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REVIEW ARTICLE

published: 15 February 2013


BEHAVIORAL NEUROSCIENCE doi: 10.3389/fnbeh.2013.00010

Understanding resilience
Gang Wu 1 , Adriana Feder 1 , Hagit Cohen 2 , Joanna J. Kim 1 , Solara Calderon 1 , Dennis S. Charney 1 and
Aleksander A. Mathé 3*
1
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA
2
Ben-Gurion University of the Negev, Beer-Sheva, Israel
3
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Edited by: Resilience is the ability to adapt successfully in the face of stress and adversity. Stressful
Michael V. Baratta, University of life events, trauma, and chronic adversity can have a substantial impact on brain function
Colorado Boulder, USA
and structure, and can result in the development of posttraumatic stress disorder (PTSD),
Reviewed by:
depression and other psychiatric disorders. However, most individuals do not develop such
Cesar Venero, Universidad Nacional
de Educación a Distancia, Spain illnesses after experiencing stressful life events, and are thus thought to be resilient.
Lihong Wang, Duke University, USA Resilience as successful adaptation relies on effective responses to environmental
*Correspondence: challenges and ultimate resistance to the deleterious effects of stress, therefore a
Aleksander A. Mathé, Department greater understanding of the factors that promote such effects is of great relevance.
of Clinical Neuroscience, Karolinska
This review focuses on recent findings regarding genetic, epigenetic, developmental,
Institutet, Psychiatry SLSO,
Karolinska University Hospital psychosocial, and neurochemical factors that are considered essential contributors to the
Huddinge, Stockholm, SE-14186, development of resilience. Neural circuits and pathways involved in mediating resilience
Sweden. are also discussed. The growing understanding of resilience factors will hopefully lead to
e-mail: aleksander.mathe@ki.se
the development of new pharmacological and psychological interventions for enhancing
resilience and mitigating the untoward consequences.

Keywords: resilience, stress, neurobiology, depression, PTSD

INTRODUCTION NEUROPEPTIDE Y (NPY)


Resilience is the capacity and dynamic process of adaptively NPY is a neuropeptide that produces anxiolytic effects and pro-
overcoming stress and adversity while maintaining normal psy- motes protective responses in the face of stress (Wu et al., 2011).
chological and physical functioning (Russo et al., 2012; Rutter, Several studies in humans showed that genetic variations of
2012b; Southwick and Charney, 2012). Every individual experi- NPY contribute to individual susceptibility to stress. One recent
ences stressful events and the majority are exposed to trauma at study found that two NPY haplotypes represented by three sin-
some point during life. Therefore, understanding how one can gle nucleotide polymorphisms (SNPs) correlated with increased
develop and enhance resilience is of great relevance to not only susceptibility to anxiety disorders after childhood adversity, and
promoting coping mechanisms but also mitigating maladaptive suggested that such behavioral effects can be mediated by altered
coping and stress response in psychiatric illnesses such as depres- NPY expression and subsequently dampened HPA-axis respon-
sion and posttraumatic stress disorder (PTSD). Although the siveness under the influence of the genetic variation (Donner
understanding of resilience is overall still at an early stage, recent et al., 2012). Other studies also demonstrated that NPY release
investigations have identified mechanisms encompassing genetic, was substantially mediated by genetic variations in the NPY locus,
epigenetic, developmental, psychological, and neurochemical fac- especially in the promoter region, and that lower haplotype-
tors that underlie the development and enhancement of resilience driven NPY expression predicted weakened resilient response to
and factors that predict vulnerability to stress and susceptibility to stress (Zhou et al., 2008; Zhang et al., 2012).
psychiatric disorders in the face of stress and trauma. This review
outlines discoveries from recent years from studies that have HPA AXIS (HYPOTHALAMIC-PITUITARY-ADRENAL AXIS)
considerably advanced our understanding of resilience to stress Alterations in genes that regulate HPA-axis functions play an
and trauma and will likely move forward the development of important role in shaping resilience. Polymorphisms in two
pharmacological and psychological interventions for enhancing key HPA-axis genes, CRHR1 [corticotropin-releasing hormone
resilience. (CRH) receptor 1 gene] and FKBP5 (FK506-binding protein
5 gene), have been found to interact with early life stress to
GENETIC FACTORS IN RESILIENCE predict susceptibility to psychiatric illnesses in adults (Gillespie
Genetic factors contribute significantly to resilient responses to et al., 2009). One study identified, in two independent popula-
trauma and stress. A range of human genes and polymorphisms tions, significant gene × environment interactions with several
associated with NPY, HPA axis, noradrenergic, dopaminergic and individual SNPs of the CRHR1 gene that influenced the risk of
serotonergic systems, and BDNF have been linked to resilient developing adult depressive symptoms in individuals with a his-
phenotypes (Table 1) (Feder et al., 2009; Russo et al., 2012). tory of child abuse (Bradley et al., 2008). The FKBP5 gene, which

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Wu et al. Neurobiology of resilience and implications for promoting resilience

Table 1 | Genetic factors in resilience.

CNS systems Genes related to resilience Influences of polymorphisms on resilience References

NPYergic Neuropeptide Y gene (NPY ) Increased susceptibility to anxiety disorders after Donner et al., 2012
childhood adversity.

HPA Axis CRH receptor 1 gene (CRHR1) Affected the likelihood of developing adult Bradley et al., 2008
depressive symptoms from child abuse.

FK506-binding protein 5 gene (FKBP5) Predicted severity of adult PTSD symptoms and Binder et al., 2008;
onset of depression in individuals with childhood Zimmermann et al., 2011
trauma.

Noradrenergic and Catechol-O-Methyltransferase gene Influenced the risks of developing PTSD and Heinz and Smolka, 2006;
Dopaminergic (COMT ) deficits in stress response and emotional Skelton et al., 2012
resilience.

Dopaminergic Dopamine transporter gene (DAT1) Contributed to susceptibility to PTSD with a Segman et al., 2002
history of trauma.

Dopamine receptor genes (e.g., DRD2, Induced differential emotional processing and Blasi et al., 2009; Ptacek
DRD4) variability in brain responses to emotional stimuli; et al., 2011
Influenced vulnerability to stress and trauma and
risk of developing PTSD.

Serotonergic Promoter region of serotonin transporter Short allele strongly associated with increased Karg et al., 2011
gene (5-HTTLPR) stress sensitivity and risk for depression upon
stress exposure, especially early life stress.

Serotonin receptor genes (e.g., HTR1A, Interacted with environment to mediate stress Gatt et al., 2010; Kim et al.,
HTR3A, HTR2C) response and to predict susceptibility to 2011a; Brummett et al., 2012
depression.

BDNF Brain-derived neurotrophic factor gene Interacted with early life stress to predict Frustaci et al., 2008; Gatt
(BDNF) syndromal depression and anxiety; no clear et al., 2009
evidence of association between the Val66 Met
polymorphism and anxiety disorders.

is involved in the modulation of glucocorticoid receptor (GR) Met/Met homozygotes, with higher levels of norepinephrine and
activity and thereby glucocorticoid signaling, was also found to dopamine, exhibited a higher risk for PTSD. Children carry-
interact with child abuse through its four SNPs to predict sever- ing the Met allele showed a higher cortisol response to stress.
ity of adult PTSD symptoms (Binder et al., 2008). A more recent However, children who had more stressful life events showed a
study showed that interactions between genetic variants of FKBP5 smaller increase in cortisol, implying that they might be more
and early life trauma strongly predicted the onset of depression resilient (Armbruster et al., 2012). This study demonstrated dif-
later in life (Zimmermann et al., 2011). ferential effects of genetic and environmental factors on reaction
to stress. Polymorphisms in the dopamine receptor genes, includ-
NORADRENERGIC AND DOPAMINERGIC SYSTEMS
ing DRD2 and DRD4, and in the dopamine transporter gene
DAT1, have also been implicated in stress responsivity, emotion
Polymorphisms in the noradrenergic and dopaminergic sys-
processing, and susceptibility to PTSD and depression (Segman
tems have also been associated with vulnerability to depres-
et al., 2002; Dunlop and Nemeroff, 2007; Blasi et al., 2009; Ptacek
sion and PTSD. Catechol-O-Methyltransferase (COMT) is
et al., 2011; Skelton et al., 2012).
an enzyme that metabolizes catecholamines including nore-
pinephrine, epinephrine and dopamine. The COMT Val158 Met
polymorphism has been linked to deficits in stress response SEROTONERGIC SYSTEM
and emotional resilience, and was found to influence the risk Studies of polymorphic traits of the serotonin transporter gene
for development of PTSD (Heinz and Smolka, 2006; Skelton SLC6A4 and receptor genes have led to several discoveries regard-
et al., 2012). In an important study, Kolassa and colleagues ing the effects of gene × environment interactions on resilience.
showed that, predictably, higher numbers of different lifetime A recent meta-analysis of 54 human studies confirmed that the
traumatic event types led to a higher prevalence of lifetime PTSD interaction of stress exposure and the polymorphism in the pro-
but that this effect was, in a typical gene-environment interac- moter region of the serotonin transporter gene (5-HTTLPR) is
tion fashion, modified by gene polymorphism (Kolassa et al., strongly associated with stress sensitivity and risk for depres-
2010). Compared to Val158 Met polymorphism, the low-activity sion, with the short, less transcriptionally efficient s-allele being

