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Integrative pathways linking close family ties to health: A neurochemical perspective

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Abstract

The quality of one's familial life, for better or worse, has been linked to physical health. Such associations are evident across a number of acute and chronic conditions and highlight the widespread impact that close relationships have on physical health. However, the field currently lacks a complete understanding of the integrative biological pathways underlying the association between close relationships and disease risk. This article reviews the main peripheral biological and central nervous system pathways linking positive and negative familial relationship processes to physical health outcomes. It emphasizes the role of neurochemical pathways in mediating the influence of social relationships on health-relevant peripheral physiological systems using the oxytocin system as a model. Such neurochemical approaches are an important step toward a more integrative understanding of complex biological pathways and has novel theoretical and intervention implications.
Integrative Pathways Linking Close Family Ties to Health:
A Neurochemical Perspective
Bert N. Uchino
University of Utah Baldwin M. Way
Ohio State University
The quality of one’s familial life, for better or worse, has been linked to physical health. Such
associations are evident across a number of acute and chronic conditions and highlight the
widespread impact that close relationships have on physical health. However, the field
currently lacks a complete understanding of the integrative biological pathways underlying
the association between close relationships and disease risk. This article reviews the main
peripheral biological and central nervous system pathways linking positive and negative
familial relationship processes to physical health outcomes. It emphasizes the role of
neurochemical pathways in mediating the influence of social relationships on health-relevant
peripheral physiological systems using the oxytocin system as a model. Such neurochemical
approaches are an important step toward a more integrative understanding of complex
biological pathways and has novel theoretical and intervention implications.
Keywords: Family relationships, social support, social negativity, oxytocin, biological
pathways
Supplemental materials: http://dx.doi.org/10.1037/amp0000049.supp
The quality of one’s close relationships has been reliably
related to disease morbidity and mortality from the cradle to
the grave (Cohen, 2004; Holt-Lunstad, Smith, & Layton,
2010; Uchino, 2009). In a meta-analysis of over 300,000
participants, Holt-Lunstad and colleagues (2010) found that
supportive relationships were related to a 46% increased
survival rate. Indeed, the link between supportive relation-
ships and lower mortality was comparable to traditional
biomedical risk factors such as diet, smoking, and exercise
(Holt-Lunstad et al., 2010). Furthermore, a recent meta-
analysis found that familial sources of support were more
strongly linked to lower mortality compared with friendship
support (Shor, Roelfs, & Yogev, 2013). There is also a
smaller but growing literature on the health risks associated
with negative aspects of familial relationships. Such social
negativity (e.g., insensitivity, conflict) is related to in-
creased physical health problems, including earlier mortal-
ity (Brooks & Dunkel Schetter, 2011; Rook, 2015). Thus,
for better or worse, close familial relationships are robust
predictors of future health problems.
A crucial next step is to test and refine theoretical models
linking relationships to health to facilitate translation into
efficacious interventions. Understanding the complex bio-
logical mechanisms linking close relationships to health is
important for both theoretical and applied reasons (Cohen,
2004). Such modeling can advance theories that make more
precise predictions about the links between close ties and
specific disease outcomes based on the contributing path-
ways. Improved knowledge of these pathways as well as the
individual differences in their function is likely to lead to
more theoretically grounded interventions, as well as sug-
gest novel interventions that better target the underlying
biology. For instance, social experiences and neural/neuro-
chemical responses in the brain reciprocally influence each
other over time such that pharmacological approaches might
prove effective as an additional intervention tool (Bakermans-
Kranenburg & van I Jzendoorn, 2013; Cacioppo & Ca-
cioppo, 2015). This article thus discusses the evidence and
Editor’s note. This article is part of a collection published in a special
issue of American Psychologist (September 2017) titled “Close Family
Relationships and Health.” Bert N. Uchino and Christine Dunkel Schetter
provided scholarly lead for the special issue, and Anne E. Kazak served as
action editor for this article.
Authors’ note. Bert N. Uchino, Department of Psychology and Health
Psychology Program, University of Utah; Baldwin M. Way, Department of
Psychology, Ohio State University.
Both authors contributed equally to this article.
