Variation in the oxytocin receptor gene influences neurocardiac reactivity to social stress and HPA function: A population based study
Highlights
► Sympathetic cardiac reactivity to social stress. ► Altered cardiodynamic reactivity to social stress. ► Diurnal rhythm in salivary cortisol.
Introduction
Oxytocin (OT) is a nonapeptide neurohormone that is involved in a broad array of physiological and behavioral processes including hypothalamic–pituitary–adrenal (HPA) axis functioning, autonomic nervous system (ANS) activity, and social behaviors, including pair bonds and social recognition in both humans and animal models (Carter et al., 2008, Kemp and Guastella, 2011, Bartz et al., 2011). Exposure to a variety of stimuli triggers the hypothalamic paraventricular nucleus to release OT into OT receptor rich cortical, limbic, and brainstem regions associated with emotion and heterarchical control of neuroendocrine and ANS functioning (Gimpl and Fahrenholz, 2001, Carter et al., 2008). Indeed, intranasal administration of OT to humans decreases amygdala activation to threatening stimuli, increases trust, and promotes the encoding of positive social memories (Kosfeld et al., 2005, Guastella et al., 2008). Genetic variation in the OT receptor gene has been shown to be associated with empathy and is associated with attachment style and pro-social temperament (Rodrigues et al., 2009, Bartz et al., 2010; Costa et al., 2009; Tost et al., 2010). Furthermore, polymorphisms in the oxytocin receptor have previously been associated with parenting behaviors (Bakermans-Kranenburg and van Ijzendoorn, 2008), adult attachment styles (Gillath et al., 2008), emotional support seeking (Kim et al., 2010) and self-esteem (Saphire-Bernstein et al., 2011).
In addition to its well-described role in regulating social processes, OT modulates autonomic nervous system activity by exerting direct effects on preganglionic sympathetic (Gilbey et al., 1982; Pardini et al., 1989) and parasympathetic neurons (Higa et al., 2002). Pharmacological administration of OT to rodents has been shown to modulate ANS functioning across various contexts (Grippo et al., 2009, Carter et al., 2008). Similarly, intranasal administration of OT in humans has been shown to increase overall cardiac control (Norman et al., 2010), and modulates phasic activity of parasympathetic nervous system functioning (Gamer and Buchel, 2012). Furthermore, OT dampens HPA axis reactivity to social stress in humans (Heinrichs et al., 2003) and rodents (Windle et al., 1997). OT has been shown to mitigate pathophysiological processes in numerous animal models of human disease (DeVries et al., 2007, Norman et al., 2010) leading some to suggest that OT may be one of the neurobiological mechanisms underlying the potent influence that social factors (e.g. social isolation, social support) have on health (Uvnas-Moberg, 1998).
In addition to pharmacological manipulations, genetic variation in the OT receptor has been shown to be associated with hypothalamic structure and function (Tost et al., 2010) and has been associated with loneliness (Lucht et al., 2009, Norman et al., 2010) and attachment style in depressed individuals (Costa et al., 2009). Additionally, OT receptor single-nucleotide polymorphisms (SNPs) have been found to be associated with modified social behavior, hypothalamus structure and function, and altered cardiac startle reflex (Bakermans-Kranenburg and van Ijzendoorn, 2008, Tost et al., 2010, Rodrigues et al., 2009). Therefore, converging evidence from pharmacological and genetic approaches suggests an important role for the OT system in the regulation of a broad array of psychological and physiological processes.
Although the data described above clearly demonstrate the influence of OT on HPA axis and cardiovascular functioning, the vast majority of these studies utilized acute pharmacological manipulations that provide minimal information into the long term effects of OT signaling in humans. In the present study, we evaluate the relationship between a common SNP in the OT receptor gene (rs53576) and its associations with individual differences in cardiovascular and HPA axis function in a population based sample of older adults. Based upon previous research from animal and human studies we hypothesized that variation in the OT receptor would relate to individual differences in autonomic and HPA axis functioning. Furthermore, given the influence of estrogens on OT receptor activity (Young et al., 1998), we hypothesized that sex would moderate the relationship between OT receptor variation and individual differences in autonomic and HPA axis function.
Section snippets
Participants
Data for this study were collected annually between 2002 and 2006, as part of Chicago, Health Aging and Social Relations Study (CHASRS). CHASRS is a longitudinal population based study of non-Hispanic White, Black, and non-Black Hispanic persons born between 1935 and 1952 and living in Cook County, IL. The sample was selected using a multistage probability design in which the first stage involved identifying a subset of households estimated to have high probability of containing at least one
Results
As displayed in Table 1, the OT receptor (rs53576) the A allele was not evenly distributed across gender and ethnicity. Therefore, demographic variables were included as covariates for all results reported below participants were of similar age, sex and ethnic makeup. Furthermore, G/G and A carrier participants had similar levels of education and income (p > 0.05). Additionally, all significant results described below were independent of individual differences in circulating estrone, estradiol
Discussion
The results of this study demonstrate that genetic variation in the OT receptor is associated with alterations in sympathetic cardiac control as well as alterations in HPA axis functioning in a population based sample of older adults. These data build upon and extend previous animal and human research utilizing pharmacological manipulations to demonstrate the association between the OT system and metabolic processes. Furthermore, these data provide the first investigation into the relationship
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