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Wu et al. Neurobiology of resilience and implications for promoting resilience

linked to increased stress sensitivity and risk of developing depres- with antidepressants, resulted in antidepressant-like responses
sion upon stress exposure (Karg et al., 2011). A particularly in several animal models (Sun et al., 2013). Histone methyl-
strong association between the s-allele and risk of developing transferases (e.g., GLP, SUV39H1, G9a) are down-regulated in
depression was found in the group with a history of child- the nucleus accumbens of susceptible mice exposed to chronic
hood maltreatment (Karg et al., 2011; Southwick and Charney, social defeat stress, while these molecules were up-regulated in
2012). The s-allele of the 5-HTTLPR gene was also found, in two resilient mice exhibiting low depression-like responses, suggest-
independent populations, to interact with childhood and adult ing that histone methylation may be adaptive in the face of
traumatic experiences to increase the risk for PTSD (Xie et al., stress and protect against development of depression (Covington
2009). Polymorphisms in several serotonin receptor genes, such as et al., 2011). Maternal care was found to influence stress response
HTR1A, HTR3A, and HTR2C, have been shown to interact with through epigenetic alterations, with offspring of high mater-
stressful life environment as well as polymorphisms from other nal care showing increased hippocampal GR expression and
genes (e.g., Val66 Met in the BDNF gene) to predict susceptibil- enhanced glucocorticoid negative feedback sensitivity, and hence
ity to depression (Kim et al., 2007, 2011a; Gatt et al., 2010), and more modest HPA response to stress, through hypomethy-
to mediate HPA-axis activation and emotional response to stress lation at the NGFI-A nerve growth factor-inducible protein
(Brummett et al., 2012). A (NGFI-A) binding site of a GR promoter (Weaver et al.,
2004).
BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) Human studies have begun to identify the effects of epige-
The role of the BDNF Val66 Met polymorphism in stress response netic changes on the regulation of the stress response. Suicide
and resilience has not been clarified. A meta-analysis of seven victims with childhood abuse had increased methylation of a GR
studies found no significant association between the Val66 Met (NR3C1) promoter in the hippocampus, and thereby decreased
polymorphism and anxiety disorders (Frustaci et al., 2008). hippocampal GR expression, compared to suicide victims with-
Specifically, two case-control studies of PTSD found no signifi- out childhood abuse and to control subjects (victims of sudden,
cant association between the Val66 Met polymorphism and PTSD accidental death without childhood abuse) (McGowan et al.,
diagnosis (Rakofsky et al., 2012). One study, however, showed 2009). This finding is consistent with those from animal stud-
that the Val66 Met polymorphism interacted with early life stress ies showing that history of early adversity is associated with
to predict syndromal depression and anxiety, with higher depres- GR expression and stress response in adulthood. Another study
sion in Met carriers (Met/Met and Met/Val) and higher anxiety showed that DNA methyltransferase (DNMT) expression was
in Val/Val genotype, indicating that both alleles, interacting with altered in a region-specific manner in the brains of suicide vic-
exposure to early life stress, may contribute to mechanisms of tims compared to controls who died of causes other than suicide
distinct risks (Gatt et al., 2009). (Poulter et al., 2008). This study found increased DNMT-3B
The field of genetics is now moving rapidly to genome-wide expression in the prefrontal cortex (PFC), and an associated
studies on large populations to examine the complex genetic con- increase in DNA methylation of the promoter region of the
tributions to resilience, with additional genetic polymorphisms, γ-aminobutyric acid (GABA) A receptor subunit alpha-1 gene
gene-by-gene and gene-by-environment interactions being cur- (GABRA1), the product of which was previously demonstrated
rently identified. As the genetic underpinnings of resilience to be down-regulated in the brains of suicide victims (Merali
become better illuminated, it is anticipated that gene and drug et al., 2004). Higher methylation of MAN2C1, a gene that encodes
therapies can be developed specifically for genetic profiles of low α-mannosidase, was shown to interact with greater exposure to
resilience. potentially traumatic events to predict an increased risk of life-
time PTSD (Uddin et al., 2011). A number of epigenetic studies in
EPIGENETIC FACTORS IN RESILIENCE animal models and humans investigating the association between
Epigenetics refers to functional modifications to the genome epigenetic changes and risk for maladaptive stress responses and
without change in the DNA sequence. Such modifications serve mental illnesses have recently been published (Radley et al., 2011;
to regulate gene expression and phenotype through mechanisms Schmidt et al., 2011; Murgatroyd and Spengler, 2012; Rusiecki
such as DNA methylation and demethylation, as well as histone et al., 2012).
modifications including methylation, acetylation, and phospho-
rylation. Epigenetic differences can be a consequence of exposure DEVELOPMENTAL FACTORS IN RESILIENCE
to stress-related factors during critical periods of development, Developmental environment is another crucial contributor to
and hence contribute to susceptibility to psychiatric disorders resilience (Rende, 2012). Severe adverse events in childhood can
(Tsankova et al., 2007; Dudley et al., 2011). negatively affect the development of stress response systems, in
Several animal studies have found that histone acetylation some cases causing long-lasting damage. Numerous rodent and
or phosphoacetylation in several subregions of the hippocam- primate studies suggest that animals abused by their mothers in
pus increased after exposure to acute stressors (social defeat the first few weeks of life show both delayed independence and
stress, forced swim stress, and predator stress) in both mice decreased stress management skills in adulthood (Feder et al.,
and rats, suggesting an adaptive role of these epigenetic changes 2011). These changes are reflected in abnormally high anxiety lev-
in memory formation and stress response (McGowan et al., els, increased HPA axis activity, and increased basal CRH levels in
2011; Sun et al., 2013). Intracerebral or systemic administration the cerebrospinal fluid (CSF) (Strome et al., 2002; Claes, 2004;
of histone deacetylase inhibitors (HDACi), alone or combined McCormack et al., 2006). It is important to note that non-human

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Wu et al. Neurobiology of resilience and implications for promoting resilience

primates, who have suffered childhood abuse, resulting in dam- this same way, humans that have been able to successfully master
aged stress response systems, may be more likely to abuse their a mild or moderate stressor (for example, the end of a friend-
own children (Maestripieri et al., 2007). In this way, the cycle of ship or illness of a parent) appear to be resilient to a variety of
abuse is continued through generations. other later stressors (Feder et al., 2009; Russo et al., 2012). This
Similar long-lasting alterations, including changes in the cen- phenomenon is called “stress inoculation,” and occurs when the
tral nervous system (CNS) circuits, have been found in studies person develops an adaptive stress response and a higher-than-
of human survivors of childhood trauma (Heim et al., 2010). average resilience to negative effects of subsequent, uncontrollable
Prenatal stress and childhood trauma have been linked to a stressors (Southwick and Charney, 2012). Stress inoculation is
hyperactive HPA axis with attendant risk of negative effects a form of immunity against later stressors, much in the same
of chronic hypercortisolemia later in life (Frodl and O’Keane, way that vaccines induce immunity against disease (Rutter, 1993).
2012). Furthermore, severe early life stress leads to hyperfunc- Research in rodents supports the stress inoculation hypothesis
tioning of the locus coeruleus-norepinephrine (LC-NE) system and has suggested that this protection against some of the later
in adulthood (Feder et al., 2011). One study of police recruits negative effects may be due to neuroplasticity in the PFC induced
with a history of childhood trauma found that in contrast to by stress inoculation (Southwick and Charney, 2012). In one
controls, the police subjects had significantly higher levels of study, young monkeys were presented with a controllable stres-
a salivary metabolite of norepinephrine when watching aver- sor (periodic short maternal separations) over a course of 10
sive videos (Otte et al., 2005). Childhood abuse can lead to a weeks (Parker et al., 2004). These monkeys experienced acute
reduction of hippocampal volume, which is frequently seen in stress during the separation periods, illustrated by agitation as
patients with mood disorders (Janssen et al., 2007; Davidson well as temporary increased levels of cortisol. Yet, at 9 months
and McEwen, 2012). As the hippocampus is one of the most of age, they experienced less anxiety and lower basal stress hor-
plastic regions of the brain, there is hope that pharmacological mone levels than monkeys who did not undergo the separations.
treatments, such as antidepressants, may be able to reverse this Additionally, at later time points, the group of stress-inoculated
decrease in volume by increasing neural progenitor cells (Boldrini monkeys showed higher cognitive control, higher curiosity in a
et al., 2012). PET studies have also revealed decreased activation stress-free situation and larger ventromedial PFC volume (Parker
in the hippocampus during memory tests in patients with a his- et al., 2005; Lyons et al., 2009).
tory of childhood abuse (Heim et al., 2010). Other brain areas It is important to note that although research has outlined
seem to be affected by childhood abuse as well. For instance, numerous ways in which developmental environment can nega-
a recent study suggests that childhood maltreatment has a pro- tively impact a person, resilience is in fact a common trait, follow-
nounced effect on two separate neuroimaging markers—reduced ing even the most severe adversities. Between 50 and 60% of the
hippocampal volume and amygdala responsiveness to negative general population experience a severe trauma during their life-
facial expressions (Dannlowski et al., 2012). Chronic, unmanage- time, yet the prevalence of PTSD is estimated at 7.8% (Russo et al.,
able social and psychological stress, and maltreatment, especially 2012). Other studies have found that neural circuits involved in
early in life, are also linked to shorter telomeres, which have resilience can be modified for many years after adversity. For
been associated with increased risk of developing somatic dis- instance, the majority of adolescents whose development was
eases such as cancer, diabetes and heart diseases, and psychiatric stunted in childhood due to trauma were able to developmentally
disorders, particularly depression (Blackburn and Epel, 2012; “catch-up” when relocated to a supportive, loving environment
Price et al., 2013). (Masten, 2001; Rutter, 2012a). The fact that not all animals or
Certain factors play major roles in determining whether a humans exposed to uncontrollable traumatic experiences develop
childhood traumatic event will lead to vulnerability or instead, stress-related disorders clearly implies that environmental factors
to resilience. One of these factors is the degree of control that the interact with genetic endowment and together, affect resilience.
person has over the stressor (Feder et al., 2011). Episodes of early In fact, resilient genes may be sufficient to help a person over-
uncontrollable stress can lead to “learned helplessness,” where a come the most traumatic developmental events in some cases
person is conditioned to believe that they are unable to change the (Feder et al., 2011).
circumstances of their situation (Overmier and Seligman, 1967).
Learned helplessness is also used as a model for depression in IMPLICATIONS FOR PROMOTING RESILIENCE IN CHILD REARING
animals. When administered inescapable and erratic shocks, ani- The findings that the developmental environment has significant
mals tend to develop heightened anxiety states and fear responses effects on building and enhancing resilience from a young age
(Overmier and Seligman, 1967). Furthermore, their active coping impart clear messages for child rearing. Several large-scale lon-
is reduced when faced with later stressors. Learned helplessness gitudinal studies have investigated resilience in participants from
in animals is also believed to lead to dysregulation of serotonergic childhood or adolescence through the transition to adulthood.
neurons in the dorsal raphe nuclei (Greenwood et al., 2003), as Results from these studies strongly indicated that key factors
well as a reduction of cell proliferation in the hippocampus (Ho including positive family functioning and peer relationships, con-
and Wang, 2010). These dysregulations are likely to have severe nections to supportive adults and prosocial romantic partners,
negative repercussions on both cognition and mood. planfulness, self-discipline, and cognitive ability, all contribute to
On the other hand, when animals are administered shocks a more successful transition to adulthood and more resilient func-
that are avoidable by behavioral modification, learned helpless- tioning (Burt and Paysnick, 2012). Interventional paradigms in
ness does not seem to develop (Seligman and Maier, 1967). In the form of foster care, adoption, and parent training can improve

