ARTICLE IN PRESS

Psychoneuroendocrinology (2007) 32, 587–603

Available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/psyneuen

REVIEW

2006 Curt P. Richter award winner

Social influences on stress responses and health
A. Courtney DeVries, Tara K.S. Craft, Erica R. Glasper, Gretchen N. Neigh1,
Jessica K. Alexander

Departments of Psychology and Neuroscience, The Institute for Behavioral Medicine Research, The Ohio State University,
Columbus, OH 43210, USA

Received 4 August 2006; received in revised form 22 March 2007; accepted 12 April 2007

KEYWORDS Summary
Stress; Both positive and negative social interactions can modulate the hypothalamic–pituitar-
Glucocorticoids; y–adrenal (HPA) axis and influence recovery from injuries and illnesses, such as wounds,
Oxytocin; stroke, and cardiac arrest. Stress exacerbates neuronal death following stroke and cardiac
Dominance; arrest, and delays cutaneous wound healing, via a common mechanism involving stress-
Behavior; induced increases in corticosterone, acting on glucocorticoid receptors. In contrast,
Social hamsters and mice that form social bonds are buffered against stress and heal cutaneous
wounds more quickly than socially isolated animals, presumably because the physical
contact experienced by the pairs releases oxytocin, which in turn suppresses the HPA axis
and facilitates wound healing. Social housing also decreases stroke-induced neuronal
death and improves functional recovery, but the mechanism appears to involve suppressing
the inflammatory response that accompanies stroke, rather than alterations in HPA axis
activity. An interaction between the HPA axis and immune system determines stroke
outcome in neonatally manipulated mice that exhibit life-long dampening of the HPA axis.
Taken together, these studies provide support for the detrimental effects of stress and
identify potential mechanisms underlying the well-documented clinical observation that
social support positively influences human health.
& 2007 Published by Elsevier Ltd.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
2. Influence of adult social interactions on the HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
2.1. Reciprocal influences: pair bonds and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589

Corresponding author. Tel.: +1 614 292 7353; fax: +1 614 688 4733.
E-mail address: devries.14@osu.edu (A.C. DeVries).
1
Current Address: Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.

0306-4530/$ - see front matter & 2007 Published by Elsevier Ltd.

doi:10.1016/j.psyneuen.2007.04.007
 ARTICLE IN PRESS
588 A.C. DeVries et al.

2.2. Stress and cutaneous wound healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590

2.3. Social interaction and cutaneous wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
2.4. Stress and cerebral ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
2.5. Social interaction and cerebral ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
3. Mother–infant interaction and its role in shaping the HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
3.1. Mother–infant interaction and adult responses to cerebral ischemia . . . . . . . . . . . . . . . . . . . . . . . . . 596
4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Role of the funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598

