on the study by Li Dai et al., PLoS One. 2012;7(6):e38513
Oxytocin and Vasopressin Are Dysregulated in Williams Syndrome, a Genetic Disorder Affecting Social Behavior
Quote from the original paper’s abstract
“Results revealed significantly higher median levels of oxytocin (OT) in Williams syndrome (WS) versus controls at baseline, with a less marked increase in arginine vasopressin (AVP). Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors”.
Given the complex cognitive processes that are implied, the scientific investigation of social behavior and attachment is extremely difficult, especially in humans. Using a relatively simple human genetic model (WS) characterized by profound disturbances in social relationships, this nice study provides new convincing experimental evidence that the neuropeptides OT and, to a lesser extent, AVP, are intimately involved in the control of human social behavior. Since many years now, in intimate association with forebrain reinforcing dopamine pathways, OT and AVP have yielded an elegant model linking genetic, molecular, cellular, and systems approaches.
Oxytocin- and AVP-related peptide lineages derive from a common ancestor gene/protein that duplicated early in evolution. Following the pioneer studies by Vincent du Vigneaud and Roger Acher in the late 1950’s, OT and AVP were shown to be the essential parts of the hypothalamic-neurohypophysial system, which was first described in fish species by the German biologists, Ernst and Britta Sharrer. After transcription of their encoding genes in hypothalamic magnocellular neurons, OT and AVP precursors are processed to generate the respective nonapeptides that are released in the blood stream from axon terminals in the neurohypophysis.
This basic model led to the foundation of neuroendocrinology and neurosecretion. The major function of neuroendocrine OT is the stimulation of milk ejection, but blood OT is also involved in the control of parturition through its potent contractile properties on the myometrium. Blood AVP is responsible for antidiuresis and thus essentially controls water homeostasis, together with an implication in the regulation of vascular tone through AVP constrictive properties on vessel smooth muscles .
Through the important connections of hypothalamic supraoptic and paraventricular neurons, as well as other brain nuclei, OT and AVP also behave as central neuropeptides that modulate fast neurotransmitters and are involved in a series of behavioral, cognitive and amnesic processes. The crucial implication of OT in the induction of maternal behavior of female rats was already reported in 1982 . This behavioral effect of OT probably results from a facilitation of approach behavior. OT also down-regulates stress responses and anxiety, while AVP is thought to stimulate the autonomic fear response.
The transmembrane receptor CD38 that catalyzes the induction of second messengers in lymphocytes is also an important component in the secretory machinery of OT neurons, and cd38-/- mice show impairment of social memory and in recognition of a conspecific female [3,4]. In prairie voles, the two nonapeptides promote pair-bond formation in both sexes although OT seems to be more important in females while AVP is more crucial in males. The OTergic system is currently known to provide the neuropeptide substrate for parental and filial attachment in many species. Oxytocin gene-deficient mice, although capable of maternal behavior, exhibit a profound social amnesia, without other apparent cognitive defects .
In human brain, OT receptors are highly expressed in dopamine-rich regions, such as the substancia nigra, globus pallidus and preoptic area . In accordance with rodent studies, the anxiogenic and anxiolytic properties of AVP and OT, respectively, have also been observed in humans. Exposure to OT dampens the rise in plasma cortisol, anxiety, and physiological measures in response to stressful contexts, suggesting an inhibition of the adaptive stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis [7,8]. In contrast, intranasal instillation of AVP leads to a relatively enhanced rise in physiological, neuroendocrine and behavioral measures of stress . These changes in the adaptive stress response may be partially mediated by neuropeptide effects on amygdala activity. Several neuroimaging studies using OT intranasal challenges have observed an attenuation of the amygdala response to negative stimuli, suggesting that OT may dampen the neural response to fearful cues . Both OT and AVP also alter the functional connectivity of the amygdala to other brain structures subserving emotional processing and regulation of the autonomic fear response [11-13].
