary public health: introducing the concept.Lancet. 2017; 390: 500-509Abstract Full Text Full Text PDF PubMed Google Scholar]. Although evolutionary perspectives can help to uncover why a phenotype evolved, they cannot easily answer how a phenotype operates. Answering these two interrelated 'how' and 'why' questions can help to uncover a rich synergistic understanding of oxytocin that would not be possible by answering each of these questions alone [29.Hofmann H.A. et al.An evolutionary framework for studying mechanisms of social behavior.Trends Ecol. Evol. 2014; 29: 581-589Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. A classic ethological approach to generate a deeper understanding of phenotypes is Nikolaas Tinbergen's 'four questions' framework [30.Tinbergen N. On aims and methods of ethology.Ethology. 1963; 20: 410-433Google Scholar]. These reciprocal questions are: (i) how did this phenotype evolve? (ii) How does this phenotype help survival? (iii) What is the physiological cause of this phenotype? (iv) How does this phenotype develop in the individual? The first two questions address evolutionary explanations whereas the second two address proximate explanations. Notably, these four questions consider not only the expression of a phenotype at a given moment but also the sequence of events that give rise to the phenotype. Tinbergen originally formulated these questions for behavioral phenotypes in animals; however, they have more recently been applied to several human characteristics, such as hormonal phenotypes [31.Calisi R.M. An integrative overview of the role of gonadotropin-inhibitory hormone in behavior: applying Tinbergen's four questions.Gen. Comp. Endocrinol. 2014; 203: 95-105Crossref PubMed Scopus (17) Google Scholar], psychiatric conditions [32.Brüne M. et al.The crisis of psychiatry – insights and prospects from evolutionary theory.World Psychiatry. 2012; 11: 55-57Crossref PubMed Scopus (0) Google Scholar], and social behaviors [29.Hofmann H.A. et al.An evolutionary framework for studying mechanisms of social behavior.Trends Ecol. Evol. 2014; 29: 581-589Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. In this article we review oxytocin through the lens of Tinbergen's four questions. In light of the two proximate and two evolutionary explanations for the role of oxytocin in behavior and physiology, we argue that the role of oxytocin in behavior and cognition is best characterized as allostatic because it facilitates adaptation, consolidation, and stability through changing environments. Unlike Cannon's original description of homeostasis [33.Cannon W.B. Organization for physiological homeostasis.Physiol. Rev. 1929; 9: 399-431Crossref Google Scholar], which refers to moment-to-moment post hoc physiological adjustments to the environment and static physiological set-points, allostasis accounts for anticipation of changes in the environment that helps to ensure the stability of the system – by integrating prior knowledge with current information to modulate behavior and adjust physiological set-points based on environmental demands (Box 1) [34.Ramsay D.S. Woods S.C. Clarifying the roles of homeostasis and allostasis in physiological regulation.Psychol. Rev. 2014; 121: 225Crossref PubMed Scopus (87) Google Scholar]. Our allostatic model of oxytocin, which recognizes both its physiological and psychological actions, contains four key cognitive and behavioral allostatic components: oxytocin-mediated sensing, learning, prediction, and response (Figure 1). Oxytocin system impairments can influence any or all of these four cognitive and behavioral allostatic components, and this has implications for several psychiatric disorders.Box 1The Difference between Allostasis and HomeostasisAllostasis and homeostasis both provide accounts for the regulation of physiological systems, but there are two crucial differences between Walter Cannon's original homeostasis proposal [33.Cannon W.B. Organization for physiological homeostasis.Physiol. Rev. 1929; 9: 399-431Crossref Google Scholar] and allostasis [34.Ramsay D.S. Woods S.C. Clarifying the roles of homeostasis and allostasis in physiological regulation.Psychol. Rev. 2014; 121: 225Crossref PubMed Scopus (87) Google Scholar]. First, allostasis suggests that organisms can anticipate future changes in the environment and make appropriate adjustments before they occur. Second, physiological set-points can be adjusted to better suit the environmental conditions within an allostatic system. To illustrate this we 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 so as to reach a predetermined metabolic activity level. By contrast, an allostatic system anticipates future environmental changes (e.g., by 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 because they can operate complementarily [86.Schulkin J. Sterling P. Allostasis: a brain-centered, predictive mode of physiological regulation.Trends Neurosci. 