1. Introduction
Social interactions profoundly influence physiology and
behavior. Depending on the specific animal and circum-
stances, they can be a source of stress or a means of
reducing stress (reviewed in DeVries et al., 2003). Most
studies aimed at examining the mechanisms underlying
social influences on the hypothalamic–pituitary–adrenal
(HPA) axis have focused on negative (i.e., stress induced)
outcomes. Indeed, social stress is an important factor in the
etiology of disease. For example, disruption of social
hierarchy in mice is associated with reactivation of latent
herpes simplex virus type-1 (Padgett et al., 1998b) and
increased susceptibility to bacterial endotoxic shock (Quan
et al., 2001). Social stress also increases susceptibility of
rhesus monkeys to simian immunodeficiency virus (SIV;
Capitanio et al., 1998). Likewise, an increased number of
stressful life events, high cortisol concentrations, and low
social support are associated with faster progression from
HIV positive status to AIDS among gay men (Leserman et al.,
2002).
In contrast to social stress and social isolation, positive
social interactions are beneficial to health; it is well
documented that social support in humans, and affiliation
in other animals, can have a positive impact on health and
decrease mortality from a myriad of different diseases,
injuries, and other health conditions (Coe, 1993; Cohen,
1988; DeVries, 2002; DeVries et al., 2003; Thomas et al.,
1985; Uchino et al., 1996). Some examples include
cardiovascular disease (Grace et al., 2002), cancer (Spiegel
and Sephton, 2001), systemic lupus erythematosus (Bae
et al., 2001), and chronic back pain (Penttinen et al., 2002).
Alternatively, loneliness, or perceived lack of social support,
is associated with a deterioration of physical and mental
health among humans (reviewed in Cacioppo et al., 2000;
Hawkley and Cacioppo, 2003; Strike and Steptoe,
2004). Despite the growing literature reporting effects
of social support and isolation on physical and psycho-
logical well-being, the physiological mechanisms underlying
these psychosocial influences on health remain largely
unknown.
Many of the benefits achieved through social support and
affiliation are presumably due to decreased HPA axis
activation. In the laboratory, social support blunts cortisol
responses to psychological stressors in humans (Kirschbaum
et al., 1995). A similar phenomenon occurs in pair bonding
rodents (Detillion et al., 2004; Sachser et al., 1998).
Oxytocin, a hypophyseal hormone perhaps best known for
its role in birth and lactation, is also released during physical
contact, and has been proposed as an effective regulator of
the HPA axis and a potential mechanism underlying the
suppressive effects of social support or affiliation on the HPA
axis. Chronic treatment of female rats with oxytocin results
in a transient increase in corticosterone, followed by
sustained suppression of the HPA axis (Petersson et al.,
1999). Pharmacological studies in men suggest that oxytocin
suppresses the HPA axis at both the levels of the pituitary
and the adrenal gland (Chiodera and Coiro, 1987; Legros
et al., 1988). Furthermore, intranasal oxytocin significantly
suppresses cortisol and anxiety responses to the Trier Social
Stress Test relative to controls, and oxytocin is most
effective in this paradigm when combined with social
support (Heinrichs et al., 2003). Suckling, nipple stimulation
and social contact, which naturally produce elevations in
oxytocin concentrations, also tend to dampen HPA axis
reactivity among humans (Amico et al., 1994; Chiodera
et al., 1991; Cook, 1997; Heinrichs et al., 2002; Grewen et al.,
2005). In contrast to the suppressive effects of oxytocin on
the HPA axis, treatment of rodents with a selective oxytocin
antagonist increases basal and stress-induced corticosterone
(Neumann et al., 2000) and reverses the effects of pair
bonding on HPA axis activity (Detillion et al., 2004).
Although some studies have failed to find an effect of
oxytocin on HPA axis activity (Lewis and Sherman, 1985;
Pfister and Muir, 1989; Taylor et al., 2006), the majority of
studies suggest that oxytocin exerts an inhibitory influence
on the HPA axis under a wide range of doses, and among a
wide variety of species.
Our goal is to understand the physiological and behavioral
consequences of social interactions and to identify the
mechanism through which they achieve their effects. We
have chosen wound healing, experimental stroke, and
cardiac arrest/cardiopulmonary resuscitation (CA/CPR) as
model systems in which to explore social influences on
physiology and behavior because: (1) wound healing, stroke,
and CA/CPR outcomes are known to be sensitive to
circulating glucocorticoid concentrations, (2) there is
extensive clinical, and rapidly growing rodent, literature
on these topics, and (3) there is a high degree of agreement
between the existing human and rodent data. When
possible, we use species known to form strong social bonds
(for example, prairie voles and California mice) to study
social influences on physiology and behavior in adults.
However, because of technical constraints associated with
the experimental stroke and CA/CPR surgeries, an inbred
mouse strain is used in these studies. Although the
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Social influences on stress
laboratory mice are polygynous, they are highly social and
do appear to benefit from pair housing. We are currently
working on adapting the experimental stroke and CA/CPR
procedures for use in pair bonding species in hopes
of assessing the influences of more complex social
circumstances, such as pair bond dissolution, on ischemic
outcome.
2. Influence of adult social interactions on the
HPA axis
2.1. Reciprocal influences: pair bonds and stress
HPA axis regulation in monogamous prairie voles (Microtus
ochrogaster) is unusual in two regards: (1) basal corticoster-
one concentrations are 8–10 times higher than in laboratory
strains of rats and mice and (2) social pairing can decrease
basal corticosterone concentrations by 50% in as little as
15 min (DeVries et al., 1995, 1997b). In addition, circulating
adrenocorticotropic hormone (ACTH) and adrenal-to-body
weight ratios are approximately three times higher in prairie
voles than most other rodents (Taymans et al., 1997).
However, prairie voles do not appear to suffer from any of
the deleterious consequences commonly associated with
chronic corticosteroid excess (for example see DeVries et
al., 1997a; Klein et al., 1996). Elevated corticosteroid
binding globulin (CBG) partially compensates for the excess
circulating corticosterone, but the amount of active, ‘‘un-
bound’’, corticosterone remains significantly higher in voles
than in rats (Taymans et al., 1997). The corticosteroid signal
in prairie voles is further reduced through decreased
glucocorticoid receptor affinity in both central and periph-
eral tissues, which is likely the result of several non-
conserved amino acid substitutions in the steroid binding
domain of the prairie vole glucocorticoid receptor gene
(Hastings et al., 1999; Taymans et al., 1997). Despite
unusually high circulating corticosterone concentrations,
the HPA axis of prairie voles remains responsive to circadian
cues (Taymans et al., 1997), social cues (DeVries et al.,
1997b) and stressors (DeVries et al., 1996, 1997a; Taymans
et al., 1997). Interestingly, prairie voles are relatively
unresponsive to pharmacological suppression of the HPA
axis via dexamethasone (Taymans et al., 1997), but both
males and females respond rapidly to animals of the
opposite sex by decreasing circulating basal corticosterone
concentrations by approximately 50% (DeVries et al., 1995,
1997b). This effect is only achieved with male–female
pairings; introducing animals of the same sex does not lead
to a decline in corticosteroid concentrations. The decline in
corticosterone concentrations also does not occur if the
experimental animal has formed a pair bond with a partner
prior to being exposed to the novel stimulus animal. The
physiological mechanism underlying this rapid decline in
corticosterone is unknown. However, the unusual response
pattern and highly specific social requirements suggest that
corticosteroids may be an important mediator of social
bonding in prairie voles.
Prairie voles are one of the few mammalian species that
form long-term pair bonds and are socially monogamous
(Carter et al., 1995; Getz et al., 1987). Pair formation
conveys several adaptive advantages in prairie voles,
589
including increased pup survival (Getz et al., 1992),
accelerated pup development (Wang and Novak, 1992),
and social buffering against stress (Carter, 1998; DeVries
et al., 1997b). Within the past decade, corticosterone, three
other hormones (oxytocin, vasopressin and corticotrophin-
releasing hormone) and one neurotransmitter (dopamine),
have been identified as modulators of social preferences in
prairie voles. In the laboratory, preference for social contact
with a familiar partner versus a novel stimulus animal is