Human studies also evidenced OT involvement in pair bonding since OT administration stimulates positive communication, affiliation, and emotional support between partners [14-17]. Interestingly, OT also increases generosity in humans . The data presented by Dai et al. provide further support for a relation between OT and social behavior. However, whereas basal OT levels were positively correlated with approach behavior, a negative correlation was observed with other aspects of social interaction, suggesting that OT does not simply promote social behavior in general. Greater neural activity was also described in OT- and dopamine-rich areas such as the left posterior cingulate cortex and caudate regions in early romantic attachment . Using a combination of OT intranasal administration, economics-related trust and risk games, as well as neuroimaging (fMRI) analysis, OT was also shown to shape the neural circuitry of trust and trust adaptation in humans that are essential to building social relationships [20-22].
Therefore, through its informative intervention at different steps of the whole reproductive process, the OTergic system appears to play a crucial role in species preservation. This statement is further reinforced by the discovery that the OT gene is transcribed in thymus epithelium of different species under the control of the Autoimmune Regulator (AIRE) transcription factor. After translation, the thymic OT precursor then is processed for presentation of OT as the tolerogenic self-antigen of the neurohypophysial peptide/gene family, thus protecting central and peripheral OT-mediated functions from potential autoimmune aggression [see complete review in Ref. 23]. In addition to the present study, the OT system has also been successfully explored in various psychiatric disorders characterized by an impairment of social relationships ranging from autism, schizophrenia, anxiety, and post-traumatic stress disorder to depression [24-26].
Oxytocin and AVP share a long evolutionary history and figure among the most important brain signals encoding significant information with regard to social behavior and attachment. Besides the signals however, the cognate OT and AVP1ra receptors have also been investigated for their association with human social behavior, from autism to altruism [27,28]. For example, one SNP across the OTR gene region is significantly associated with autism and pro-social behavior studied in nonclinical subjects .
To conclude this commentary, we would like to quote these appealing sentences at the end of a recent and excellent review about genetics of human social behavior : “The past two decades have seen remarkable progress in unraveling the complexities of the neurogenetic architecture of the human social brain. Nevertheless, much remains to be learned, especially about how our species has created a global society composed of billions of interacting individuals whose basic brain structure has remained mostly unchanged for the past 50,000 years. This global society is indeed a remarkable achievement for an organ weighing only 1350 g, and attests to its remarkable plasticity in processing a continuous stream of environmental information using neuroanatomical and neurogenetic mechanisms laid down over millions of years of hominid evolution.” We also wish to remind that Gerald Edelman, in his book ‘Second Nature’ (2006), stated that the central unresolved issue in modern neuroscience is the question of subjectivity and individuality and that it could well remain unsolvable forever.
Vincent Geenen, MD, PhD – Research director at F.S.R. – NFSR University of Liege, GIGA-I3 – Center of Immunology, CHU-B34, Belgium
Julie Bakker, PhD & Elseline Hoekzema, PhD – University of Liege, GIGA – Neurosciences, Neuroendocrinology of Behavior, CHU-B36, Belgium
Gabrielle Scantamburlo, MD, PhD – University Hospital of Liege, Division of Psychiatry, CHU-B35, B-4000 Liege-Sart Tilman, Belgium
Corresponding author: Vincent Geenen, MD, PhD, email: email@example.com
- Landgraf R, Neumann ID. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 2004; 25: 150-176.
- Pedersen CA, Ascher JA, Monroe YL, PrangeAJ Jr. Oxytocin induces maternal behavior in virgin female rats. Science 1982; 216: 648-649.
- Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA, Yamada K, Noda M, Seike T et al. CD38 is critical for social behavior by regulating oxytocin secretion. Nature 2007; 446: 41-45.
- Neumann ID. Oxytocin: the neuropeptide of love reveals some of its secrets. Cell Metabolism 2007; 5: 231-233.
- Ferguson J, Young LJ, Hearn E, Insel T, Winslow J. Social amnesia in mice lacking the oxytocin gene. Nat Genet 2000; 25: 284-288.