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Wu et al. Neurobiology of resilience and implications for promoting resilience

the quality of parenting, family function, and attachment rela- A review of efficacy of different interventions for children
tionship, and in turn promote adaptive functioning and resilience and adolescents with a history of trauma exposure indicates that
in children and youth (Sapienza and Masten, 2011). cognitive-behavioral treatment, in both individual and group for-
Children with a history of maltreatment showed lower resilient mats, is effective in reducing psychological harm such as anxiety
functioning than those without maltreatment (Cicchetti and and depressive disorders and symptoms (Wethington et al., 2008).
Rogosch, 2012). Children with exposure to war and related trau- Stress inoculation training (SIT), a preventive and interventional
matic experiences (e.g., child soldiers, rape, bombing, forced cognitive-behavioral paradigm, has been shown to be helpful
displacement) showed increased risks for PTSD as well as other in reducing anxiety and stress-related symptoms in adolescents
medical conditions such as cardiovascular diseases in adulthood (Maag and Kotlash, 1994). School-based interventions, including
(Werner, 2012). Protective factors against deleterious impact of SIT, can improve adaptive coping skills and decrease the likeli-
war-related adversities in children include a strong, positive bond hood of developing PTSD symptoms in children exposed to war
between the primary caregiver and the child, the social sup- (Werner, 2012).
port from teachers and peers, a shared sense of values, religious In summary, it is critical to provide children with a lov-
beliefs that find meaning in suffering, and humor and altru- ing, healthy and supportive environment as they grow up, to
ism as defense mechanisms (Werner, 2012). Besides children avoid exposing them to repeated unmanageable stress, and to
from an abusive and life-threatening environment, a newly iden- offer them chances to embrace and conquer life challenges so
tified group at risk is youth from affluent families, who may as to develop mastery of critical life stressors and acquire “stress
face higher risk of adjustment problems (e.g., substance use, inoculation” (Southwick and Charney, 2012). Education on suc-
depression, and anxiety) (Luthar and Barkin, 2012). Parents’ lax cessful parenting should be able to help to foster children in a
repercussions on discovering substance use was shown to be a resilience-promoting environment and to minimize occurrence
major vulnerability factor. Moreover, the levels of teens’ symp- of impaired stress response through generations. Moreover, train-
toms (rule breaking, anxious-depressed, and somatic symptoms) ing programs for children that focus on constructing and main-
were found to correlate more strongly with the teens’ relation- taining supportive social networks, enhancing prosocial behavior
ships with mothers than with fathers, which may in part reflect and cognitive reappraisal, and promoting coping self-efficacy and
greater amount of time spent with mothers, who are generally the self-esteem, can all contribute to resilience building from an early
primary caregivers of their children. Therefore, positive changes age (Figure 1).
in parenting for affluent youth are of critical importance, includ-
ing adopting a strict zero-tolerance policy regarding students’ law PSYCHOLOGICAL FACTORS IN RESILIENCE
breaking, remaining vigilant about their children’s activities out- Significant research has been done on the psychosocial factors
side school, and engaging in talks and workshops for families of stress tolerance and resilience building (Duryea et al., 1990;
in distress and holding support groups particularly for mothers Chemtob et al., 1997; Pietrzak et al., 2010). Cognitive processes,
(Luthar and Barkin, 2012). personality traits, and active coping mechanisms, among others,

FIGURE 1 | Promoting resilience in child rearing.

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Wu et al. Neurobiology of resilience and implications for promoting resilience

contribute to resilience. These qualities also interact with biolog- employ positive emotions to help them regulate their emotions
ical factors to enhance adaptation in the face and aftermath of to a larger extent than men; it is possible that in men, use
traumatic events, and confer resilience (Charney, 2004). of emotion regulation is more automatic (McRae et al., 2008).
Utilizing a randomized control design, an intervention study
INDIVIDUAL CHARACTERISTICS AND BEHAVIORS in Israeli citizens under ongoing war stress found that gender
Characteristics such as high level of intellectual functioning, effi- might act as a moderator in the development of resilience and
cient self-regulation, active coping styles, optimism, and secure reduction of helplessness (Farchi and Gidron, 2010). While the
attachment were observed in youth who had faced adverse situa- “psychological inoculation” intervention was expected to increase
tions and settings, yet did not succumb to the adverse impact of coping self-efficacy and to improve mental resilience more
extreme stress (Richardson, 2002). so than ventilation, the intervention’s efficacy differed by sex.
Psychological inoculation, possibly augmenting self-efficacy and
Optimism hope, appeared to decrease helplessness in men, while the venti-
Positive affect has been found to be protective in the face of lation intervention appeared to decrease helplessness in women.
stress in numerous studies. In addition to decreasing autonomic The ventilation intervention may have had calming effects and
arousal upon stress exposure (Folkman and Moskowitz, 2000), lent a sense of connectedness that was helpful to women.
positive affect is also associated with quicker recovery times and
better overall physical health (Scheier et al., 1989; Warner et al., Active coping
2012). Similarly, optimism, herein defined as the expectation for Coping, using behavioral or psychological techniques utilized to
good outcomes, has been consistently associated with the employ- reduce or overcome stress, has been linked to resilience in indi-
ment of active coping strategies, subjective well-being, physical viduals (Feder et al., 2009) and is coming to be recognized for its
health, and larger and more fulfilling social networks and connec- intervention potential (Taylor and Stanton, 2007). The literature
tions (Stewart and Yuen, 2011; Galatzer-Levy and Bonanno, 2012; distinguishes between active coping, involving behavioral and/or
Gonzalez-Herero and Garcia-Martin, 2012; Colby and Shifren, psychological strategies to change qualities of the stressor, the
2013). Unlike pessimists, optimists reported less hopelessness and stressor itself, or how the stressor is perceived, and avoidant cop-
helplessness and are less likely to use avoidance as a coping mech- ing, involving activities and mental processes that are employed
anism when under duress (e.g., among breast cancer patients) in lieu of dealing directly with the stressful trigger (Chesney
(Carver et al., 2010). et al., 2006). Emotional or behavioral withdrawal, alcohol use,
and other substance use are classic examples of avoidant coping
Cognitive reappraisal behavior (Lawler et al., 2005). While individuals who primar-
Strongly associated with resilience is the ability to monitor and ily exercise avoidant coping are at risk of psychological distress
assess negative thoughts and replace them with more positive and subsequent negative responses, active coping has consistently
ones, or cognitive reappraisal (McRae et al., 2012). Known as been associated with adaptability and psychological resilience
cognitive flexibility or cognitive reframing, this emotion regu- (Holahan and Moos, 1987; Moos and Schaefer, 1993). Among
lation strategy involves changing the way one views events or chronic pain patients, passive coping strategies were correlated
situations. Consciously reassessing adverse or traumatic events to with psychological distress and depression, while active coping
find the silver lining is associated with resilience (Gross, 2002). strategies were inversely correlated with psychological distress
Viktor Frankl, the author of Man’s Search for Meaning and the (Snow-Turek et al., 1996). In a study examining two groups of
founder of logotherapy, attributed his psychological endurance Israeli veterans and former POWs, Solomon and colleagues found
and survival of concentration camps mainly to “meaning find- that high sensation seeking and low sensation seeking POWs sig-
ing,” the belief that the striving to find a meaning in one’s life nificantly differed in their subjective assessments of suffering,
is the most important, powerful motivating and driving force use of coping methods, and emotional states while in prison
to continue living (Frankl, 2006). In a study examining cogni- (Solomon et al., 1995). Low sensation seeking former POWs
tive protective factors in the face of stress, women with high reported more symptoms of PTSD and other psychiatric symp-
cognitive reappraisal ability exhibited less depressive symptoms toms. Further distinguishing coping styles, task-oriented coping
than their cohorts with low cognitive reappraisal ability (Troy was positively correlated with resilience while emotion-oriented
et al., 2010). Attachment style may also play a role in reap- coping was related to low resilience among undergraduate stu-
praisal ability and resilience. In a study of 632 men and women, dents (Campbell-Sills et al., 2006). Drawing a relationship with
researchers found that secure attachment was associated with personality, resilience among these young adults was inversely
higher cognitive reappraisal and resilience and that these two related with neuroticism but positively so with extraversion and
factors partially mediated individuals’ well-being (Karreman and conscientiousness. Even among sport performers, individuals
Vingerhoets, 2012). Securely attached participants were more with high hardiness or resilience tend to employ active coping
likely to reframe situations as less emotional and less likely to strategies during stressful (competitive) situations compared with
suppress emotional expression. As expected, preoccupied attach- low hardiness groups (Hanton et al., 2013).
ment was inversely related to well-being due to less utilization of
cognitive reappraisal. Social support
A possible gender difference in emotional regulation/cognitive Both the presence of social support and the behavior of seeking
reappraisal is of note. Neural data suggest that women might social support have been associated with psychological hardiness