assessed in a three chamber apparatus and used as an index
of pair bonding. The effects of stress and corticosterone on
partner preference in prairie voles are sexually dimorphic
(DeVries et al., 1995, 1996). Socially naı̈ve females typically
form preferences within several hours of being introduced to
a novel male, when corticosterone concentrations are low
(DeVries et al., 1995). Likewise, artificially reducing
corticosterone concentrations via adrenalectomy facilitates
partner preference formation, whereas treatment with
exogenous corticosterone inhibits partner preferences in
female prairie voles (DeVries et al., 1995). Corticosteroids
appear to delay partner preference development in females
through stimulation of the glucocorticoid type II receptor
(GR; Curtis and Wang, 2004). In contrast, male prairie voles
require more time than females to form partner prefer-
ences, which is temporally associated with the return of
corticosteroids to basal concentrations (DeVries et al.,
1996). Indeed, exposure to stress, treatment with exogen-
ous corticosterone, and treatment with exogenous cortico-
tropin-releasing hormone are all effective in facilitating the
formation of partner preferences in male prairie voles
(DeVries, 2002; DeVries et al., 1996; Lim et al., 2007).
Furthermore, adrenalectomy inhibits partner preference in
males. Thus, low circulating corticosteroid concentrations
inhibit the formation of partner preferences in male prairie
voles, but facilitate the formation of partner preferences in
female prairie voles. Sexual dimorphism in the regulation of
pair bonding by stress-related hormones may reflect
competing interests of male and female prairie voles during
unstable environmental or social conditions (DeVries et al.,
1996).
Taken together, these prairie vole studies suggest that
social stimuli can alter HPA axis activity, and that altered
HPA axis activity, in turn, influences the rate at which prairie
voles form social preferences. Involvement of the HPA axis in
social bonding provides a mechanism through which envir-
onmental cues, such as temperature, season, or population
density, can influence social structure (Nelson et al., 1996).
There also is potential overlap among corticosteroids and
the other hormones (oxytocin and vasopressin) and a
neurotransmitter (dopamine) involved in the regulation of
partner preference (Fig. 1; reviewed in DeVries et al.,
2003). For example, vasopressin directly facilitates partner
preference formation in male prairie voles (Cho et al., 1999;
Winslow et al., 1993; Young, 1999); but it also is a potent
ACTH secretagogue which could subsequently increase
corticosterone concentrations. In contrast, oxytocin, which
facilitates partner preference formation in female prairie
voles (Cho et al., 1999; Wang and Aragona, 2004; Williams
et al., 1994), produces rapid and prolonged suppression of
the HPA axis (reviewed above). Dopamine regulation of pair
bonding also provides a common pathway through which
oxytocin in female prairie voles and vasopressin in male
 ARTICLE IN PRESS
590
Figure 1 Modulators of social preference in prairie voles. The
effects of stress and corticosterone on partner preference in
prairie voles are sexually dimorphic. Socially naı̈ve females form
preferences with a novel male when corticosterone concentra-
tions are low. In contrast, male prairie voles form partner
preferences after exposure to a stressor, when circulating
corticosteroids are higher. Other hormones (oxytocin and
vasopressin) and a neurotransmitter (dopamine) also are
involved in partner preference formation in prairie voles.
Vasopressin directly facilitates partner preference in male
prairie voles, while oxytocin facilitates partner preference in
female prairie voles through its effects on dopamine, and
potentially by reducing circulating corticosteroids. Dopamine
appears to play a role in the reward and reinforcement of social
bonding in both male and female prairie voles.
prairie voles can affect partner preference (reviewed in
Wang and Aragona, 2004). The role of dopamine in reward
and reinforcement has been well described in the context of
social bonding and other behaviors (Di Chiara, 2002; Insel,
2003). In prairie voles, blockade of dopamine (D-2)
receptors in the nucleus accumbens prevents oxytocin-
induced partner preferences (Liu and Wang, 2003; Aragona
et al., 2006). Furthermore, it has been proposed that
simultaneous activation of olfactory and reward pathways
lead to convergent vasopressin and D-2 receptor activation
in the ventral forebrain and a conditioned partner pre-
ference (Lim et al., 2004). Corticosteroids also are well
known to sensitize the dopamine reward system and
contribute to individual differences in vulnerability to drugs
(de Jong and De Kloet, 2004); a similar interaction between
corticosteroids and dopamine may contribute to stress-
induced pair bonding in male prairie voles (DeVries et al.,
1996). Additional research is needed to determine the
precise nature of interactions among corticosterone, vaso-
pressin, oxytocin, and dopamine in modulating social
bonding. Understanding how social bonds are formed is
important because it is clear that the development of social
bonds and social networks in humans and other species can
influence HPA axis reactivity and impact health.
2.2. Stress and cutaneous wound healing
Stress-induced activation of the HPA axis has been shown
repeatedly to delay cutaneous wound healing in humans and
other animals (Table 1). Initially, it was documented that
A.C. DeVries et al.
women who were exposed to the chronic stress of caring for
a relative with Alzheimer’s disease required 24% longer to
heal than age-matched controls (Kiecolt-Glaser et al.,
1991). Women reporting high levels of general life-stress
also exhibit suppressed immune function at blister wound
sites relative to women who report low levels of life-stress
(Glaser et al., 1999). Furthermore, an academic exam,
which is a transient, predictable stressor administered to
young adults, delays wound healing by 40% compared to
wounds produced at other times of the academic year
(Marucha et al., 1998). Thus, both acute and chronic stress
delay wound healing in humans and have been associated
with elevated cortisol and immune dysregulation. However,
determining the mechanism by which stress affects wound
healing, and establishing a causal relationship, is more
easily accomplished in rodents than humans. Therefore,
much of what is known about the mechanisms underlying
stress-induced delays in wound healing has been learned
from rats and mice. Fortunately, the effects of stress on
healing rates and immune function at the wound site have
been remarkably consistent across human and rodent
studies.
To study wound healing in rodents, a standard size
circular wound (3.5 mm diameter) is created on the dorsum
using a punch biopsy tool. The wounds are photographed and
measured daily to assess healing rate. There are three
general stages of wound healing: (1) an inflammatory stage,
(2) a proliferative stage, and (3) a remodeling stage (Hubner
et al., 1996). Stress delays wound healing primarily by
altering the early inflammatory stage of healing; an effect
that is mediated by stress-induced increases in circulating
glucocorticoid concentrations (Padgett et al., 1998a).
Removal of endogenous corticosteroids via adrenalectomy
is effective in preventing stress-induced delays in wound
healing, but has no effect on healing rate among hamsters
that are not subjected to stress (Detillion et al., 2004).
Treatment with a glucocorticoid receptor antagonist prior to
restraint also attenuates the effects of stress on both wound
cellularity and wound size in mice (Padgett et al., 1998a). In
contrast, treatment with dexamethasone, a synthetic
glucocorticoid, delays wound healing (Gordon et al., 1994;
Hubner et al., 1996). Taken together, these data suggest
that corticosteroid concentrations do not negatively impact
wound healing until they increase beyond typical basal
concentrations. However, even a relatively modest stress-
induced delay in wound healing can compromise health; one
mechanism by which this may occur is increased incidence of
opportunistic infection (Rojas et al., 2002). Such infections
could have particularly disastrous consequences for immu-
no-compromised individuals, such as diabetics, cancer
patients, AIDS patients, and organ transplant recipients
(Becker, 1986; Hollenbeak et al., 2001).
The effects of stress and glucocorticoids on wound healing
are likely achieved through immunosuppression at the
wound site. Chronic stress or treatment with exogenous
glucocorticoids down-regulate interleukin 1 (IL-1a and IL-1b)
and platelet-derived growth factor (PDGF) mRNA expression
in the tissue surrounding the wound, an effect that is
abolished by pretreatment with a glucocorticoid receptor
antagonist or androstenediol (Hubner et al., 1996;
Mercado et al., 2002; Head et al., 2006). Similarly, stress
decreases tissue expression of pro-inflammatory chemokines
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Social influences on stress 591