2019; 42: 740-752Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Although predicting future conditions is efficient over the long term, prediction errors are certain 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.Ramsay D.S. Woods S.C. Clarifying the roles of homeostasis and allostasis in physiological regulation.Psychol. Rev. 2014; 121: 225Crossref PubMed Scopus (87) Google Scholar]. 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. Allostasis and homeostasis both provide accounts for the regulation of physiological systems, but there are two crucial differences between Walter Cannon's original homeostasis proposal [33.Cannon W.B. Organization for physiological homeostasis.Physiol. Rev. 1929; 9: 399-431Crossref Google Scholar] and allostasis [34.Ramsay D.S. Woods S.C. Clarifying the roles of homeostasis and allostasis in physiological regulation.Psychol. Rev. 2014; 121: 225Crossref PubMed Scopus (87) Google Scholar]. First, allostasis suggests that organisms can anticipate future changes in the environment and make appropriate adjustments before they occur. Second, physiological set-points can be adjusted to better suit the environmental conditions within an allostatic system. To illustrate this we 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 so as to reach a predetermined metabolic activity level. By contrast, an allostatic system anticipates future environmental changes (e.g., by 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 because they can operate complementarily [86.Schulkin J. Sterling P. Allostasis: a brain-centered, predictive mode of physiological regulation.Trends Neurosci. 2019; 42: 740-752Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Although predicting future conditions is efficient over the long term, prediction errors are certain 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.Ramsay D.S. Woods S.C. Clarifying the roles of homeostasis and allostasis in physiological regulation.Psychol. Rev. 2014; 121: 225Crossref PubMed Scopus (87) Google Scholar]. 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. Identifying the physiological and behavioral effects of oxytocin that are highly conserved across species can help to clarify its purpose. Novel regulatory circuits develop from older circuits [35.Carter C.S. Oxytocin pathways and the evolution of human behavior.Annu. Rev. Psychol. 2014; 65: 17-39Crossref PubMed Scopus (275) Google Scholar], and it therefore follows that unraveling the origins of a circuit can provide a better understanding of its present role. Thus, to help to decipher the role of oxytocin in human social behavior, it is instructive to characterize its evolutionary history (i.e., phylogeny). Oxytocin-like peptides are at least 600 million years old [36.Gwee P.-C. et al.Characterization of the neurohypophysial hormone gene loci in elephant shark and the Japanese lamprey: origin of the vertebrate neurohypophysial hormone genes.BMC Evol. Biol. 2009; 9: 47Crossref PubMed Scopus (55) Google Scholar], and the precursor to mammalian oxytocin arose before vertebrates diverged from invertebrates [37.Liutkeviciute Z. et al.Global map of oxytocin/vasopressin-like neuropeptide signalling in insects.Sci. Rep. 2016; 6: 39177Crossref PubMed Scopus (21) Google Scholar]. Vasopressin shares its ancestry with this precursor, which is reflected by its structural similarity to oxytocin and the affinity of oxytocin for the V1A vasopressin receptor [38.Manning M. et al.Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics.J. Neuroendocrinol. 2012; 24: 609-628Crossref PubMed Scopus (235) Google Scholar]. Oxytocin-like signaling influences behavioral responses to changing environments in organisms with relatively unsophisticated nervous systems that shared ancient common ancestors with humans. For instance, straightforward associative learning paradigms demonstrate that wild-type roundworms (Caenorhabditis elegans) can learn to associate particular environments with aversive properties. However, roundworms lacking an oxytocin homolog (nematocin) and its receptor fail to demonstrate the same degree of avoidance after pre-exposure to the aversive stimulus [39.Beets I. et al.Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans.Science. 2012; 338: 543-545Crossref PubMed Scopus (96) Google Scholar]. This points to an error in the allostatic loop because mutant roundworms could not integrate current sensory information with prior knowledge owing to a deficit in associative learning. The role of oxytocin in adjusting to changes in environmental conditions, based on prior learning, seems to be conserved in humans [40.Hurlemann R. et al.Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.J. Neurosci. 2010; 30: 4999-5007Crossref PubMed Scopus (449) Google Scholar]. Rapidly learning which behaviors best suit a new environment is integral to the success of an organism. This has been demonstrated in neurally unsophisticated invertebrate organisms such the roundworm, as described above [39.Beets I. et al.Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans.Science. 2012; 338: 543-545Crossref PubMed Scopus (96) Google Scholar], in which nematocin is expressed in sensory neurons that detect thermal or mechanical changes in the environment [39.Beets I. et al.Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans.Science. 2012; 338: 543-545Crossref PubMed Scopus (96) Google Scholar,41.Garrison J.L. et al.Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior.Science. 2012; 338: 540-543Crossref PubMed Scopus (129) Google Scholar]. Oxytocin also influences memory and learning processes in a range of vertebrates [42.Chini B. et al.Learning about oxytocin: pharmacologic and behavioral issues.Biol. 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In humans, intranasal oxytocin administration facilitates rapid adaptation to social fear signals, which has survival value in rapidly changing environments [45.Eckstein M. et al.Oxytocin facilitates Pavlovian fear learning in males.Neuropsychopharmacology. 2016; 41: 932-939Crossref PubMed Scopus (31) Google Scholar]. However, although the effects of oxytocin administration on memory and learning in humans have been less consistent than in animal research [42.Chini B. et al.Learning about oxytocin: pharmacologic and behavioral issues.Biol. Psychiatry. 2014; 76: 360-366Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,46.Brambilla M. et al.Effects of intranasal oxytocin on long-term memory in healthy humans: a systematic review.Drug Dev. 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Oxytocin-like mediation of tissue contraction can be observed in invertebrates, such as earthworms (Eisenia foetida) and leeches (Whitmania pigra), where injection of an oxytocin-like peptide (anetocin) regulates the contraction of the earthworm gut and uterus homolog [48.Fujino Y. et al.Possible functions of oxytocin/vasopressin-superfamily peptides in annelids with special reference to reproduction and osmoregulation.J. Exp. Zool. Part Ecol. Genet. Physiol. 1999; 284: 401-406Crossref Scopus (45) Google Scholar,49.Oumi T. et al.Annetocin, an annelid oxytocin-related peptide, induces egg-laying behavior in the earthworm, Eisenia foetida.J. Exp. Zool. 1996; 276: 151-156Crossref PubMed Google Scholar]. A similar physiological response has also been observed in sea squirts, where an oxytocin-like peptide was shown to influence osmoregulation via syphon contraction [50.Ukena K. et al.Unique form and osmoregulatory function of a neurohypophysial hormone in a urochordate.Endocrinology. 2008; 149: 5254-5261Crossref PubMed Scopus (0) Google Scholar]. The role of oxytocin in osmoregulation is conserved in humans where it acts on oxytocin receptors in the cardiovascular system and the kidneys [51.McCann S.M. et al.Oxytocin, vasopressin and atrial natriuretic peptide control body fluid homeostasis by action on their receptors in brain, cardiovascular system and kidney.Prog. Brain Res. 2002; 139: 309-328Crossref PubMed Scopus (0) Google Scholar]. The effects of oxytocin on smooth muscle contraction are also conserved in humans, and oxytocin-mediated smooth muscle contractions play a role in human parturition, copulation, reproduction, gastric emptying, and cardiovascular regulation [2.Jurek B. Neumann I.D. The oxytocin receptor: from intracellular signaling to behavior.Physiol. Rev. 2018; 98: 1805-1908Crossref PubMed Scopus (87) Google Scholar]. Therefore, although oxytocin seems to have first assisted basic tissue contraction, evolutionary pressures appear to have coopted the contractile effects of oxytocin for a broad range of physiological systems in mammals that underlie allostasis. Crucially, the effects of oxytocin on smooth muscle contraction seem to operate with adjustable set-points depending on situational demands (e.g., digestion, birth, lactation) [52.Russell J.A. et al.The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy.Front. 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Long-range axonal projections from oxytocin and oxytocin-like neurons to other regions of the brain are only consistently found in complex vertebrates such as mammals [56.Eliava M. et al.A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing.Neuron. 2016; 89: 1291-1304Abstract Full Text Full Text PDF P