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Wu et al. Neurobiology of resilience and implications for promoting resilience

and flourishing in the face of major adverse life events (Ozbay Greece showed that higher altruism resulted in lower classroom
et al., 2008). The inverse also appears to be true; poorer social competitiveness and was associated with higher empathy and
support has been linked to psychiatric disorders including PTSD resilience (Leontopoulou, 2010). Studies also show the birth of
(Tsai et al., 2012). Research with cancer patients found depression prosocial behavior and action from trauma enduring during
to be correlated with poor social support and higher exter- times of civil conflict and unrest as a byproduct of personal
nal locus of control (Grassi et al., 1997). Depressed patients healing (Hernández-Wolfe, 2010).
consistently reported weak or a lack of support from family,
friends, and other social contacts (such as neighbors, colleagues, Trait mindfulness
and less intimate relatives). Such patients were also often char- Trait mindfulness is another psychological factor associated with
acterized by early maladjustment to their diagnosis of cancer resilience. Originated as a Buddhist meditation practice, mind-
(Grassi et al., 1997). fulness concentrates on moment-to-moment awareness of bod-
ily activities, feelings, emotions, or sensations, while purposely
Humor perceiving and discarding any distracting thoughts that come
Humor has been identified as a form of active coping contribut- into awareness (Thompson et al., 2011). Studies on trait mind-
ing to resilience not only for its capability for alleviating tension fulness suggest that strong pre-trauma mindfulness skills may
and but also for its ability to attract social support (Vaillant, help prevent ruminative, depressogenic thinking, thereby coun-
1992). Humor is widely used by veterans, repatriates, terminally teracting the development of depression and PTSD symptoms
ill patients, and youth alike and has been shown to be protec- following trauma (Thompson et al., 2011). A study of 124 fire-
tive against stress (Southwick and Charney, 2012). Cameron and fighters showed that trait mindfulness was negatively related
colleagues employed an ecological research method to examine to depressive and PTSD symptoms, physical symptoms, and
the type and role of humor in resilient adolescents’ daily social alcohol problems, suggesting that trait mindfulness may reduce
functioning and found that humor served various socioemotional avoidant coping in response to stress and contribute to resilience
functions and was a buffer in risky situations (Cameron et al., (Smith et al., 2011).
2010). In a study of 215 sojourn students from Mainland China
studying at a Hong Kong university, humor was seen as impera- MORAL COMPASS
tive to students’ ability to adjust to the new culture and thrive in The existence of a moral compass or an internal belief system
the face of acculturative stress (Cheung and Yue, 2012). In fact, guiding values and ethics is commonly shared among resilient
humor increased with an increase in frequency of acculturative individuals (Southwick et al., 2005). Though religion or spiri-
hassles. tuality is often a facet in one’s moral compass, the concept of a
moral compass is grounded in a more innately human belief in
Physical exercise morality. A study of 121 outpatients diagnosed with depression
Physical exercise has positive effects on psychological well-being and/or an anxiety disorder showed that a low or lack of purpose
as well as mood, clinical depression, and self-esteem. Physical in life and less frequent physical exercise were correlated with low
exercise has been shown to affect neurobiological factors of resilience, but low spirituality prevailed as a leading predictor of
resilience in animal (Fleshner et al., 2011) and human studies low resilience (Min et al., 2012). Similarly, purpose in life was
(Wittert et al., 1996; Winter et al., 2007). In a 10-year study of a key factor linked to resilience in a study of 259 primary care
424 depressed adult patients, Harris and colleagues examined the patients with a history of exposure to a range of severe traumatic
relationship between physical activity, exercise coping and depres- events (Alim et al., 2008).
sion at 1-year, 4-year, and 10-year follow-up points (Harris et al.,
2006). While no significant relationship between physical activ- NEUROCHEMICAL FACTORS IN RESILIENCE
ity and subsequent depression was found, physical activity was A number of neurochemicals have been found to be involved
negatively correlated with concurrent depression. In other words, in resilience. These neurochemicals have been shown to interact
physical activity may be beneficial to those currently depressed or with and to balance each other to produce regulatory effects on
facing major stressors. Moreover, in a rat model of depression, acute and long-lasting adaptations to stress.
voluntary running had antidepressant-like effects in behavioral
tests and in parallel enhanced NPY expression and neurogenesis NPY
(Bjornebekk et al., 2005, 2006). NPY is widely distributed in the brain (Wu et al., 2011; Sah
and Geracioti, 2012). It counteracts anxiogenic effects of CRH in
Prosocial behavior several brain regions that regulate stress and anxiety, including
Altruism has also been associated with resilience in both adults the hypothalamus, hippocampus, amygdala, and locus coeruleus
and children (Southwick et al., 2005; Leontopoulou, 2010). Staub (Sajdyk et al., 2004). Many studies on animal models and humans
and Vollhardt examined case studies and qualitative studies where have confirmed the beneficial role of NPY in mediating resilience
individuals’ victimization and suffering bred prosocial behav- and vulnerability to stress and anxiety. Animals with PTSD-like
ior, ultimately promoting recovery from trauma, post-traumatic behaviors showed a significant down-regulation of NPY in sev-
growth, and resilience, and suggested that post-traumatic inter- eral brain regions including the amygdala and hippocampus,
ventions may promote “altruism born of suffering” (Staub and and centrally administered NPY reversed the negative behav-
Vollhardt, 2008). A study of 232 elementary school children in ioral effects of predator-scent stress (Cohen et al., 2012). Human

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Wu et al. Neurobiology of resilience and implications for promoting resilience

studies found that, under uncontrollable stress induced by harsh CRHR1 as a potential therapeutic intervention targeting aberrant
military training, plasma NPY levels were markedly increased, CRH levels in mood and anxiety disorders and have generated
and higher NPY levels were associated with better behavioral some encouraging results (Paez-Pereda et al., 2011). CRHR-2
performance and stress response (Morgan et al., 2000, 2002). mainly modulates the effects of CRHR-1 signaling and can be
Higher plasma NPY levels were also found in combat-exposed either anxiolytic or anxiogenic depending on the circumstances
veterans without PTSD than in those with PTSD (Yehuda et al., (Hauger et al., 2009; Binder and Nemeroff, 2010).
2006). Significantly lower NPY levels in CSF were found in men
with combat-related PTSD compared to healthy controls with- NORADRENERGIC AND DOPAMINERGIC SYSTEMS
out PTSD (Sah et al., 2009). Thus, a wealth of studies indicate a The noradrenergic system is activated upon stress, resulting in
positive correlation between NPY levels and resilience to deleteri- increased release of norepinephrine primarily from the locus
ous effects of stress, and suggest a potential pharmacotherapeutic coeruleus to its many projection sites that modulate stress
target for effectively reducing anxiety and enhancing resilience to responses and emotional behaviors, including the amygdala,
adversity and stress. Studies are currently being conducted in this hippocampus, hypothalamus and PFC, all of which constitute
regard, using possibly effective delivery routes such as intranasal the LC-NE system (Aston-Jones and Cohen, 2005; Strawn and
administration. Geracioti, 2008). The activation of the LC-NE system under
acute stress leads to generation and transmission of negative
HPA AXIS emotional memories starting from the amygdala, a process that
Upon stress exposure, CRH is released from the hypothalamus can be inhibited by blocking norepinephrine activity (Charney,
and acts on the pituitary gland, causing it to release adrenocorti- 2004). Hyperresponsiveness of the LC-NE system may result in
cotropic hormone (ACTH), which in turn stimulates the adrenal chronic anxiety and fear (Feder et al., 2009). An imaging study
cortex to release cortisol and dehydroepiandrosterone (DHEA). in humans showed that disinhibited norepinephrine signaling
Cortisol exerts negative feedback effects on the hypothalamus may contribute to the etiology of PTSD by enhancing baso-
and pituitary, suppressing CRH and ACTH production, while lateral amygdala responses to fear stimuli (Onur et al., 2009).
DHEA is thought to have anti-glucocorticoid effects by inhibit- The norepinephrine transporter (NET) and receptors (α- and β-
ing or blocking the effects of cortisol (Jones and Moller, 2011). adrenoreceptors) involved in norepinephrine signaling have been
This complex set of feedback interactions constitutes the HPA implicated as biological mediators of stress-related psychiatric
axis, which is a key neuroendocrine player modulating behavioral disorders and resilience (Krystal and Neumeister, 2009; Jhaveri
responses to stress (Russo et al., 2012). et al., 2010). Dopamine release upon stress is increased in the PFC
Cortisol levels are linked to risk and resilience to stress-related and inhibited in the nucleus accumbens, an area mainly associ-
psychiatric disorders, with higher levels associated with depres- ated with the reward pathway (Charney, 2004). Some studies have
sion (Nemeroff and Vale, 2005), and lower levels with PTSD either found decreased levels of circulating dopamine in depression and
as a possible trait that predisposes to the development of PTSD elevated urinary and plasma dopamine concentrations in PTSD
or as a consequence of trauma (Radley et al., 2011; Binder and (Charney, 2004; Dunlop and Nemeroff, 2007). A recent imag-
Holsboer, 2012). DHEA together with DHEA sulfate (DHEA-S), ing study in humans showed that striatal dopamine transporter
have also been implicated in stress response and psychiatric dis- (DAT) density was higher in PTSD patients than in trauma-
orders, with lower levels of DHEA(S) associated with depression, tized controls, suggesting a possible higher dopamine turnover
and elevated levels of DHEA(S) associated with PTSD (Maninger in PTSD that can contribute to potentiation of exaggerated fear
et al., 2009; Rasmusson et al., 2010). Of note, some studies have response to a stressful stimulus (Hoexter et al., 2012). Dopamine
generated mixed findings (Hoge et al., 2007; Maninger et al., D1 and D2 receptors can form heterodimers by binding directly
2009). Because cortisol and DHEA(S) are released synchronously to each other, and these heterodimers were markedly elevated in
and function together through their antagonistic, dualistic home- the striatum in postmortem brains from patients with depression
ostasis, the DHEA(S)/cortisol ratio has been found to be a crucial (Pei et al., 2010). Disrupting the coupling of D1 and D2 receptors
parameter that indicates differential stress vulnerability (Morgan has been shown to produce antidepressant-like effects, provid-
et al., 2004; Markopoulou et al., 2009; Jones and Moller, 2011; ing a possible novel target for antidepressant treatment (Pei et al.,
ó Hartaigh et al., 2012). 2010; Wong and Liu, 2012).
CRH and its two receptors, CRHR-1 and CRHR-2, are impor-
tant mediators of stress response (Southwick et al., 2005). In SEROTONERGIC SYSTEM
depression and PTSD, increased CRH levels in CSF have been Serotonin is one of the most studied neurotransmitters in rel-
found, which may relate to the dysregulation of signal transduc- evance to mood and anxiety. Acute stress leads to increased
tion via the two receptors (Charney, 2004). CRHR-1 and CRHR-2 serotonin turnover in multiple brain areas, including the amyg-
are differentially distributed in the brain, with CRHR-1 primarily dala, hypothalamus, PFC and nucleus accumbens (Feder et al.,
found in the neocortex, basolateral amygdala, and hippocampus, 2009). Serotonin affects the regulation of stress response and
and CRHR-2 in the lateral septum, medial and cortical nuclei emotional behaviors through 5-HT1−7 receptors in separate brain
of the amygdala, and dorsal raphe (Holsboer and Ising, 2010). regions. The 5-HT1A receptor is anxiolytic and may play an
CRHR-1 signaling plays a crucial role in anxiogenic circuits and important role in the etiology of anxiety disorders. Animal stud-
contributes to anxiety-like response to stress. Consequently, pre- ies have found anxiety-like behaviors after knocking out 5-HT1A
clinical and clinical studies have examined the antagonism of (Akimova et al., 2009). A few human imaging studies have also