Table 1 Effects of stress on wound healing.

Species Sex or Duration and type of Effects on wound Reference

gender stressor

Siberian M 2 h restraint stress m healing Kinsey et al. (2003)

hamster
Siberian F 2 h restraint stress k healing Detillion et al. (2004)
hamster
SKH-1 Mice F 15 h restraint stress k proinflammatory cytokines Mercado et al. (2002)
SKH-1 Mice F 15 h restraint stress k proinflammatory cytokines Mercado et al. (2002)
SKH-1 Mice F 12 h restraint stress k healing; reduced inflammation Padgett et al. (1998a, b)
SKH-1 Mice F 15 h restraint stress k healing; increase in opportunistic Rojas et al. (2002)
bacteria
C57BL/6 Mice M 12 h restraint stress k healing Sheridan et al. (2004)
C57BL/6 Mice M Social disruption stress no effect Sheridan et al. (2004)
Human F Perceived life stress k proinflammatory cytokines Glaser et al. (1999)
Human F Psychological stress k healing compared to controls Kiecolt-Glaser et al.
(1995)
Human M and F Examination stress k healing Marucha et al. (1998)

(interleukin-8 and macrophage inhibitory protein-1a) during

the early phases of wound healing in rhesus monkeys (Kalin
et al., 2006). Lesioning the central nucleus of the amygdala
reduces the monkeys’ HPA axis responses to stress, and
eliminates the effects of stress on these chemokines at the
wound site (Kalin et al., 2006). In humans, cytokine
production (IL-1b, IL-6 and tumor necrosis factor a) is lower
at blister wound sites when established couples participate
in a discussion that elicits conflict compared to when they
participate in a discussion that elicits social support
(Kiecolt-Glaser et al., 2005). In keeping with this immune
pattern, the couples heal at a slower rate after the conflict
discussion than after the social support discussion. Cytokines
play a critical role in the early stages of wound healing, thus
their sensitivity to modulation by glucocorticoids and other
stress-related hormones provides a mechanism through
which stress can affect wound healing.
Figure 2 Social modulation of wound healing (MEAN; based on
area of wound relative to initial wound size). Chronic stress
2.3. Social interaction and cutaneous wound delays wound healing in rodents. The negative effects of stress
healing on wound healing can be eliminated in Siberian hamsters (a
species known to form social bonds) by pair housing prior to and
following wounding. Chronic stress causes single-housed ham-
It is now well established that stress can severely hamper
sters to heal at a slower rate than pair housed hamsters, as
wound healing (Table 1); however, very little is known
indicated by the significantly larger wound size at each time
regarding the ability of positive social interaction to
point. (Adapted from Detillion et al., 2004.)
ameliorate stress and subsequently facilitate the healing
process. In general, research on the psychosocial factors
affecting health has focused primarily on negative con- exhibit a significant social preference for a female sibling
sequences. In contrast, the mechanisms through which versus a novel conspecific, which is an indication of pair
positive social interaction improves health and immune bonding (Detillion et al., 2004) and has been demonstrated
function remain largely unspecified (Kiecolt-Glaser et al., between same-sex prairie voles (DeVries et al., 1997b).
2002). To determine if amicable social relationships affect Indeed, in our study, the female–female Siberian hamster
wound healing, we adapted a mouse model of stress and pairs benefited from stress buffering and improved wound
cutaneous wounds to Siberian hamsters (Phodopus sun- healing compared to individually housed hamsters (Detillion
gorus), which form social bonds with familiar conspecifics et al., 2004). Socially isolated Siberian hamsters exhibited
(Crawley, 1984). Pair separation in this species results in a greater corticosteroid responses to restraint and slower
persistent increase in basal serum cortisol concentrations wound healing than paired hamsters (Fig. 2). Furthermore,
and concomitant behavioral alterations (Castro and Matt, stress delayed wound healing in socially isolated hamsters as
1997; Crawley, 1984). Female Siberian hamsters likewise expected, but had no impact on wound healing in paired
 ARTICLE IN PRESS
592
Table 2 Effects of social facilitation on wound healing.
Species Sex or gender Duration of social facilitation
P. californicus mice M 2 weeks of
P. eremicus mice M 2 weeks of
P. leucopus mice M 2 weeks of
Siberian hamster F 2 weeks of
hamsters. Among socially isolated hamsters, stress-induced
cortisol secretion was likely responsible for the delayed
wound healing because removing endogenous cortisol via
adrenalectomy ameliorated the effects of restraint on
wound closure. Thus, stress exposure delayed wound healing
in SHAM-adrenalectomized, but not adrenalectomized,
hamsters. Although social housing did not affect basal
cortisol concentrations, the paired hamsters had signifi-
cantly lower cortisol than socially isolated hamsters upon
removal from restraint, thereby suggesting that social
housing provides a buffer against stress-induced activation
of the HPA axis. Next, we hypothesized that the social
interaction and physical contact among pairs released
oxytocin, which in turn suppressed the HPA axis during
stress, and ultimately facilitated wound healing. In support
of this hypothesis, stress-induced cortisol concentrations
were approximately 35% lower in hamsters treated with
oxytocin versus the vehicle. Furthermore, wounds were
approximately 20% smaller in the oxytocin- versus vehicle-
treated hamsters during the first 3 days following wounding,
and a significant difference between groups persisted
through the end of the experiment at day 7 post-wounding.
Finally, pretreatment with an oxytocin receptor antagonist
significantly increased wound size. Thus, social housing
appears to improve wound healing through a mechanism
that involves oxytocin-induced suppression of HPA axis
reactivity to stress (Detillion et al., 2004).
Further studies have confirmed that physical contact is an
important component of social facilitation of wound heal-
ing. Both Peromyscus californicus (monogamous) and Per-
omyscus eremicus (facultative monogamous) have lower
corticosterone concentrations and heal more quickly when
housed in male–female pairs versus alone (Glasper and
DeVries, 2005). Indeed, stimulus animals of the same and
opposite sex are equally effective in facilitating wound
healing among P. californicus mice (Glasper and DeVries, in
review). However, when the pairs are housed in the same
cage, but prevented from physically interacting by a double-
screen barrier, corticosteroid concentrations increase and
wound size is similar to socially isolated mice (Glasper and
DeVries, 2005). Furthermore, the beneficial effects of social
interaction for wound healing do not persist beyond pair
dissolution in either P. californicus or P. eremicus. Overall,
the experimental mice that had been separated from their
partner had corticosteroid concentrations that were similar
to socially isolated mice, and both the socially isolated and
separated mice exhibited corticosteroid concentrations that
were significantly higher than the pair-housed mice.
It is important to note that not all species benefit from
social interaction. For example, despite sharing nests and
spending significant amounts of time in physical contact
A.C. DeVries et al.
Effects on wound Reference
pair housing m healing Glasper and DeVries (2005)
pair housing m healing Glasper and DeVries (2005)
pair housing No effect Glasper and DeVries (2005)
pair housing m healing Detillion et al. (2004)
with their partner, social pairing does not alter HPA activity
or wound healing in male P. leucopus mice, a typically
solitary species (Glasper and DeVries, 2005, in review). It is
possible that the brains of polygynous species, such as P.
leucopus, are not organized to respond to oxytocin release
during social interaction in a manner similar to monogamous
or highly social species, which would explain the lack of an
effect of social housing on HPA axis activity and wound
healing in polygynous mice. Evidence from studies compar-
ing monogamous and polygynous voles (Microtus) and mice
(Peromyscus) suggest that developmental differences in
oxytocin and vasopressin receptor expression in the brain
may contribute to species differences in propensity to form
social bonds (Insel et al., 1991; Insel and Shapiro, 1992;
Young et al., 2001). Indeed, for some species, pair or group
housing may induce social stress and have deleterious
effects on health measures (Gattermann et al., 2002;
Hannes and Franck, 1983; Sachser et al., 1998). Of course,
the direction in which social interaction affects corticoster-
oid concentrations and immune function also may be
impacted by several other factors, including the sex of the
experimental and stimulus animals (Klein et al., 1997; Klein
and Nelson, 1997), social status (Bartolomucci et al., 2003;
Devoino et al., 2003; Spencer et al., 1996), group size
(Grewal et al., 1997; Karp et al., 1997), and the level of
aggression among group members (de Groot et al., 2002).
Collectively, these studies suggest that social contact
facilitates wound healing (Table 2) via a mechanism that
involves oxytocin-induced suppression of HPA axis activity.
However, the benefits of social contact do not persist
following pair dissolution and are not achieved when the
pairs are prevented from interacting physically. Further-
more, the beneficial effects of social housing are not
equivalent for all species (or potentially individuals), and
may be limited to those that are monogamous or highly
social. Identification of oxytocin as the mechanism by which
social contact facilitates wound healing suggests a ther-
apeutic target that could be exploited to improve wound
healing in socially isolated individuals or others at risk for
impaired wound healing.
2.4. Stress and cerebral ischemia
Exposure to stress is a universal human experience, but the
magnitude, duration, frequency, and nature of stressors,
and the specific coping mechanisms used to deal with stress
vary greatly among individuals. There are many circum-
stances under which acute activation of the HPA axis during
stress may be adaptive, but chronic activation of the HPA
axis often has deleterious consequences on the brain (see
 ARTICLE IN PRESS
Social influences on stress 593