We thank John T. Cacioppo for his helpful comments on a draft of this
article. Of course, all errors of fact or emphasis are ours.
Correspondence concerning this article should be addressed to Bert N.
Uchino, Department of Psychology, University of Utah, 380 South 1530
East, Room 502, Salt Lake City, Utah 84112. E-mail: bert.uchino@psych
.utah.edu
American Psychologist © 2017 American Psychological Association
2017, Vol. 72, No. 6, 590– 600 0003-066X/17/$12.00 http://dx.doi.org/10.1037/amp0000049
590
implications of the major integrative peripheral physiolog-
ical pathways linking close family relationships to health, as
well as outlines a model for how neurochemical pathways
may mediate between them. Close family relationships are
broadly defined as those characterized by frequent, strong,
and enduring interdependence (e.g., long-term romantic or
cohabiting relationships, immediate family members, Kel-
ley & Thibaut, 1978). These close familial relationships are
more likely to influence the long-term development and
course of chronic health conditions because of their stability
and importance (Uchino, 2009).
Basic Links Between Close Familial Ties and
Peripheral/Central Biological Processes
Most of the existing work linking familial ties to physi-
ology has focused on isolated peripheral biological mea-
sures that tap into autonomic, endocrine, and immune func-
tion (Uchino, 2006). Altered levels of these peripheral
biological measures have been directly linked to the leading
causes of death worldwide, including cardiovascular dis-
ease, cancer, and infectious diseases (Uchino, Smith, Holt-
Lunstad, Campo, & Reblin, 2007).
The autonomic nervous system is divided into the sym-
pathetic nervous system (SNS) and parasympathetic ner-
vous systems (PNS). Observational work suggests that so-
cial support from close others predicts lower catecholamine
(CAT) levels, which reflects less SNS activity (Grewen,
Girdler, Amico, & Light, 2005). That is, familial social
support has been linked to lower urinary CATs, whereas
familial strain has been related to higher CATs (Seeman,
Gruenewald, Cohen, Williams, & Matthews, 2014). In
terms of the PNS, studies have utilized respiratory sinus
arrhythmia (RSA) as an index. RSA is the rhythmical fluc-
tuations in heart periods occurring at the respiration band
(i.e., .12–.40 Hz, Berntson, Cacioppo, & Grossman, 2007).
General models in the area highlight the potential role of the
PNS in social engagement and self-regulatory processes
important to close relationships (Porges, 2007; Thayer,
Hansen, Saus-Rose, & Johnsen, 2009). More specific con-
ceptual models suggest that (a) positive emotions, social
functioning, and tonic RSA reciprocally influence each
other over time (Kok et al., 2013); and (b) alterations in
RSA reflect a depletion of self-regulatory resources linked
to close ties (e.g., conflict) that may compromise health
(Smith et al., 2011).
Cardiovascular activity is one important health-relevant
outcome that is regulated by the SNS and PNS. Consistent
with the research reviewed previously, parent–adolescent
dyads and married couples that engage in more positive
relationship interactions show dampened cardiovascular re-
activity compared with more negative relationship interac-
tions (Manczak, McLean, McAdams, & Chen, 2015;
Nealey-Moore, Smith, Uchino, Hawkins, & Olson-Cerny,
2007). Higher marital quality is also associated with lower
cardiovascular reactivity during lab-based conflict discus-
sions (Robles, Slatcher, Trombello, & McGinn, 2014). Sim-
ilar findings are evident in studies examining family rela-
tionship processes on ambulatory blood pressure (ABP)
during daily life (Stadler, Snyder, Horn, Shrout, & Bolger,
2012). For instance, higher marital quality as well as inter-
ventions aimed to improve marital function are linked to
lower ABP (Holt-Lunstad, Birmingham, & Light, 2008;
Stadler et al., 2012).