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Wu et al. Neurobiology of resilience and implications for promoting resilience

showed decreased 5-HT1A binding and functioning in the amyg- NEURAL CIRCUITRY OF RESILIENCE
dala, anterior cingulate cortex and raphe nuclei in patients with Animal and human studies have investigated the brain circuits
anxiety disorders compared to healthy controls (Akimova et al., implicated in mood and anxiety and have shown that dysregu-
2009). The 5-HT2A receptor, on the other hand, is thought to lated functions and interactions among these circuits can result
be anxiogenic, and 5-HT2A antagonists prevent anxious behav- in low resilience phenotypes (Feder et al., 2009; Franklin et al.,
ior and dysregulated stress responses following early life stress 2012). The reward and fear circuits play critical roles in the devel-
(Benekareddy et al., 2011). Other serotonin receptors (such as opment of resilient character traits and adaptive social responses
5-HT1B and 5-HT2C ) have also been implicated in adaptive to stress.
responses to stress (Krystal and Neumeister, 2009). For example,
overexpressing 5-HT1B in the caudal dorsal raphe nucleus led to NEURAL CIRCUITRY OF REWARD
reduced conditioned fear and helplessness in animal stress models Enhanced functioning of the reward circuitry contributes to
(McDevitt et al., 2011). resilience to stress and trauma (Charney, 2004). A key reward
circuit is the mesolimbic dopamine pathway, which carries
BDNF dopamine signaling from the ventral tegmental area of the mid-
BDNF, a neurotrophic factor expressed in various brain regions brain to the nucleus accumbens in the limbic system, and also
including the amygdala, hippocampus, PFC and basal fore- to other brain regions such as the amygdala, hippocampus,
brain, is implicated in mood and anxiety disorders (Yamada and and medial PFC. The mesolimbic dopamine pathway is linked
Nabeshima, 2003; Angelucci et al., 2005; Duman, 2009). BDNF to behavioral responses to rewards (e.g., food, sex, and drugs
supports neuronal proliferation, differentiation and growth dur- of abuse), and functional abnormalities in this pathway can
ing development, and promotes neuronal survival and func- contribute notably to key depressive symptomatology such as
tioning in adulthood (McAllister, 2002). Several studies have anhedonia, decreased energy, and reduced motivation seen in
shown down-regulation of BDNF in the hippocampus after individuals with depression (Nestler and Carlezon, 2006). Studies
exposure of animals to various types of stress, and in post- have shown that the onset of depression is likely to happen dur-
mortem studies of suicide-depression patients (Duman and ing adolescence, when reward functioning is generally higher than
Monteggia, 2006; Duman, 2009). Hippocampal BDNF expres- during childhood and adulthood, and that increased reactivity in
sion contributed critically to resilient adaptations to chronic the medial PFC and decreased reactivity in the striatum are impli-
stress (Taliaz et al., 2011). BDNF acts through its two main cated in adolescent depression (Forbes and Dahl, 2012). Children
receptors, TrkB and p75 (Castren and Rantamaki, 2010). The of depressed parents, therefore at high risk for depression, showed
BDNF-TrkB pathway has been associated with both PTSD in altered amygdala and nucleus accumbens activation to affective
humans and in animal models of fear conditioning, extinc- stimuli compared to those of non-depressed parents, therefore
tion and inhibitory learning (Mahan and Ressler, 2012). Central at low risk for depression (Monk et al., 2008). Depressed and
administration of BDNF has antidepressant-like effects and can PTSD patients showed weakened responses to rewards in the stri-
enhance hippocampal neurogenesis (Li et al., 2008; Autry and atal areas including the nucleus accumbens (Sailer et al., 2008;
Monteggia, 2012). Evidence from animal and human stud- Pizzagalli et al., 2009). Deep brain stimulation in the nucleus
ies shows that administration of antidepressants can lead to accumbens has antidepressant, anti-anhedonic and anxiolytic
increase of BDNF and TrkB expression in the hippocampus and effects in patients with treatment-resistant depression, suggest-
PFC, suggesting a role of BDNF-TrkB signaling in the behav- ing that modulating a dysfunctional reward system can lead to
ioral effects of antidepressants (Masi and Brovedani, 2011). improvement of the core symptoms in depression (Schlaepfer
Nevertheless, there is also evidence for antidepressant effects et al., 2008; Bewernick et al., 2010). Although compelling evi-
without changes in BDNF or neurogenesis (David et al., 2009; dence has shown that an enhanced, highly functional reward
Petersen et al., 2009; Hansson et al., 2011). Much less work has system may be beneficial for positive, adaptive response to stress,
been done regarding the exact role of the BDNF-p75 signaling one study found that Special Forces soldiers of high resilience
pathway in resilience, probably due to the low affinity of p75 showed less activation in the subgenual PFC and nucleus accum-
(Numakawa et al., 2010). bens under a high-reward condition compared to healthy civilian
controls, suggesting that a potentially “sturdy” reward system
GLUTAMATE, GABA, AND ENDOCANNABINOIDS may contribute to resilience (Vythilingam et al., 2009). The exact
Glutamate, GABA, and endocannabinoids have also been widely role of the reward system and the associated neurotransmit-
studied and implicated in the stress response, resilience, and ters in the development of resilience and pathophysiology and
pathophysiology of mood and anxiety disorders (Harvey and even etiology of stress-related psychiatric disorders needs further
Shahid, 2012; Hill, 2012; Sanacora et al., 2012). The dysregu- elucidation.
lation of these systems can lead to profound deficits in suc-
cessful adaptation to acute and chronic stress. Pharmacological NEURAL CIRCUITRY OF FEAR
studies targeting these systems in psychiatric disorders have Resilience to extreme stress entails the ability to avoid exces-
begun to show promising results in achieving therapeutic sive overgeneralized fear responses and to enhance favorable
effects (Hill and Gorzalka, 2009; Murrough and Charney, 2010; reconsolidation and extinction processes related to fear memo-
Kirilly et al., 2012; Mathew et al., 2012; Mathews et al., ries (Charney, 2004). Several studies have identified the com-
2012). ponents of the neural circuitry of fear response, which includes

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Wu et al. Neurobiology of resilience and implications for promoting resilience

the amygdala, hippocampus, medial PFC, nucleus accumbens, the consolidation and extinction of fear conditioning, primarily
ventromedial hypothalamus, and a number of brain stem nuclei by modulating glutamatergic and GABAergic signaling (Mahan
(Davis, 2006; Maren, 2008; Quirk and Mueller, 2008). These and Ressler, 2012). These neurochemical systems involved in the
regions play key roles in fear processing including the fear learn- fear circuitry provide potential pharmacological targets for reduc-
ing/conditioning, perception of threat, execution of efferent com- ing dysregulated fear response in PTSD and enhancing resilience
ponents of fear response, and modulation of fear memories to inappropriate fear associations in individuals susceptible to
through potentiation, consolidation, reconsolidation, and extinc- stress-related psychiatric disorders.
tion (Shin and Liberzon, 2010). Patients with PTSD showed
hyperactivation in the amygdala and hypoactivation in the ven- ADDITIONAL NEURAL CIRCUITRY OF RESILIENCE
tromedial PFC and anterior hippocampus, which may indicate Neural circuits underlying psychological characteristics that ren-
reduced top-down inhibition of the amygdala and account for der adaptive social behavior and promote resilience in individ-
exaggerated fear responses (Etkin and Wager, 2007). Other brain uals have been examined. Psychobiological qualities important
regions such as the dorsal anterior cingulate cortex and insular in prosocial behavior include emotion regulation, empathy, and
cortex have also been implicated in the maladaptive regulation of altruism, among others (Charney, 2004; Feder et al., 2009).
fear responses in PTSD, with some studies showing hyperrespon- Animal and human studies have identified functional neural cir-
siveness and some showing hyporesponsiveness of these regions cuits and interactions among multiple brain regions, such as the
(Shin and Liberzon, 2010). Compared to trauma victims without amygdala, PFC and nucleus accumbens, that are involved in the
PTSD, individuals with PTSD demonstrated behavioral sensiti- regulation of adaptive psychobiological responses to stress and
zation to stress, overgeneralization of the conditioned stimulus adversities (Charney, 2004; Feder et al., 2009; Kim et al., 2011b;
(CS)-unconditioned stimulus (US) response, impaired CS-US Cusi et al., 2012; Morishima et al., 2012). Reduced Insular activa-
pairings and impaired fear inhibitory learning, all of which are tion under stress has been linked to greater non-reactivity to inner
thought to be characteristic of dysregulated fear responses and experience, a key component of trait mindfulness which may
can result in the core symptoms seen in PTSD, such as intrusive protect against negative bias and reduce depression vulnerabil-
memories and flashbacks, enhanced avoidance of reminders, and ity (Paul et al., 2013). By potentially targeting the top-down and
autonomic hyperarousal (Mahan and Ressler, 2012). One study bottom-up regulation of these neural circuits, psychotherapeutic
found higher potentiation of the startle response to safety cues interventions including cognitive behavioral therapy with cogni-
in patients with PTSD compared to traumatized controls, and tive reappraisal, positive emotion exercises, coping skill training,
that this impaired fear inhibition may be associated with altered well-being therapy, and mindfulness meditation, can be effica-
HPA-axis functioning in PTSD (Jovanovic et al., 2010). cious approaches to build and enhance resilient psychosocial
Animal studies have shown that proper fear conditioning and responses to stress (Southwick and Charney, 2012).
extinction learning require synaptic plasticity, and thus impaired
synaptic plasticity may underlie impaired fear and extinction SUMMARY
processes in PTSD (Mahan and Ressler, 2012). The BDNF-TrkB Resilience is a complex multidimensional construct and the study
signaling pathway, a ligand-receptor system involved in synaptic of its neurobiology is a relatively young area of scientific inves-
plasticity, has been shown to be necessary for sustaining nor- tigation (Southwick and Charney, 2012). Multiple interacting
mal functioning of fear conditioning, extinction, and inhibitory factors including genetics, epigenetics, developmental environ-
learning in three brain regions, the amygdala, hippocampus, and ment, psychosocial factors, neurochemicals, and functional neu-
medial PFC, all of which are associated with PTSD (Mahan and ral circuitry, play critical roles in developing and modulating
Ressler, 2012). Consolidation of fear conditioning and extinction resilience in an integrated way. For instance, genetic and epige-
was impaired when BDNF signaling was inhibited in the amyg- netic factors interact with each other and determine the biological
dala (Rattiner et al., 2004; Chhatwal et al., 2006). Heterogeneous characteristics and regulation of neurochemicals and receptors.
BDNF knockout mice (BDNF±) demonstrated malfunctioning Environmental factors influence these characteristics and reg-
contextual fear conditioning, which can be partially reversed with ulation processes through gene and environment interactions
recombinant BDNF infusion into the hippocampus (Liu et al., throughout development, contributing to adaptive changes in
2004). Altered BDNF expression in the prelimbic and infralim- gene regulation, plasticity in the growth and modulation of neu-
bic areas of the medial PFC can also lead to functional changes rocircuits, and the shaping of psychological factors and behavioral
in fear consolidation and expression, suggesting a role of BDNF endpoints that underlie the manifestation of resilience.
as a key mediator of neural plasticity in these regions (Choi et al., Our growing understanding of the neurobiology of resilience
2010; Peters et al., 2010). Glutamatergic and GABAergic signal- has significant implications for the prevention and treatment
ing pathways have also been implicated in the regulation of fear of stress-related psychiatric disorders. Pharmacological interven-
consolidation, expression and extinction (Mahan and Ressler, tions targeting the neurochemical systems involving NPY, BDNF,
2012). For instance, disrupting NMDA and AMPA receptor func- CRH, and HPA axis, among others, are being investigated as
tioning impaired the extinction of fear conditioning (Dalton potential treatments for depression and PTSD. For instance, phar-
et al., 2008; Liu et al., 2009; Zimmerman and Maren, 2010). macological agents targeting the hyperactivity and malfunction
Other ligand-receptor signaling systems such as those involving of HPA axis and CRH can possibly reduce the likelihood of
norepinephrine, nitric oxide, endocannabinoids, dopamine and pathological response to stress. Also, for individuals with altered
acetylcholine have also been shown to play a modulatory role in NPYergic system, enhancing NPY levels and function may help