review, McEwen, 2000). In particular, chronic psychological
stress has been associated with an increased incidence or
exacerbation of several neurological disorders including
multiple sclerosis, Parkinson’s disease, depression, and age-
related dementia (Baum and Posluszny, 1999; Zigmond and
Stricker, 1984). Among the general public, it is commonly
believed that stress can precipitate stroke (House et al.,
1990); however, only a few clinical studies and case reports
have provided support of a relationship between severe
emotional stress and stroke incidence (Carasso et al., 1981;
Harmsen et al., 1990; House et al., 1990). There also are
several reports that provide no evidence for an effect of
emotional factors on stroke incidence (Agewall et al., 1998;
Gentry et al., 1979; Macko et al., 1996; Storey, 1985). The
discrepancy in conclusions among these clinical studies may
reflect many factors, including small sample size in some of
the studies, differences in mean age of subjects, the
methods associated with identifying, reporting, and rating
of stressful events, and individual differences in psycholo-
gical and physiological responses to potential stressors.
Furthermore, it is difficult to distinguish between the
effects of stress on stroke incidence versus stroke outcome
in clinical populations. This is particularly pertinent to
small, so-called ‘‘silent’’, strokes which are under-reported
in the general population, but may be unmasked by factors,
such as stress, that exacerbate their severity and clinical
presentation.
Despite disagreement regarding the effects of prior
exposure to stress on stroke incidence, several clinical and
rodent studies have provided convincing evidence that peri-
stroke concentrations of glucocorticoid hormones affect
stroke outcome. Stroke is itself a stressor; activation of the
HPA axis is among the first, easily quantifiable, physiological
changes to occur during an ischemic event among humans
(Fassbender et al., 1994; Johansson et al., 1997; Olsson,
1990; Olsson et al., 1992). There is convincing evidence to
suggest that intra-ischemic and post-ischemic serum gluco-
corticoid concentrations alter stroke outcome in both
humans and rodents. Elevated cortisol concentrations
following stroke are significantly correlated with increased
morbidity and mortality in humans (Davalos et al., 1996;
Fassbender et al., 1994; Feibel et al., 1977) and increased
infarct size in mice (DeVries et al., 2001). Furthermore, a
causal link between corticosteroid concentration and stroke
outcome is suggested by animal studies in which manipulat-
ing blood corticosteroid concentrations before, during, or
after an ischemic event alters infarct size (DeVries et al.,
2001; May et al., 2002; Morse and Davis, 1990; Rami et al.,
1998; Sapolsky and Pulsinelli, 1985; Smith-Swintosky et al.,
1996; Sugo et al., 2002). Examination of SHAM-stroke
animals that were exposed to stress confirms that relatively
acute exposure to elevated glucocorticoid concentrations
does not kill neurons in the absence of concomitant neural
trauma (DeVries et al., 2001; Sugo et al., 2002), but instead
may increase stroke-induced neuronal death by creating a
sub-lethal state of catabolic crisis that renders neurons less
likely to survive a subsequent ischemic injury (Sapolsky,
1985).
Our studies have focused on documenting the effects of
positive and negative social interactions on stroke outcome
in mice and determining the mechanism by which social cues
affect stroke outcome. We experimentally induce stroke in
mice by inserting an occluder into the common carotid
artery, then advancing it through the internal carotid artery
to the origin of the middle cerebral artery, which results in a
90% decrease in blood flow to the areas of the cortex and
striatum that are served by the middle cerebral artery. The
occlusion is maintained for 60 min, produces a core infarct
(neuronal death) of approximately 15% of the affected
hemisphere, and is referred to as transient middle cerebral
artery occlusion (MCAO). Exposure of male mice to social
stress (an aggressive male) for several days prior to inducing
stroke produces substantially larger core infarcts, even
though the last exposure to social stress occurs 24 h prior to
stroke (Fig. 3B; DeVries et al., 2001; Sugo et al., 2002). The
increase in infarct size among stressed animals (approxi-
mately 300%) is functionally significant because they are less
likely to learn and retain a passive avoidance task than other
stroke mice (Sugo et al., 2002). Furthermore, the effects of
stress on histological and behavioral outcomes are repro-
duced through chronic treatment with exogenous corticos-
terone. In contrast, treatment with a glucocorticoid
receptor antagonist 30 min prior to social stress ameliorates
the effects of stress on both infarct size and performance in
a passive avoidance task among stroke mice. Taken together,
these data suggest that prior exposure to chronic stress

Figure 3 bcl-2 expression and ischemic damage following 60 min of experimental stroke in male mice exposed repeatedly to social
stress or the control condition. (A) bcl-2 expression, as measured by RNase protection assay, was significantly suppressed in male
mice that were exposed to social stress prior to stroke. These data suggest that stress inhibits an important injury-induced
endogenous neuroprotective mechanism. (B) Infarct size was quantified as a percentage of the contralateral hemisphere after
correcting for edema. Mice exposed to social stress had infarcts that were approximately four times as large as males not exposed to
stress. An asterisk (*) denotes Pp0.05. (Adapted from DeVries et al., 2001; Sugo et al., 2002.)
 ARTICLE IN PRESS
594 A.C. DeVries et al.