Another component of the response to stress affected by
close family relationships is activation of the hypothalamic-
pituitary-adrenal (HPA) axis that culminates in the release
of cortisol. Cortisol is an important endocrine hormone that
has broad biological influences including increased glucose
metabolism/lipolysis and inhibition of immune processes
(Sapolsky, Romero, & Munck, 2000). Studies suggest that
close family relationships affect cortisol levels in both lab-
oratory settings and daily life. In laboratory studies, lower
maternal sensitivity and mother–child separation are related
to increases in infant cortisol level and delays in recovery
(Hostinar, Sullivan, & Gunnar, 2014). In addition, familial
processes in everyday life (e.g., intimacy) are linked to more
favorable cortisol profiles (Ditzen, Hoppmann, & Klumb,
2008; Stadler et al., 2012). However, a recent meta-analysis
did not find marital quality to predict cortisol levels (Robles
et al., 2014). There was significant variability but too few
studies to conduct a formal analysis, so more work will be
needed to determine potential moderators of the connection
between marital quality and cortisol levels.
The quality of close familial relationships has also been
linked to immune system function, which is the body’s main
Bert N. Uchino
591
RELATIONSHIPS AND NEUROCHEMICAL PATHWAYS
defense against infectious and malignant diseases (Uchino,
Vaughn, Carlisle, & Birmingham, 2012). The biological
significance of these associations is evident because higher
marital satisfaction is associated with a stronger antibody
response to vaccination, and increased marital conflict is
related to slower wound healing (Kiecolt-Glaser et al.,
2005; Phillips et al., 2006). One of the most active recent
areas of research is on inflammation, which is the immune
system response to infection and injury. While local/short-
term inflammation is typically beneficial in processes such
as wound healing, systemic/long-term inflammation (e.g.,
C-reactive protein, IL-6) is related to health problems such
as diabetes, cardiovascular disease, and some cancers
(Kiecolt-Glaser, Gouin, & Hantsoo, 2010). It is important
that the perception of supportive family relationships is
related to lower inflammation, whereas negativity in family
relationships results in acute increases in inflammation
(Kiecolt-Glaser et al., 2005; Yang, Schorpp, & Harris,
2014).
Each of these peripheral physiological systems are regu-
lated by brain structures that are also integral for responding
to social stressors and rewards (Eisenberger, 2013; Lieber-
man, 2007). Therefore, structures such as the cingulate and
insular cortices are important mediators of social stressors
on peripheral physiology. Not surprisingly, social support
appears to act in these areas to reduce peripheral effects of
social stressors (e.g., Eisenberger, Taylor, Gable, Hilmert,
& Lieberman, 2007). In addition, positive experiences with
close others are not only associated with decreased activity
in these regions (e.g., cingulate) but also associated with
increased activity in “reward” brain regions such as the
ventral striatum, septal area, and ventral tegmental area
(Cacioppo, Bianchi-Demicheli, Hatfield, & Rapson, 2012;
Inagaki & Eisenberger, 2012). Reward-related stimuli that
activate these areas can in some cases reduce stress-related
neuroendocrine responses (Creswell, Pacilio, Denson, &
Satyshur, 2013). Coan, Schaefer, and Davidson (2006)
found that holding a spouse’s hand during stress was asso-
ciated with attenuated threat-related responses in the insula
and hypothalamus, areas that influence the aforementioned
peripheral physiological pathways. Moreover, marital satis-
faction scores were directly correlated with lower threat-
related neural activation in these areas while holding the
spouse’s hand.
The Neurochemistry of Close Relationships:
Oxytocin as a Model System
A persistent and critical challenge for the field has been
determining how these robust associations between close
ties and disease-relevant peripheral physiology are instan-
tiated. In other words, what interactional processes are
involved in converting ongoing social interactions into a
cascade of enduring physiological signatures that affect
health? One important class of models centers around the
notion of coregulation which involves the coordination of
gaze, speech, and movements between individuals that
serve to strengthen (or weaken) the bond between them
(Semin & Cacioppo, 2008). It is important that this coordi-
nation of interpersonal processes is also reflected in each
individual’s underlying physiological activity. This inter-
weaving of physiology between individuals serves as a
springboard for multiple models and has been variously
termed coregulation, synchrony, attunement, social base-
line, or interpersonal emotion regulation (e.g., Sbarra &
Hazan, 2008). Although there are differences between mod-
els (Hove & Risen, 2009; Sbarra & Hazan, 2008), these
general processes appear important for the development and
maintenance of close relationships and may be key contrib-
utors to physiology and health.