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Wu et al. Neurobiology of resilience and implications for promoting resilience

to improve stress and anxiety regulation and to minimize the enabling them to adaptively react to and master future challenges
anxiogenic effects of CRH (Southwick and Charney, 2012). and stressors, thereby reducing susceptibility to stress-related
Behavioral training targeting psychosocial risk factors and psychopathology.
related neural pathways is also likely to increase resilience to How to apply what we currently know about resilience to
stress (Karatsoreos and McEwen, 2011). Practice and training on further the promotion of resilience and the prevention and treat-
enhancing stress-protective factors can lead to augmented plas- ment of stress-related psychopathology is one of the most crit-
ticity and regulation of neural circuits that modulate reward ical questions for future studies. In addition, multidisciplinary
and motivation, fear response, learning memory, emotion reg- research on the neurobiology of resilience should help to fur-
ulation, attention, cognitive executive function, adaptive social ther identify risk and protective factors as well as their complex
behavior, and cognitive reappraisal, thereby result in improved interactions and thereby facilitate the development of evidence-
adaptation to stress and trauma, increased speed of recovery based interventions for enhancing resilience and mitigating risk
from adversities, and decreased susceptibility to stress-related for stress-related psychiatric disorders.
psychopathology throughout life (Southwick and Charney, 2012).
Furthermore, maintaining a supportive environment and pro- ACKNOWLEDGMENTS
viding resilience-building classes for child rearing can be partic- We sincerely acknowledge the support from the Icahn School
ularly beneficial, in that children can learn how to master life of Medicine at Mount Sinai, the Karolinska Institutet, and the
challenges and acquire “stress inoculation” while growing up, Swedish Medical Research Council Grant 10414.

REFERENCES Bewernick, B. H., Hurlemann, R., control as well as brain activity and Castren, E., and Rantamaki, T. (2010).
Akimova, E., Lanzenberger, R., Matusch, A., Kayser, S., Grubert, connectivity during emotion pro- The role of BDNF and its receptors
and Kasper, S. (2009). The C., Hadrysiewicz, B., et al. (2010). cessing in humans. J. Neurosci. 29, in depression and antidepressant
serotonin-1A receptor in anxi- Nucleus accumbens deep brain 14812–14819. drug action: reactivation of develop-
ety disorders. Biol. Psychiatry 66, stimulation decreases ratings Boldrini, M., Hen, R., Underwood, mental plasticity. Dev. Neurobiol. 70,
627–635. of depression and anxiety in M. D., Rosoklija, G. B., Dwork, 289–297.
Alim, T. N., Feder, A., Graves, R. E., treatment-resistant depression. A. J., Mann, J. J., et al. (2012). Charney, D. S. (2004). Psychobiological
Wang, Y., Weaver, J., Westphal, M., Biol. Psychiatry 67, 110–116. Hippocampal angiogenesis and mechanisms of resilience and
et al. (2008). Trauma, resilience, Binder, E. B., and Holsboer, F. (2012). progenitor cell proliferation are vulnerability: implications for
and recovery in a high-risk African- Low cortisol and risk and resilience increased with antidepressant use in successful adaptation to extreme
American population. Am. J. to stress-related psychiatric disor- major depression. Biol. Psychiatry stress. Am. J. Psychiatry 161,
Psychiatry 165, 1566–1575. ders. Biol. Psychiatry 71, 282–283. 72, 562–571. 195–216.
Angelucci, F., Brene, S., and Mathe, Binder, E. B., and Nemeroff, C. B. Bradley, R. G., Binder, E. B., Epstein, Chemtob, C. M., Tomas, S., Law,
A. A. (2005). BDNF in schizophre- (2010). The CRF system, stress, M. P., Tang, Y., Nair, H. P., Liu, W., and Cremniter, D. (1997).
nia, depression and corresponding depression and anxiety-insights W., et al. (2008). Influence of child Postdisaster psychosocial interven-
animal models. Mol. Psychiatry 10, from human genetic studies. Mol. abuse on adult depression: moder- tion: a field study of the impact of
345–352. Psychiatry 15, 574–588. ation by the corticotropin-releasing debriefing on psychological distress.
Armbruster, D., Mueller, A., Strobel, Binder, E. B., Bradley, R. G., Liu, hormone receptor gene. Arch. Gen. Am. J. Psychiatry 154, 415–417.
A., Lesch, K. P., Brocke, B., and W., Epstein, M. P., Deveau, T. Psychiatry 65, 190–200. Chesney, M. A., Neilands, T. B.,
Kirschbaum, C. (2012). Children C., Mercer, K. B., et al. (2008). Brummett, B. H., Kuhn, C. M., Boyle, Chambers, D. B., Taylor, J. M.,
under stress - COMT geno- Association of FKBP5 polymor- S. H., Babyak, M. A., Siegler, I. and Folkman, S. (2006). A validity
type and stressful life events phisms and childhood abuse with C., and Williams, R. B. (2012). and reliability study of the coping
predict cortisol increase in an risk of posttraumatic stress disor- Cortisol responses to emotional self-efficacy scale. Br. J. Health
acute social stress paradigm. Int. der symptoms in adults. JAMA 299, stress in men: association with a Psychol. 11, 421–437.
J. Neuropsychopharmacol. 15, 1291–1305. functional polymorphism in the Cheung, C. K., and Yue, X. D. (2012).
1229–1239. Bjornebekk, A., Mathe, A. A., and 5HTR2C gene. Biol. Psychol. 89, Sojourn students’ humor styles as
Aston-Jones, G., and Cohen, J. D. Brene, S. (2005). The antidepressant 94–98. buffers to achieve resilience. Int.
(2005). An integrative theory of effect of running is associated with Burt, K. B., and Paysnick, A. A. J. Intercult. Relat. 36, 353–364.
locus coeruleus-norepinephrine increased hippocampal cell prolifer- (2012). Resilience in the transition Chhatwal, J. P., Stanek-Rattiner,
function: adaptive gain and optimal ation. Int. J. Neuropsychopharmacol. to adulthood. Dev. Psychopathol. 24, L., Davis, M., and Ressler, K. J.
performance. Annu. Rev. Neurosci. 8, 357–368. 493–505. (2006). Amygdala BDNF signaling
28, 403–450. Bjornebekk, A., Mathe, A. A., and Cameron, E. L., Fox, J. D., Anderson, is required for consolidation but
Autry, A. E., and Monteggia, L. M. Brene, S. (2006). Running has dif- M. S., and Cameron, C. A. (2010). not encoding of extinction. Nat.
(2012). Brain-derived neurotrophic ferential effects on NPY, opiates, Resilient youths use humor to Neurosci. 9, 870–872.
factor and neuropsychiatric disor- and cell proliferation in an ani- enhance socioemotional func- Choi, D. C., Maguschak, K. A., Ye,
ders. Pharmacol. Rev. 64, 238–258. mal model of depression and con- tioning during a day in the life. K., Jang, S. W., Myers, K. M., and
Benekareddy, M., Vadodaria, K. C., trols. Neuropsychopharmacology 31, J. Adolesc. Res. 25, 716–742. Ressler, K. J. (2010). Prelimbic cor-
Nair, A. R., and Vaidya, V. A. (2011). 256–264. Campbell-Sills, L., Cohan, S. L., and tical BDNF is required for memory
Postnatal serotonin type 2 recep- Blackburn, E. H., and Epel, E. S. (2012). Stein, M. B. (2006). Relationship of learned fear but not extinction
tor blockade prevents the emergence Telomeres and adversity: too toxic of resilience to personality, cop- or innate fear. Proc. Natl. Acad. Sci.
of anxiety behavior, dysregulated to ignore. Nature 490, 169–171. ing, and psychiatric symptoms in U.S.A. 107, 2675–2680.
stress-induced immediate early gene Blasi, G., Lo Bianco, L., Taurisano, young adults. Behav. Res. Ther. 44, Cicchetti, D., and Rogosch, F. A.
responses, and specific transcrip- P., Gelao, B., Romano, R., Fazio, 585–599. (2012). Gene x Environment inter-
tional changes that arise following L., et al. (2009). Functional varia- Carver, C. S., Scheier, M. F., and action and resilience: effects of
early life stress. Biol. Psychiatry 70, tion of the dopamine D2 receptor Segerstrom, S. C. (2010). Optimism. child maltreatment and serotonin,
1024–1032. gene is associated with emotional Clin. Psychol. Rev. 30, 879–889. corticotropin releasing hormone,

Frontiers in Behavioral Neuroscience www.frontiersin.org February 2013 | Volume 7 | Article 10 | 11