exacerbates histological and behavioral stroke outcome brain and further exacerbates CA/CPR-induced neuronal
through a mechanism that likely involves corticosterone death and anxiety-like behavior (Neigh et al., unpublished).
acting through glucocorticoid receptors (Sugo et al., 2002). Collectively, these data suggest that a history of exposure to
This observation extends previous studies in which treat- stress increases the microglial response to ischemic injury
ment with exogenous glucocorticoids potentiates the neu- and augments neuronal damage and anxiety-like behavior.
rodegenerative processes that occur during stroke. Intra-
ischemic treatment of rats with metyrapone, a drug that
attenuates stress-induced corticosterone production during 2.5. Social interaction and cerebral ischemia
MCAO, reduces infarct volume in the cortex and striatum by
approximately 50% (Smith-Swintosky et al., 1996). In In addition to studying the effects of stress on stroke
contrast, treatment with exogenous corticosterone daily, outcome, we have examined the effects of social isolation
beginning at reperfusion, results in a significant increase in versus pair housing on stroke-induced infarct size and
infarction volume in the hippocampus, neocortex, and functional recovery in male and female mice (C57BL/6;
striatum following global ischemia (Koide et al., 1986; Craft et al., 2005). For 2 weeks prior to stroke and during
Sapolsky and Pulsinelli, 1985). Taken together, these studies the 1-week recovery period, the mice were housed with an
suggest that there is a potentially wide temporal window ovariectomized female. Paired male and female mice had
during which elevated serum glucocorticoid concentrations significantly smaller stroke-induced infarcts and sensorimo-
can affect stroke-induced neuronal death. tor deficits than socially isolated mice (Figs. 4 and 5).
There are several mechanisms through which stress and Contrary to our initial hypothesis, the effects of pair housing
glucocorticoid treatment may affect stroke outcome. For on ischemic outcome do not appear to be related to intra-
example, glucocorticoids have been shown to decrease local ischemic or post-ischemic corticosterone concentration
cerebral glucose utilization in vivo (Kadekaro et al., 1988) (Fig. 6A), because hormone concentration did not vary
and inhibit glucose transport in neurons in vitro (Horner significantly as a function of housing. In contrast, social
et al., 1990). By impairing glucose transport, glucocorticoids housing did influence c-reactive protein (CRP) concentra-
cause a subsequent ATP depletion and increased neuronal
vulnerability to excitotoxicity (reviewed in Sapolsky, 1994).
Stress also may affect infarct size indirectly by suppressing
endogenous expression of bcl-2, an anti-apoptotic protein
that is typically induced following ischemia. Increased bcl-2
expression promotes cell survival and protects against
apoptosis and cellular necrosis in numerous neurodegenera-
tive disorders (Bergeron and Yuan, 1998). Stressed mice
express approximately 70% less bcl-2 mRNA than unstressed
mice in response to stroke (Fig. 3A), which suggests that
stressful pre-stroke social milieu strongly compromises this
endogenous molecular mechanism of neuroprotection and
could explain the substantial increase in neuronal death
among stressed mice (Fig. 3B; DeVries et al., 2001). This
study also provided the first evidence that extrinsic factors,
such as chronic social intimidation and stress, could alter
bcl-2 expression in the brain and exacerbate experimental
stroke outcome. Despite similar post-stroke corticosterone
concentrations, high corticosterone was significantly corre-
lated with larger infarcts in wild-type mice, but not
transgenic mice that constitutively over-express bcl-2
(DeVries et al., 2001).Thus, preserved bcl-2 expression can
provide a buffer against stress-induced exacerbation of
ischemic injury. Figure 4 Neuronal damage following 60 min of experimental
Exposure to stress also compromises neuronal survival in stroke (middle cerebral artery occlusion, MCAO). Transient focal
the hippocampus and increases inflammation throughout the ischemia is achieved by inserting a monofilament occluder that
brain following global ischemia induced via 8 min of CA/CPR blocks blood flow to the middle cerebral artery for 60 min,
(Neigh et al., in review). Our mouse model of CA/CPR typically resulting in an infarct limited to the caudate putamen.
reproduces many of the physiological and behavioral Sham surgeries follow the same protocol as MCAO, except the
changes that are observed in humans following cardiac located arteries are unmanipulated. Following reperfusion (7
arrest, including HPA axis dysregulation (Neigh et al., 2005), days), 2,3,5-triphenyltetrazolium (TTC) is used to stain live
sensitized peripheral inflammatory response (Neigh et al., mitochondria in the neural tissue; thus, infarcted tissue
2005), increased anxiety (Neigh, 2004; Neigh et al., 2004b), containing dead neurons appears white. Neuronal tissue of
cognitive deficits (Neigh et al., 2004a), social deficits (Neigh Sham mice is undamaged and healthy (i.e. fully stained).
et al., 2004b), and neuronal death in the hippocampus Though both MCAO groups have the expected size and location
(Kofler et al., 2004; Neigh et al., 2005, 2004a, b). Interest- of infarct, pair housing for two weeks prior to and following
ingly, exposure to 3 weeks of stress prior to CA/CPR causes a surgery significantly reduces infarct size compared to isolated
significant increase in microglial activation throughout the mice. (Adapted from Craft et al., 2006.)
 ARTICLE IN PRESS
Social influences on stress 595

Figure 5 Ischemic damage and functional deficits following 60 min of experimental stroke (MCAO; Mean7SEM). (A) Infarct size was
quantified as a percentage of the contralateral hemisphere after correcting for edema. Results indicate that mice pair-housed with
an ovariectomized female prior to and following stroke surgery have significantly smaller infarcts at recovery day 7 compared to
isolated mice. (B) Functional deficits following stroke were assessed using the cylinder test. Mice were placed in a Plexiglas cylinder
for 5 min to assess left and right paw use during rearing. Decreases in left paw use following MCAO indicate a functional deficit
contralateral to the hemisphere sustaining stroke damage. Socially isolated, but not paired, males exhibit a significant decrease in
post-stroke left paw use compared to baseline. An asterisk (*) denotes Pp0.05. (Adapted from Craft et al., 2005.)

Figure 6 Intraischemic corticosterone and C-reactive protein (CRP) concentrations (Mean7SEM). Blood samples were collected at
60 min of MCA occlusion. Though isolated and pair housed males have similar intraischemic corticosterone responses to stroke (A),
pair housed males have significantly lower CRP concentrations than socially isolated males at 60 min of ischemia (B). The socially
isolated males go on to develop larger infarcts than paired males. An asterisk (*) denotes Pp0.05. (Adapted from Craft et al., 2005.)