In the following section, these theories are extended by
focusing on how coregulation may occur at a neurochemical
level and how this may impact the regulation of the afore-
mentioned peripheral physiological systems that influence
disease. Multiple neurochemical systems in the brain influ-
ence the regulation of peripheral physiology and are likely
to mediate social influences on health. However, because of
space constraints the focus is on the oxytocin system be-
cause it has the largest evidence base. To orient the reader,
a brief introduction to the anatomy of the oxytocin system is
provided (see supplementary information for greater detail).
Oxytocin neurons reside in the hypothalamus and because
forebrain inputs synapse in limbic (e.g., lateral septum,
medial amygdala) or hypothalamic nuclei before signaling
oxytocin neurons, social information that reaches oxytocin
neurons is likely to be highly processed and elaborated.
Baldwin M. Way
592 UCHINO AND WAY
Once activated, oxytocin neurons can signal in several dif-
ferent ways. One is via axonal projections to the pituitary
that release oxytocin into the bloodstream to act as a hor-
mone by binding to receptors on cells. Another is via
projections from the hypothalamus to many forebrain re-
gions including the ventral striatum and amygdala as well as
the cingulate, insular, and association cortices (Knobloch et
al., 2012) where oxytocin can signal in a more targeted
fashion on the oxytocin receptors located in these areas. The
degree to which release between these forebrain and pitu-
itary projections is coordinated depends on the stimulus and
context, with some situations eliciting coordinated release
and others not (Neumann, 2007).
Oxytocin and Coregulation
A major reason to focus on the oxytocin system is that
there is evidence in both human and animal models that
interacting with one’s partner or offspring can impact one’s
oxytocin transmission and that changes in oxytocin trans-
mission can promote behaviors that facilitate further bond-
ing. Thus, oxytocin signaling may be an important nexus in
a positive feedback loop of reciprocal coregulation. Because
of oxytocinergic influences on the HPA axis, immune sys-
tem, and autonomic nervous system, this coregulation of
oxytocin is poised to have physiological effects that impact
health. This model of neurochemically mediated coregula-
tion and health is depicted schematically in Figure 1 and
discussed in greater detail below. The evidence reviewed
below should be considered in light of general methodolog-
ical concerns regarding this area and the field more gener-
ally (see online supplementary information). Nevertheless,
when the animal and human literature on oxytocin, stress,
and social interaction is viewed as a whole there is an
emerging picture supportive of the model in Figure 1. Al-
though not a focus of this article, the model is generally
consistent with psychological models which suggest that
relationship threats (e.g., negativity; Taylor, Saphire-
Bernstein, & Seeman, 2010) or closeness (e.g., positivity;
Carter, 2014) can modulate oxytocin release and that ele-
vations in oxytocin can increase social salience (Shamay-
Tsoory & Abu-Akel, 2016), approach (Kemp & Guastella,
2011), or affiliative motivation depending on the context
(Bartz, 2016). The critical emphasis here is that neurochem-
ical signaling is not just an intrapersonal process, but also an
interpersonal one. Below, evidence is reviewed in support
of the model by focusing on studies of closely bonded
individuals for whom affiliation is a salient goal. As dis-
cussed later, the effects of oxytocin may be very different in
other contexts.
The first step in identifying oxytocin’s role in coregula-
tion is demonstrating that social interactions influence oxy-
tocin signaling. This evidence is based on inferences from
peripheral measures of oxytocin. For example, the duration
of gaze at an infant by a mother during a structured labo-
ratory interaction is related to her increase in extracted
plasma oxytocin (Kim, Fonagy, Koos, Dorsett, & Strath-
earn, 2014). During a structured interaction with their in-
fant, the more affectionate touch the mother displayed or the
Positive Family
Relationships:
Stress-Buffering,
Caring, Warmth
Negative Family
Relationships:
Insensitivity,
Conflict,
Interference
Neural
Regions for
Socio-
emotional
Processing:
(e.g., ventral
striatum,
cingulate,
amygdala).