Wu et al. Neurobiology of resilience and implications for promoting resilience

dopamine, and oxytocin genes. Dev. for involvement of glutamate Franklin, T. B., Saab, B. J., and role of dorsal raphe serotonergic
Psychopathol. 24, 411–427. decarboxylase 1 and neuropeptide Y Mansuy, I. M. (2012). Neural neurons. J. Neurosci. 23, 2889–2898.
Claes, S. J. (2004). Corticotropin- in anxiety susceptibility. Am. J. Med. mechanisms of stress resilience Gross, J. J. (2002). Emotion regula-
releasing hormone (CRH) in Genet. B Neuropsychiatr. Genet. and vulnerability. Neuron 75, tion: affective, cognitive, and social
psychiatry: from stress to psy- 159B, 316–327. 747–761. consequences. Psychophysiology 39,
chopathology. Ann. Med. 36, Dudley, K. J., Li, X., Kobor, M. S., Frodl, T., and O’Keane, V. (2012). 281–291.
50–61. Kippin, T. E., and Bredy, T. W. How does the brain deal with Hansson, A. C., Rimondini, R., Heilig,
Cohen, H., Liu, T., Kozlovsky, N., (2011). Epigenetic mechanisms cumulative stress? A review with M., Mathe, A. A., and Sommer,
Kaplan, Z., Zohar, J., and Mathe, mediating vulnerability and focus on developmental stress, HPA W. H. (2011). Dissociation of
A. A. (2012). The neuropeptide Y resilience to psychiatric disor- axis function and hippocampal antidepressant-like activity of
(NPY)-ergic system is associated ders. Neurosci. Biobehav. Rev. 35, structure in humans. Neurobiol. escitalopram and nortriptyline
with behavioral resilience to stress 1544–1551. Dis. doi: 10.1016/j.nbd.2012.03.012. on behaviour and hippocampal
exposure in an animal model of Duman, R. S. (2009). Neuronal damage [Epub ahead of print]. BDNF expression in female rats.
post-traumatic stress disorder. and protection in the pathophysi- Frustaci, A., Pozzi, G., Gianfagna, F., J. Psychopharmacol. 25, 1378–1387.
Neuropsychopharmacology 37, ology and treatment of psychiatric Manzoli, L., and Boccia, S. (2008). Hanton, S., Neil, R., and Evans, L.
350–363. illness: stress and depression. Meta-analysis of the brain-derived (2013). Hardiness and anxiety inter-
Colby, D. A., and Shifren, K. (2013). Dialogues Clin. Neurosci. 11, neurotrophic factor gene (BDNF) pretation: an investigation into cop-
Optimism, mental health, and qual- 239–255. Val66Met polymorphism in anxiety ing usage and effectiveness. Eur. J.
ity of life: a study among breast can- Duman, R. S., and Monteggia, L. M. disorders and anxiety-related per- Sport Sci. 13, 96–104.
cer patients. Psychol. Health Med. (2006). A neurotrophic model for sonality traits. Neuropsychobiology Harris, A. H., Cronkite, R., and Moos,
18, 10–20. stress-related mood disorders. Biol. 58, 163–170. R. (2006). Physical activity, exercise
Covington, H. E. 3rd., Maze, I., Sun, Psychiatry 59, 1116–1127. Galatzer-Levy, I. R., and Bonanno, G. A. coping, and depression in a 10-year
H., Bomze, H. M., Demaio, K. D., Dunlop, B. W., and Nemeroff, C. B. (2012). Heterogeneous patterns of cohort study of depressed patients.
Wu, E. Y., et al. (2011). A role (2007). The role of dopamine in stress over the four years of college: J. Affect. Disord. 93, 79–85.
for repressive histone methylation the pathophysiology of depression. associations with anxious attach- Harvey, B. H., and Shahid, M. (2012).
in cocaine-induced vulnerability to Arch. Gen. Psychiatry 64, 327–337. ment and ego-resiliency. J. Pers. doi: Metabotropic and ionotropic glu-
stress. Neuron 71, 656–670. Duryea, E. J., Ransom, M. V., and 10.1111/jopy.12010. [Epub ahead of tamate receptors as neurobiological
Cusi, A. M., Nazarov, A., Holshausen, English, G. (1990). Psychological print]. targets in anxiety and stress-related
K., Macqueen, G. M., and immunization: theory, research, and Gatt, J. M., Nemeroff, C. B., Dobson- disorders: focus on pharmacology
McKinnon, M. C. (2012). current health behavior applica- Stone, C., Paul, R. H., Bryant, and preclinical translational mod-
Systematic review of the neural tions. Health Educ. Q. 17, 169–178. R. A., Schofield, P. R., et al. els. Pharmacol. Biochem. Behav. 100,
basis of social cognition in patients Etkin, A., and Wager, T. D. (2007). (2009). Interactions between BDNF 775–800.
with mood disorders. J. Psychiatry Functional neuroimaging of anxi- Val66Met polymorphism and early Hauger, R. L., Risbrough, V., Oakley,
Neurosci. 37, 154–169. ety: a meta-analysis of emotional life stress predict brain and arousal R. H., Olivares-Reyes, J. A., and
Dalton, G. L., Wang, Y. T., Floresco, processing in PTSD, social anxiety pathways to syndromal depression Dautzenberg, F. M. (2009). Role of
S. B., and Phillips, A. G. (2008). disorder, and specific phobia. Am. and anxiety. Mol. Psychiatry 14, CRF receptor signaling in stress vul-
Disruption of AMPA receptor J. Psychiatry 164, 1476–1488. 681–695. nerability, anxiety, and depression.
endocytosis impairs the extinction, Farchi, M., and Gidron, Y. (2010). The Gatt, J. M., Nemeroff, C. B., Schofield, Ann. N.Y. Acad. Sci. 1179, 120–143.
but not acquisition of learned effects of “psychological inocula- P. R., Paul, R. H., Clark, C. R., Heim, C., Shugart, M., Craighead, W.
fear. Neuropsychopharmacology 33, tion” versus ventilation on the men- Gordon, E., et al. (2010). Early life E., and Nemeroff, C. B. (2010).
2416–2426. tal resilience of Israeli citizens under stress combined with serotonin Neurobiological and psychiatric
Dannlowski, U., Stuhrmann, A., continuous war stress. J. Nerv. Ment. 3A receptor and brain-derived consequences of child abuse
Beutelmann, V., Zwanzger, P., Dis. 198, 382–384. neurotrophic factor valine 66 to and neglect. Dev. Psychobiol. 52,
Lenzen, T., Grotegerd, D., et al. Feder, A., Charney, D. S., and Collins, methionine genotypes impacts 671–690.
(2012). Limbic scars: long-term K. (2011). “Neurobiology of emotional brain and arousal cor- Heinz, A., and Smolka, M. N.
consequences of childhood mal- resilience,” in Resilience and Mental relates of risk for depression. Biol. (2006). The effects of catechol
treatment revealed by functional Health, eds S. M. Southwick, Psychiatry 68, 818–824. O-methyltransferase genotype on
and structural magnetic reso- B. T. Litz, D. S. Charney, and Gillespie, C. F., Phifer, J., Bradley, B., brain activation elicited by affective
nance imaging. Biol. Psychiatry 71, M. J. Friedman (New York, NY: and Ressler, K. J. (2009). Risk and stimuli and cognitive tasks. Rev.
286–293. Cambridge University Press). resilience: genetic and environmen- Neurosci. 17, 359–367.
David, D. J., Samuels, B. A., Rainer, Q., Feder, A., Nestler, E. J., and Charney, tal influences on development of the Hernández-Wolfe, P. (2010). Altruism
Wang, J. W., Marsteller, D., Mendez, D. S. (2009). Psychobiology and stress response. Depress. Anxiety 26, born of suffering: how colom-
I., et al. (2009). Neurogenesis- molecular genetics of resilience. 984–992. bian human rights activists
dependent and -independent effects Nat. Rev. Neurosci. 10, 446–457. Gonzalez-Herero, V., and Garcia- transform pain into prosocial
of fluoxetine in an animal model Fleshner, M., Maier, S. F., Lyons, D. Martin, M. A. (2012). Personality, action. J. Humanist. Psychol. 51,
of anxiety/depression. Neuron 62, M., and Raskind, M. A. (2011). The activities, and well-being: a study 229–249.
479–493. neurobiology of the stress-resistant based on women in late adulthood. Hill, M. N. (2012). Introduction to the
Davidson, R. J., and McEwen, B. S. brain. Stress 14, 498–502. J. Women Aging 24, 152–168. special issue on stress, emotional
(2012). Social influences on neu- Folkman, S., and Moskowitz, J. T. Grassi, L., Malacarne, P., Maestri, A., behavior, and the endocannabi-
roplasticity: stress and interven- (2000). Positive affect and the other and Ramelli, E. (1997). Depression, noid system: a decade of research.
tions to promote well-being. Nat. side of coping. Am. Psychol. 55, psychosocial variables and occur- Neuroscience 204, 1–4.
Neurosci. 15, 689–695. 647–654. rence of life events among patients Hill, M. N., and Gorzalka, B. B. (2009).
Davis, M. (2006). Neural systems Forbes, E. E., and Dahl, R. E. (2012). with cancer. J. Affect. Disord. 44, The endocannabinoid system and
involved in fear and anxiety mea- Research review: altered reward 21–30. the treatment of mood and anxiety
sured with fear-potentiated startle. function in adolescent depression: Greenwood, B. N., Foley, T. E., Day, disorders. CNS Neurol. Disord. Drug
Am. Psychol. 61, 741–756. what, when and how? J. Child H. E., Campisi, J., Hammack, S. Targets 8, 451–458.
Donner, J., Sipila, T., Ripatti, S., Psychol. Psychiatry. 53, 3–15. H., Campeau, S., et al. (2003). Ho, Y. C., and Wang, S. (2010).
Kananen, L., Chen, X., Kendler, Frankl, V. E. (2006). Man’s Search for Freewheel running prevents learned Adult neurogenesis is reduced
K. S., et al. (2012). Support Meaning. Boston, MA: Beacon Press. helplessness/behavioral depression: in the dorsal hippocampus of

Frontiers in Behavioral Neuroscience www.frontiersin.org February 2013 | Volume 7 | Article 10 | 12