- Loup F, Tribollet E, Dubois-Dauphin M, Dreifuss JJ. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain: an autoradiographic study. Brain Res 1991; 555: 220-232.
- Legros JJ. Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying-yang neurohormones? Psychoneuroendocrinology 2001; 26: 649-655.
- Ditzen B, Shaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs M. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry 2009; 65: 728-731.
- Ebstein RP, Israel S, Lerer E, Uzefovsky F, Shalev I, Gritsenko I, Riebold M, Salomon S, Yirmyia N. Arginine vasopressin and oxytocin modulate human social behavior. Ann NY Acad Sci 2009; 1167: 87-102.
- Petrovic P, Kalisch R, Singer T, Dolan RJ. Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J Neurosci 2008; 28: 6607-6615.
- Rilling JK, DeMarco AC, Hackett PD, Thompson R, Ditzen B, Patel R, Pagnoni G. Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 2012; 37: 447-461.
- Zink CF, Stein JL, Kempf L, Hakimi S, Meyer-Lindenberg A. Vasopressin modulates medial prefrontal cortex-amygdala circuitry during emotion processing in humans. J Neurosci 2010; 30: 7017-7022.
- Lischke A, Gamer M, Berger C, Grossmann A, Hauenstein K, Heinrichs M, Herpertz SC, Domes G. Oxytocin increases amygdala reactivity to threatening sciences in females. Psychoneuroendocrinology 2012; 37: 1431-1438.
- Carter CS. Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology 1998; 23: 779-818.
- Insel TR, Young LJ. The neurobiology of attachment. Nat Rev Neuroscience 2001;2: 129-136.
- Young LJ, Wang Z. The neurobiology of pair bonding. Nat Neuroscience 2004; 10: 1048-1054.
- Carter CS, Grippo AJ, Pournajafi-Nazarloo H, Ruscio MG, Porges SW. Oxytocin, vasopressin and sociality. Prog Brain Res 2008; 170: 331-336.
- Zak PJ, Stanton AA, Ahmadi S. Oxytocin increases generosity in humans. PLoS ONE 2007; 2: e1128.
- Bartels A, Zeki S. The neural correlates of maternal and romantic love. Neuro-Image 2004; 21: 1155-1166.
- Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005; 435: 673-676.
- Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron 2008; 58: 639-650.
- Mikolajczak M, Gross JJ, Lane A, Corneille O, de Timary P, Luminet O. Oxytocin makes people trusting, not gullible. Psychol Sci 2010; 21: 1072-1074.
- Geenen V. Presentation of neuroendocrine self in the thymus: a necessity for integrated evolution of the immune and neuroendocrine systems. Ann NY Acad Sci 2012; 1261: 42-48.
- Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 2010;107: 4389-4394.
- Scantamburlo G, Ansseau M, Geenen V, Legros JJ. Oxytocin: from milk ejection to maladaptation in stress response and psychiatric disorders. A psychoneuroendocrine perspective. Ann Endocrinol (Paris) 2009; 70: 449-454.
- Scantamburlo G, Ansseau M, Geenen V, Legros JJ. Intranasal oxytocin as an adjunct to escitalopram in major depression. J Neuropsychiatry Clin Neurosci 2011; 23: E5.
- Israel S, Lerer E, ShalevI,Uzefovsky F, Riebold M, Bachner-Melman R, Granot R, Bornstein G, Knafo A, Yimiya N, Ebstein RP. Molecular studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OTR) in human behavior: from autism to altruism with some notes in between. Prog Brain Res 2008; 170: 435-449.
- Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001; 81: 629-683.
- Israel S, Lerer E, Shalev I, Uzefovsky F, Riebold M, Laiba E, Bechner-Melman R, Maril A, Bornstein G, Kanfo A, Ebstein RP. The oxytocin receptor (OTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task. PLoS ONE 2009; 4: e5535.
- Ebstein RP, Israel S, Chew SH, Zhong S, Knafo A. Genetics of human social behavior. Neuron 2010; 65: 831-844.