Acute/Chronic
Disease
Morbidity
Mortality
Neurochemical
Pathways:
(e.g., Oxytocin)
Person, Experiental, Situational Factors
(e.g. Genetic variation, early life adversity, relationship type)
Disease-
Relevant
Peripheral
Physiological
Pathways:
Autonomic,
Endocrine,
and Immune
Figure 1. General neurochemical model linking positive and negative aspects of close relationships to health
outcomes.
593
RELATIONSHIPS AND NEUROCHEMICAL PATHWAYS
more stimulatory touch (e.g., prodding to induce play) the
father showed, the greater the increase in unextracted
plasma and salivary oxytocin in the parent (Feldman, Gor-
don, Schneiderman, Weisman, & Zagoory-Sharon, 2010).
These effects can also be seen at the neural level. A moth-
er’s increase in plasma oxytocin (extracted) when interact-
ing with her infant is correlated with neural activation in the
ventral striatum and hypothalamus when looking at images
of her infant relative to other infants (Strathearn, Fonagy,
Amico, & Montague, 2009). The ventral striatum is a crit-
ical region for reward and these results suggest that gazing
at their infant is more rewarding for mothers whose oxyto-
cin levels show the largest response to gazing at their infant.
Furthermore, hearing comforting and reassuring words from
one’s mother by phone after a stressor increases urinary
oxytocin relative to a comforting conversation via instant
message (Seltzer, Prososki, Ziegler, & Pollak, 2012) or no
interaction (Seltzer, Ziegler, & Pollak, 2010).
A second element of coregulation is that oxytocin appears
to increase behaviors facilitating social engagement. When
receiving intranasal oxytocin, fathers show greater stimula-
tion of their toddler’s exploration during a play session in the
laboratory compared with placebo (Naber, van Ijzendoorn,
Deschamps, van Engeland, & Bakermans-Kranenburg, 2010).
Similarly, when fathers receive intranasal oxytocin they
show greater touching behavior (index of affectionate and
stimulatory touch) compared with placebo (Weisman,
Zagoory-Sharon, & Feldman, 2012).
Especially intriguing is that these oxytocin induced be-
havioral changes can influence oxytocin levels in the inter-
action partner, suggesting that coregulation can be a dyadic
process. In the aforementioned study, when the father re-
ceives intranasal oxytocin the interaction with his infant
triggers a larger increase in the infant’s unextracted salivary
oxytocin than when the father receives placebo. Further-
more, these changes are associated with increased tonic
RSA in both the father and the infant, thereby affecting
peripheral measures of health in both individuals. This
mutual coordination of peripheral oxytocin (extracted) and
tonic RSA has even been seen between humans and their pet
when intranasal oxytocin was given to the dog (Nagasawa et
al., 2015; Romero, Nagasawa, Mogi, Hasegawa, & Kikusui,
2014). The intranasal oxytocin facilitated the dog’s gaze
with their owner, which lead to corresponding increases in
urinary oxytocin in the owner as well as the dog. These
intriguing findings demonstrate how two bonded individu-
als can mutually influence each other’s physiology in a
salubrious manner.
There is some evidence that coregulation of oxytocin is
occurring in romantic relationships as well. For example, in
an initial study of male subjects and a replication, partici-
pants rated their partners as more attractive when receiving
intranasal oxytocin than when receiving placebo. In both
studies, oxytocin increased activity in the ventral striatum to
viewing their partner’s face relative to an unfamiliar wom-
an’s face, suggesting that oxytocin enhanced the reward
value of their partner (Scheele et al., 2013). In another
study, plasma oxytocin (unextracted) was higher in new
lovers than individuals not in a relationship and was corre-
lated with an index of behavioral and affective reciprocity
recorded during a conversation about a shared positive
experience (Schneiderman, Zagoory-Sharon, Leckman, &
Feldman, 2012). Similarly, expression of affiliative cues
while recounting an experience of love was also associated
with an increase in unextracted plasma oxytocin (Gonzaga,
Turner, Keltner, Campos, & Altemus, 2006). It should be
noted an association between positive social interactions
with close others and increases in peripheral measures of
oxytocin has not been universally found (Ditzen et al., 2008;
Gouin et al., 2010; Smith et al., 2013), which could reflect
methodological reasons at either the biological (e.g., oxy-
tocin assay differences) or psychological (e.g., context,
Bartz, Zaki, Bolger, & Ochsner, 2011) levels.