tions; pair housed males had significantly lower blood CRP
concentrations at 60 min of stroke than socially isolated
males (Fig. 6B). In apparently healthy humans, social stress
or low levels of social support also are associated with
increased CRP concentrations (Schnorpfeil et al., 2003;
McDade et al., 2006). CRP is produced by hepatocytes and
transcription is primarily under control of IL-6, a pro-
inflammatory cytokine (reviewed in Pepys and Hirschfield,
2003). Following inflammatory stimuli, CRP concentrations
in blood increase so dramatically that it is often used
clinically as an index of inflammation (Szalai and McCrory,
2002), which can be an important risk factor for stroke
(Lindsberg and Grau, 2003). Indeed, high CRP concentration
is predictive of future stroke in both men and women
(Arenillas et al., 2003; Rost et al., 2001) and the association
remains strong during a 20-year follow-up period (Curb
et al., 2003). Elevated CRP concentrations following stroke
also are associated with higher Canadian Neurological Stroke
Scores and Barthel Index Scores at 1-year following
discharge from the hospital (Di Napoli et al., 2001). Future
studies will be aimed at determining whether elevated CRP
concentrations in socially isolated mice directly influence
infarct size or whether they are a marker of an altered
stroke-induced neuroinflammatory response.
In conclusion, psychosocial factors affect both histological
and behavioral stroke outcomes. A negative social environ-
ment adversely affects cerebrovascular health through a
mechanism that involves increased activation of the HPA
axis and secondary suppression of bcl-2 mRNA expression.
The effects of stress on behavioral and histological outcomes
of ischemia are reproduced via treatment with exogenous
corticosterone and ameliorated by pre-treatment with a
 ARTICLE IN PRESS
596
glucocorticoid antagonist. Positive social interaction also
decreases stroke-induced neuronal death and improves
behavioral recovery, possibly through a mechanism that
involves reduced stroke-induced inflammation.
3. Mother–infant interaction and its role in
shaping the HPA axis
Individual differences in stress responsivity play an impor-
tant role in determining the acute and cumulative effect of
glucocorticoid exposure. There are significant differences in
how individuals perceive and interpret stressors, and the
encoding of memories of past stressful events influences
one’s physiological and behavioral responses to future
stressors (Buchanan and Lovallo, 2001; Marti et al., 2001;
McEwen, 1998; Wolf et al., 2003). Neonatal environment
may be a particularly important determinant of adult stress
responsivity that ultimately affects allostatic load and the
onset of psychopathology and age-related disease (Barring-
ton, 2001; Matthews, 2000; McEwen, 2002). Although there
are not yet a plethora of studies on the topic, it does appear
that human HPA axis reactivity can be programmed in early
life (reviewed in Seckl et al., 2000; Phillips and Jones,
2006).
The effect of neonatal manipulations on HPA axis
development is more thoroughly understood in experimental
studies. In rats, for example, prenatal stress (PNS) is
associated with exaggerated physiological and behavioral
responses to stressors (Lemaire et al., 2000; reviewed in
McEwen, 2003). Specifically, offspring of dams that are
exposed to stress during the last 8 days of pregnancy exhibit
increased and prolonged corticosterone release following
exposure to a stressor as an adult (McEwen, 2003; Vallee
et al., 1997; Weinstock et al., 1992). In addition, PNS mice
display increased levels of anxiety, sensitivity to addictive
drugs, emotionality, and depressive-like behaviors in a
variety of behavioral tests (reviewed in Maccari et al.,
2003), as well as a greater age-related decline in cognitive
function compared to controls (Lemaire et al., 2000). These
behavioral effects are attributed to a reduction in gluco-
corticoid type I and type II receptor concentration in the
hippocampus of PNS rats, increased occurrence of hypogly-
cemia, and increased 5-hydroxytryptamine (5-HT) in several
brain regions (reviewed in Maccari et al., 2003). Similar
physiological and behavioral effects have been reported in
rats and mice that receive extended maternal separation
(EMS) during the first 2 weeks of life (Parfitt et al., 2004;
Romeo et al., 2003).
In contrast to PNS and EMS, brief maternal separation
(BMS; i.e., the neonatal handling paradigm) appears to
improve HPA axis regulation in several species. BMS is
associated with dampened physiological and behavioral
responses to stressors (Francis et al., 1999; Liu et al.,
1997; Meaney et al., 1991a; Vallee et al., 1997). Separation
of neonatal rats from their mother and home cage for 15 min
per day during the first 2 weeks of life results in increased
hippocampal cAMP concentrations (Meaney et al., 2000).
Presumably, the increased licking and grooming that the
neonates experience once reunited with their mother
permanently increases glucocorticoid receptor gene expres-
sion in the hippocampus and frontal cortex and alters the
A.C. DeVries et al.
development of stress reactivity (Francis et al., 1999; Liu
et al., 2000; Meaney et al., 1985; O’Donnell et al., 1994).
The increase in glucocorticoid receptor expression is likely
achieved through a process that involves DNA demethylation
(Weaver et al., 2004). Thus, BMS animals, with increased
glucocorticoid receptor expression, are more sensitive to
the negative feedback effects of high concentrations of
circulating GCs, exerting greater inhibitory control over
subsequent adrenocortical activity (Meaney et al., 1989). In
regard to behavioral outcome, adult BMS rats engage in high
levels of exploratory behavior, which is correlated with low
secretion of corticosterone in response to novel environ-
ments or stress (Vallee et al., 1997). BMS also appears to be
protective against the decline in cognitive function (Meaney
et al., 1988) and neuronal density in the hippocampus that is
typically observed in aged, non-handled rats (Meaney et al.,
1991b). It is clear that the increased efficiency of the HPA
axis resulting from postnatal handling minimizes the
animal’s response to stress, and decreases cumulative
glucocorticoid exposure over the course of its life.
3.1. Mother–infant interaction and adult responses
to cerebral ischemia
In a recent study in our laboratory, a brief maternal
separation paradigm (Meaney et al., 1987) was used to
produce mice with blunted corticosteroid responses to
ischemic stress. The goal was to determine whether HPA
axis hyporesponsivity is associated with neuroprotection
following stroke (Craft et al., 2006). Both clinical and rodent
data provide evidence that peri-ischemic glucocorticoid
concentration influences stroke outcome (as reviewed
above). Thus, we predicted that a neonatal manipulation
that causes life-long suppression of HPA axis reactivity would
improve neuronal integrity and survival following an
ischemic insult. The BMS group consisted of offspring
exposed to 2 weeks of mother–infant separation (15 min
per day) beginning 1 day after birth. BMS produced mice
with lower intra-ischemic corticosterone concentrations,
but contrary to our initial hypothesis, an increased suscept-
ibility to stroke-induced neuronal death compared to mice
raised under typical colony conditions (referred to as
undisturbed or UD mice). The mean BMS infarct size was
approximately three times larger than the mean undis-
turbed control infarct size at 72 h post-stroke (Fig. 7; Craft
et al., 2006). The group difference in infarct size (encom-
passing approximately 30% of ipsilateral hemisphere in BMS
mice versus 12% of the contralateral hemisphere in
undisturbed mice) was functionally significant as indicated
by the post-stroke decrease in contralateral paw use during
rearing in the BMS mice. In keeping with the group
difference in infarct evolution, the BMS mice exhibited
significantly more post-stroke edema (Fig. 8) and pro-
inflammatory cytokine expression in the brain than the UD
mice (Craft et al., 2006). There also was a 60% decrease in
the survival rate of BMS mice relative to UD mice at 7 days of
recovery. When the BMS and UD mice were adrenalecto-
mized and given a relatively low replacement dose of