Oxytocin Effects on Disease Relevant Peripheral
Physiological Systems
A key component of the model (Figure 1) is that shifts in
oxytocin levels can have direct effects on the peripheral
physiological systems impacting health as shown by prior
studies on familial positivity/negativity and the autonomic,
neuroendocrine, and immune systems. One system directly
influenced by oxytocin is the HPA axis. The neurons in the
hypothalamus that initiate the HPA response express the
receptor for oxytocin (Neumann, Wigger, Torner, Holsboer,
& Landgraf, 2000). When oxytocin binds to this receptor, it
inhibits HPA axis activation and thus cortisol release. The
inhibitory effect of oxytocin on stress-induced cortisol re-
lease is also enhanced by social support from close others
(Heinrichs, Baumgartner, Kirschbaum, & Ehlert, 2003). In
other words, social support and oxytocin act synergistically
to dampen stress reactivity. Oxytocin can also act in brain
stem areas controlling vagal output (Higa, Mori, Viana,
Morris, & Michelini, 2002). Accordingly, intranasal admin-
istration of oxytocin elicits an increase in RSA (Norman et
al., 2011), which is associated with social engagement and
improved self-regulatory capabilities. Although less studied
in terms of close relationship processes, there is also evi-
dence that oxytocin can decrease blood pressure (Gut-
kowska & Jankowski, 2012); relationship interventions that
increase oxytocin also decrease blood pressure (Holt-
Lunstad et al., 2008).
There has been less extensive investigation of oxytocin’s
effects on inflammation, though there is good reason to
expect it to be involved with familial influences on inflam-
mation as well. Experimental stimulation of the immune
system with a bacterial challenge (endotoxin administra-
tion) induces a robust increase in proinflammatory cyto-
594 UCHINO AND WAY
kines, as well as feelings of social disconnection (Eisen-
berger, Inagaki, Mashal, & Irwin, 2010). The increase in
cytokines after bacterial challenge is reduced by peripheral
administration of oxytocin (Clodi et al., 2008). The specific
pathways responsible for these anti-inflammatory effects
are being investigated in ongoing work but one possibility is
that oxytocin is acting centrally on brainstem nuclei con-
trolling the vagus nerve to suppress peripheral production of
inflammatory cytokines (Higa et al., 2002; Tracey, 2007).
Thus, oxytocin can impact multiple health-relevant physio-
logical pathways and is ideally positioned to bridge the
social realm and the biological systems that contribute to
disease.
Findings in animal models corroborate and extend the
human results reported here. In rodent models, administra-
tion of oxytocin prevents the negative effects of social
isolation on the cortisol response to stress (Detillion, Craft,
Glasper, Prendergast, & DeVries, 2004), neuroinflamma-
tion (Karelina et al., 2011), and vagal tone (Grippo, Traha-
nas, Zimmerman, Porges, & Carter, 2009). Conversely,
blockade of central oxytocin receptors, which cannot be
done in humans, prevents the positive effects of social
housing on each of these peripheral physiological measures.
The consistency of these data across both human and animal
models (which afford greater control) strongly suggest that
oxytocin mediates a portion of the social effects on health
(Taylor et al., 2000). It is important that animal models
show that oxytocin has protective effects on diverse health
conditions such as myocardial infarction, hypertension, and
obesity (Blevins & Baskin, 2015; Jameson et al., 2016;
Moghimian et al., 2013). However, direct evidence for
oxytocin’s protective role in human disease outcomes is
virtually nonexistent and should be a priority of future
research on the model.
The model in Figure 1 also suggests that health problems
can ultimately develop when individuals have insufficient
social contact. Parental neglect of a child is a well-
documented risk factor for poor relationship as well as
health outcomes in adulthood. Thus, infants and children
who receive less attuned parenting will experience less of an
increase in oxytocin during this critical period of brain
development, which might have enduring effects on the
function of their oxytocin system and its influence on the
mechanistic central and peripheral pathways detailed ear-
lier. Consistent with this, women who suffered childhood
abuse have lower cerebrospinal fluid oxytocin concentra-
tions in adulthood (Heim et al., 2009). Similarly, men who
experienced early life stress have lower unextracted plasma
concentrations of oxytocin (Opacka-Juffry & Mohiyeddini,
2012). That early life stress alters the oxytocin system is
further supported by studies administering oxytocin (see
Bakermans-Kranenburg & van I Jzendoorn, 2013, for a
review). For example, individuals who grew up with a
mother who frequently withdrew her love showed less al-
truistic behavior after oxytocin administration when adults
(Riem, Bakermans-Kranenburg, Huffmeijer, & van Ijzen-
doorn, 2013). Such preliminary data are consistent with a
life history strategy of reduced investment in social bonds
and relationships triggered by experiences of early life
stress (Del Giudice, Ellis, & Shirtcliff, 2011).
Future Directions and Conclusions
The existing work on neurochemical models involved in
the pathways from close social relationships to health holds
much promise. However, there are several issues that will
require additional attention. One issue is the need to eluci-
date the role of genetic variation in the oxytocin system. In
light of the methodological challenges associated with mea-
suring oxytocin or administering it intranasally (see online
supplemental material), genetic approaches have the poten-
tial to provide convergent evidence for the role of oxytocin
in connecting familial relationships with health. Animal
models suggest that such variation can have robust effects
on social bonding (King, Walum, Inoue, Eyrich, & Young,
2016), but this potential has not been realized yet in hu-
mans, as associations between variation in oxytocin recep-
tor genes and behavior have not been particularly robust
(Bakermans-Kranenburg & van Ijzendoorn, 2014). There
are multiple reasons for the lack of consistency, but one is
that the most studied genetic variants within the oxytocin
gene or the oxytocin receptor gene (OXTR) do not have
clearly defined effects on cellular function. Alternative ap-
proaches to be taken in the future are to look at variants in
the OXTR that have demonstrated cellular-level functional
effects (Myers et al., 2014), variants in other genes that are
involved in oxytocin signaling (e.g., CD38; Algoe & Way,
2014), or epigenetic marks affecting oxytocin (Haas et al.,
2016) or oxytocin receptor expression (Gregory et al.,
2009). These approaches will provide greater opportunity to
investigate the effects of the oxytocin system outside of the
laboratory. With increasing evidence that epigenetic marks
in peripheral tissue can be correlated with central ones
(Turecki & Meaney, 2016), it will be possible to examine
how familial experiences elicit epigenetic changes that lead
to enduring changes in the expression of genes within the
oxytocin system. Likewise, as additional functional oxyto-
cinergic gene variants become identified it will be possible
to examine how they moderate familial experiences.
Oxytocin is also just one of a cocktail of neurochemicals
that are likely involved in social influences on health. For
example, there is increasing evidence for the opioid system
mediating social influences on health in a manner similar to
the oxytocin system (Way, 2013). In multiple species,
blockade of the primary opioid receptor prevents the for-
mation of bonds between mothers and infants (Shayit,
Nowak, Keller, & Weller, 2003) as well as partners (Re-
sendez et al., 2013). Social sadness leads to reductions in
595
RELATIONSHIPS AND NEUROCHEMICAL PATHWAYS
endogenous opioid signaling (Zubieta et al., 2003). Simi-
larly, blockade of endogenous opioid signaling reduces
daily reports of feeling socially connected with close others
(Inagaki, Ray, Irwin, Way, & Eisenberger, 2016). These
psychological effects are likely to have important peripheral
physiological effects as well. For example, the endogenous
opioids are powerful regulators of peripheral physiological
systems such as the HPA axis (Wuarin & Dudek, 1996). An
important area for future research will be delineating the
relative and interactive role of the oxytocin, opioid, and
other neurochemical systems in mediating social influences
on health.