exogenous corticosterone (achieving 160 ng/ml in blood),
there was no significant difference in infarct size between
groups. However, a higher replacement dose (achieving
 ARTICLE IN PRESS
Social influences on stress
Figure 7 Neuronal damage following 60 min of experimental
stroke in mice that experienced brief maternal separations
(BMS) for 15 min per day during the first 2 weeks of life versus
mice that were not disturbed during development (undisturbed;
UD). Tissue containing dead neurons appears white. Infarct sizes
were similar between UD and BMS at 24 h after stroke, however,
by 72 h, the BMS infarcts had grown to approximately three
times the size of the UD infarcts. (Adapted from Craft et al.,
2006.)
Figure 8 Brain edema following 60 min of experimental stroke
in BMS and UD mice. Edema index was significantly greater in
BMS than UD mice at 48 h post-stroke and may have contributed
to the increased secondary neuronal death depicted among BMS
mice at 72 h in Fig. 7. (Adapted from Craft et al., 2006.)
270 ng/ml in blood) reinstated the patterns of infarct and
behavioral deficits observed in mice with intact adrenal
glands; mean infarct size in the high-dose adrenalectomized
BMS mice was approximately twice as large as the high-dose
adrenalectomized UD mice at 72 h reperfusion. Thus, the
BMS mice appear to be more sensitive than UD mice to
stroke-induced inflammation and neuronal death when
exposed to sustained elevations of corticosterone.
In addition to the role of glucocorticoids and glucocorti-
coid receptors in determining stroke outcome, a growing
body of literature suggest that brain injury also is
accompanied by a marked inflammatory reaction, charac-
terized by infiltration of granulocytes, monocytes, and
macrophages into the respective brain parenchyma (Perry
and Gordon, 1991), activation of microglia and astrocytes,
and expression of pro-inflammatory cytokines, adhesion
molecules, and other inflammatory mediators (Dinkel et al.,
2003; Dirnagl et al., 1999; Feuerstein et al., 1998).
Cytokines, in particular, exhibit a marked upregulation
597
following stroke (reviewed in DeGraba, 1998), and can
become a secondary cause of neuronal death. Experimental
models of stroke have demonstrated increased concentra-
tions of interleukin mRNA in ischemic tissue, including IL-1a,
IL-1b, IL-1ra, and IL-6 (Hill et al., 1999; Legos et al., 2000;
Zhai et al., 1997). Similar evidence exists in clinical studies,
with increased interleukin concentrations reported in both
cerebrospinal fluid (CSF) and blood (Ferrarese et al., 1999;
Tarkowski et al., 1995). Furthermore, post-ischemic con-
centrations of pro-inflammatory cytokines are positively
correlated with infarct size in rodents (Tarkowski et al.,
1995; Touzani et al., 2002; Vila et al., 1999; Yang et al.,
1999), while overexpression of anti-inflammatory cytokines,
such as IL-1ra, reduces ischemic injury (Yang et al., 1997).
Thus, cytokine regulation is vital to ischemic outcome, and
has become a key target for therapeutic and preventive
treatment of stroke. Therefore, the exacerbated stroke
outcome observed in BMS mice relative to controls is, in
part, due to an imbalance between the HPA axis and the
immune system; the BMS mice responded to stroke with low
concentrations of stress hormones but increased neuroin-
flammation. Indeed, significantly more edema (swelling of
the brain) and IL-1b and TNF-a mRNA expression are
observed following stroke in BMS than UD mice (Fig. 8;
Craft et al., 2005). Increased pro-inflammatory cytokine
expression can contribute indirectly to neuronal death by
increasing post-stroke edema, but it also may mediate post-
stroke depressive-like behavior (Craft and DeVries, 2006).
Ongoing projects will determine whether prenatal stress and
extended maternal separation have similar or opposing
effects on ischemic outcome.
In summary, BMS produces animals that initially exhibited
a dampened corticosteroid response to ischemia, as pre-
dicted by previous studies using the handling model
(reviewed above). However, ultimately, the BMS mice are
more sensitive to stroke than the UD mice. The increased
neuronal death in the BMS mice appears to be due to
sustained exposure to high corticosteroid concentrations,
increased neuroinflammation (Craft et al., 2005), and
possibly altered glutamate sensitivity (Horvath et al.,
2004). Thus, a cost associated with increased efficiency of
negative feedback regulation and decreased lifetime allo-
static load may be increased susceptibility of cells to
sustained glucocorticoid and inflammatory influences on
cell death.
4. Concluding remarks
Exposure to stress is a universal experience shared by all
living creatures, but the magnitude, duration, frequency,
and nature of stressors and their impact on health is highly
individualistic. Indeed, individual differences in stress
responsivity play an important role in determining the
long-term consequences of stress exposure. The majority of
biomedical research involving stress has focused on the
negative outcomes, though there is accumulating evidence
that stress, particularly acute stress, can actually improve
some important measures of health (for example, Dhabhar,
2000; Dhabhar and McEwen, 1999). Our own work on stroke,
cardiac arrest, and wound healing confirm that chronic
stress can have deleterious effects, which in these models,
 ARTICLE IN PRESS
598
is mediated by stress-induced increases in corticosteroids
acting on glucocorticoid receptors. However, the relation-
ship between corticosteroids and stroke outcome clearly is
more complex than just ‘‘more is worse’’. The mice we
manipulated using the brief maternal separation (i.e.
neonatal handling) paradigm did exhibit decreased HPA
reactivity during stroke, but after three days of exposure to
elevated corticosterone they sustained more neuronal
damage than mice that had been left undisturbed during
development. The neonatal manipulation appears to create
an imbalance between corticosteroids and immune function
that is detrimental in mice exposed to stroke. These data
also suggest that a potential cost associated with increased
HPA axis efficiency may be increased susceptibility to
prolonged glucocorticoid and inflammatory influences on
cell death.
The good news, however, is that once a stable social bond
has formed, positive social interaction can suppress HPA
reactivity to stress, facilitate wound healing, and improve
the histological and behavioral outcomes of stroke. Among
highly social species, positive social interaction appears to
suppress the HPA axis via a mechanism than involves
contact-induced oxytocin release. In contrast, the mechan-
ism by which social interaction improves stroke outcome
appears to involve suppression of the inflammatory response
that occurs during cerebral ischemia rather than an
alteration in HPA axis reactivity. Taken together, these data
suggest that the mechanisms by which social interaction and
social support affect health outcomes may be specific to the
affliction. However, there is no doubt that both positive and
negative social interactions can profoundly affect health.
Role of the funding sources
Funding for this study was provided by the National
Institutes of Health (RO1 NS40267-05 and R01HL080249-01
to ACD, NINDS F31 to ERG), The American Heart Association
(EIA award to ACD), a seed grant from the Stress and Wound
Healing Center Grant at Ohio State University (NIDCR P50
DE13749 to ACD), and The Ohio State University (Presiden-
tial Fellowship Support to GN and TKSC). None of the
organizations funding the research had any further role in
study design, in the collection, analysis or interpretation of
the data, in the writing of the manuscript, or in the decision
to submit the manuscript for publication.
Conflicts of interest
All authors declare that they have no conflicts of interest in
publishing this manuscript.
Acknowledgements
We are grateful for research support provided by NINDS (RO1
NS40267-05 and R01HL080249-01 to ACD), NINDS Pre-
doctoral Fellowship (ERG), The American Heart Association
(EIA award to ACD), a seed grant from the Stress and Wound
Healing Center Grant at Ohio State University (NIDCR P50
DE13749 to ACD), and Ohio State University Presidential
Fellowship Support (GN and TKSC).
A.C. DeVries et al.
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