In light of the number of clinical trials testing intranasal
oxytocin administration for mental health disorders (Wu-
darczyk, Earp, Guastella, & Savulescu, 2013), the question
arises as to whether it could be used to improve relation-
ships and subsequent physical health. This is unlikely to be
a simple panacea. Although the focus of this review is on
closely bonded individuals, there are multiple examples of
how intranasal oxytocin can have different effects depend-
ing the nature of the person one is interacting with (Bartz et
al., 2011). For instance, intranasal oxytocin increases in-
group trust but has more complex (nonsignificant) influ-
ences on out-group distrust (see meta-analysis by van Ijzen-
doorn & Bakermans-Kranenburg, 2012). Familial ties also
differ in their underlying positivity and negativity so it is
unclear to what extent such an approach would facilitate
strictly positive interactions (Uchino, Smith, & Berg, 2014).
A final therapeutic challenge is that oxytocin is less likely to
help those who need it the most. As described previously,
those experiencing early adversity are less responsive to
intranasal oxytocin, as are those who are lonely (Norman et
al., 2011).
Based on the studies indicating that intranasal oxytocin
interacts synergistically with social support behaviors (Hei-
nrichs et al., 2003), it is postulated that if oxytocin is to be
used successfully in therapy to improve health, it is likely to
have the most positive effects by being combined with
interventions that involve a social component. Oxytocin
might thus be combined with empirically supported inter-
ventions (e.g., functional family therapy, Alexander, Wal-
dron, Robbins, & Neeb, 2013), as well as more recent
relationship interventions such as meditation (e.g., loving-
kindness meditation, Isgett, Algoe, Boulton, Way, &
Fredrickson, 2016), dyadic approaches (e.g., marital, Sher
et al., 2014), and more general family based primary pre-
vention efforts (Repetti, Robles, & Reynolds, 2011). In an
intriguing study, Johnson and colleagues (2013) found that
emotionally focused therapy, which attempts to strengthen
attachment bonds, lowered threat-related neural activity in
distressed couples. These changes were particularly pro-
nounced in couples who were lower in marital quality to
begin with. Of course, primary prevention efforts are likely
to have the biggest long-term payoff and one recent inter-
vention found that training families in parenting skills was
related to lower levels of inflammation in the child approx-
imately 8 years later (Miller, Brody, Yu, & Chen, 2014). A
novel future research agenda would thus be to examine if
integrating such relationship interventions with neurochem-
ical approaches would provide further benefits. For exam-
ple, optimizing these psychosocial or behavioral interventions
to maximize drug response or using epigenetic information to
target therapy.
In conclusion, the more immediate benefit of studies of
oxytocin, and, the neurochemical approach more generally,
is to facilitate theoretical understanding of the mechanisms
by which close ties impact health. Carefully integrating
psychological and biological approaches will be critical for
a complete understanding of social influences on health as
evidenced by the last decade of oxytocin research. Were
oxytocin studied without attention to the psychological con-
text, it would be viewed as having inconsistent or nonre-
producible effects: increasing a particular behavior in one
study and decreasing it in another. However, when one
considers the psychological context (e.g., the nature of one’s
relationship to the interaction partner) a more coherent
picture emerges. Thus, psychologists and neuroscientists
have much to learn from each other and it is hoped that the
coming decade witnesses increased interdisciplinary dia-
logue that aides in the ultimate goal of utilizing integrative
theories to promote physical health outcomes.
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Received February 2, 2016
Revision received July 25, 2016
Accepted July 28, 2016
600 UCHINO AND WAY
... Likewise, positive social interactions were shown to be associated with reduced stress (e.g., Bernstein et al. 2017). Consequently, positive social interactions and social support were shown to be of major relevance for buffering stress and its deleterious effects on mental and physical health (Dickman et al. 2020;Ditzen and Heinrichs 2014;Uchino and Way 2017), which have been well documented and replicated during the last few decades (Chrousos 2009;McEwen 2017). ...
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... Importantly, they also provide scarce ecologically valid evidence for a stress-buffering role of social interactions on biological stress axes. 5 Finally, the results of the present study are an indirect validation of the theories which aimed at describing the neural mechanisms on how social interactions buffer the activity of the bodily stress axes (Hostinar et al. 2014;Uchino and Way 2017). ...
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