Wu et al. Neurobiology of resilience and implications for promoting resilience

rats displaying learned helpless- the mediatingrole of emotionregu- Liu, J. L., Li, M., Dang, X. R., Wang, depression: current evidence. CNS
ness behavior. Neuroscience 171, lation and resilience. Pers. Individ. Z. H., Rao, Z. R., Wu, S. X., et al. Drugs 26, 189–204.
153–161. Dif. 53, 821–826. (2009). A NMDA receptor antago- Mathews, D. C., Henter, I. D., and
Hoexter, M. Q., Fadel, G., Felicio, A. Kim, H. K., Kim, S. J., Lee, Y. J., nist, MK-801 impairs consolidating Zarate, C. A. (2012). Targeting
C., Calzavara, M. B., Batista, I. R., Lee, H. J., Kang, S. G., Choi, extinction of auditory conditioned the glutamatergic system to treat
Reis, M. A., et al. (2012). Higher J. E., et al. (2011a). Influence fear responses in a Pavlovian major depressive disorder: rationale
striatal dopamine transporter den- of the interaction between the model. PLoS ONE 4:e7548. doi: and progress to date. Drugs 72,
sity in PTSD: an in vivo SPECT serotonin 1A receptor C-1019G 10.1371/journal.pone.0007548 1313–1333.
study with [(99m)Tc]TRODAT-1. polymorphism and negative life Luthar, S. S., and Barkin, S. H. McAllister, A. K. (2002). Spatially
Psychopharmacology (Berl.). 224, stressors on the development of (2012). Are affluent youth truly “at restricted actions of BDNF. Neuron
337–345. depression. Neuropsychobiology 64, risk”? Vulnerability and resilience 36, 549–550.
Hoge, E. A., Austin, E. D., and Pollack, 1–8. across three diverse samples. Dev. McCormack, K., Sanchez, M. M.,
M. H. (2007). Resilience: research Kim, M. J., Loucks, R. A., Palmer, A. Psychopathol. 24, 429–449. Bardi, M., and Maestripieri, D.
evidence and conceptual considera- L., Brown, A. C., Solomon, K. M., Lyons, D. M., Parker, K. J., Katz, (2006). Maternal care patterns and
tions for posttraumatic stress disor- Marchante, A. N., et al. (2011b). M., and Schatzberg, A. F. (2009). behavioral development of rhesus
der. Depress. Anxiety 24, 139–152. The structural and functional con- Developmental cascades linking macaque abused infants in the first
Holahan, C. J., and Moos, R. H. (1987). nectivity of the amygdala: from nor- stress inoculation, arousal reg- 6 months of life. Dev. Psychobiol. 48,
Risk, resistance, and psychologi- mal emotion to pathological anxi- ulation, and resilience. Front. 537–550.
cal distress: a longitudinal analysis ety. Behav. Brain Res. 223, 403–410. Behav. Neurosci. 3:32. doi: McDevitt, R. A., Hiroi, R., Mackenzie,
with adults and children. J. Abnorm. Kim, J. M., Stewart, R., Kim, S. 10.3389/neuro.08.032.2009 S. M., Robin, N. C., Cohn, A.,
Psychol. 96, 3–13. W., Yang, S. J., Shin, I. S., Kim, Maag, J. W., and Kotlash, J. (1994). Kim, J. J., et al. (2011). Serotonin
Holsboer, F., and Ising, M. (2010). Y. H., et al. (2007). Interactions Review of stress inoculation train- 1B autoreceptors originating in the
Stress hormone regulation: biolog- between life stressors and suscepti- ing with children and adolescents. caudal dorsal raphe nucleus reduce
ical role and translation into ther- bility genes (5-HTTLPR and BDNF) Issues and recommendations. expression of fear and depression-
apy. Annu. Rev. Psychol. 61, 81–109, on depression in Korean elders. Biol. Behav. Modif. 18, 443–469. like behavior. Biol. Psychiatry 69,
C101–C111. Psychiatry 62, 423–428. Maestripieri, D., Lindell, S. G., 780–787.
Janssen, J., Hulshoff Pol, H. E., De Kirilly, E., Gonda, X., and Bagdy, G. and Higley, J. D. (2007). McGowan, P. O., Sasaki, A., D’Alessio,
Leeuw, F. E., Schnack, H. G., Lampe, (2012). CB1 receptor antagonists: Intergenerational transmission A. C., Dymov, S., Labonte, B., Szyf,
I. K., Kok, R. M., et al. (2007). new discoveries leading to new per- of maternal behavior in rhesus M., et al. (2009). Epigenetic regu-
Hippocampal volume and subcor- spectives. Acta Physiol. (Oxf.) 205, macaques and its underlying lation of the glucocorticoid recep-
tical white matter lesions in late 41–60. mechanisms. Dev. Psychobiol. 49, tor in human brain associates with
life depression: comparison of early Kolassa, I. T., Kolassa, S., Ertl, V., 165–171. childhood abuse. Nat. Neurosci. 12,
and late onset depression. J. Neurol. Papassotiropoulos, A., and De Mahan, A. L., and Ressler, K. J. (2012). 342–348.
Neurosurg. Psychiatr. 78, 638–640. Quervain, D. J. (2010). The risk Fear conditioning, synaptic plastic- McGowan, P. O., Suderman, M., Sasaki,
Jhaveri, D. J., Mackay, E. W., Hamlin, of posttraumatic stress disor- ity and the amygdala: implications A., Huang, T. C., Hallett, M.,
A. S., Marathe, S. V., Nandam, der after trauma depends on for posttraumatic stress disorder. Meaney, M. J., et al. (2011). Broad
L. S., Vaidya, V. A., et al. (2010). traumatic load and the catechol- Trends Neurosci. 35, 24–35. epigenetic signature of maternal
Norepinephrine directly activates o-methyltransferase Val(158)Met Maninger, N., Wolkowitz, O. M., Reus, care in the brain of adult rats.
adult hippocampal precursors polymorphism. Biol. Psychiatry 67, V. I., Epel, E. S., and Mellon, S. PLoS ONE 6:e14739. doi: 10.1371/
via beta3-adrenergic receptors. 304–308. H. (2009). Neurobiological and journal.pone.0014739
J. Neurosci. 30, 2795–2806. Krystal, J. H., and Neumeister, A. neuropsychiatric effects of dehy- McRae, K., Ciesielski, B., and Gross, J.
Jones, T., and Moller, M. D. (2011). (2009). Noradrenergic and sero- droepiandrosterone (DHEA) and J. (2012). Unpacking cognitive reap-
Implications of hypothalamic- tonergic mechanisms in the DHEA sulfate (DHEAS). Front. praisal: goals, tactics, and outcomes.
pituitary-adrenal axis functioning neurobiology of posttraumatic Neuroendocrinol. 30:65–91. doi: Emotion 12, 250–255.
in posttraumatic stress disorder. stress disorder and resilience. Brain 10.1016/j.yfrne.2008.11.002 McRae, K., Ochsner, K. N., Mauss, I.
J. Am. Psychiatr. Nurses Assoc. 17, Res. 1293, 13–23. Maren, S. (2008). Pavlovian fear con- B., Gabrieli, J. D., and Gross, J. J.
393–403. Lawler, C., Ouimette, P., and Dahlstedt, ditioning as a behavioral assay for (2008). Gender differences in emo-
Jovanovic, T., Norrholm, S. D., D. (2005). Posttraumatic stress hippocampus and amygdala func- tion regulation: an fMRI study of
Blanding, N. Q., Phifer, J. E., symptoms, coping, and physical tion: cautions and caveats. Eur. J. cognitive reappraisal. Group Process.
Weiss, T., Davis, M., et al. (2010). health status among university stu- Neurosci. 28, 1661–1666. Intergr. Relat. 11, 143–162.
Fear potentiation is associated dents seeking health care. J. Trauma. Markopoulou, K., Papadopoulos, A., Merali, Z., Du, L., Hrdina, P., Palkovits,
with hypothalamic-pituitary- Stress 18, 741–750. Juruena, M. F., Poon, L., Pariante, M., Faludi, G., Poulter, M. O.,
adrenal axis function in PTSD. Leontopoulou, S. (2010). An C. M., and Cleare, A. J. (2009). et al. (2004). Dysregulation in the
Psychoneuroendocrinology 35, exploratory study of altruism The ratio of cortisol/DHEA in suicide brain: mRNA expression
846–857. in Greek children: relations with treatment resistant depression. of corticotropin-releasing hormone
Karatsoreos, I. N., and McEwen, B. empathy, resilience and classroom Psychoneuroendocrinology 34, receptors and GABA(A) receptor
S. (2011). Psychobiological allosta- climate. Psychology 1, 377–385. 19–26. subunits in frontal cortical brain
sis: resistance, resilience and vul- Li, Y., Luikart, B. W., Birnbaum, S., Masi, G., and Brovedani, P. (2011). The region. J. Neurosci. 24, 1478–1485.
nerability. Trends Cogn. Sci. 15, Chen, J., Kwon, C. H., Kernie, S. hippocampus, neurotrophic factors Min, J. A., Jung, Y. E., Kim, D. J., Yim,
576–584. G., et al. (2008). TrkB regulates hip- and depression: possible implica- H. W., Kim, J. J., Kim, T. S., et al.
Karg, K., Burmeister, M., Shedden, pocampal neurogenesis and governs tions for the pharmacotherapy of (2012). Characteristics associated
K., and Sen, S. (2011). The sero- sensitivity to antidepressive treat- depression. CNS Drugs 25, 913–931. with low resilience in patients with
tonin transporter promoter variant ment. Neuron 59, 399–412. Masten, A. S. (2001). Ordinary magic. depression and/or anxiety disorders.
(5-HTTLPR), stress, and depres- Liu, I. Y., Lyons, W. E., Mamounas, Resilience processes in develop- Qual. Life Res. doi: 10.1007/s11136-
sion meta-analysis revisited: evi- L. A., and Thompson, R. F. (2004). ment. Am. Psychol. 56, 227–238. 012-0153-3. [Epub ahead of print].
dence of genetic moderation. Arch. Brain-derived neurotrophic factor Mathew, S. J., Shah, A., Lapidus, K., Monk, C. S., Klein, R. G., Telzer, E.
Gen. Psychiatry 68, 444–454. plays a critical role in contextual Clark, C., Jarun, N., Ostermeyer, H., Schroth, E. A., Mannuzza,
Karreman, A., and Vingerhoets, J. J. M. fear conditioning. J. Neurosci. 24, B., et al. (2012). Ketamine for S., Moulton, J. L., et al. (2008).
(2012). Attachment and well-being: 7958–7963. treatment-resistant unipolar Amygdala and nucleus accumbens

Frontiers in Behavioral Neuroscience www.frontiersin.org February 2013 | Volume 7 | Article 10 | 13


Wu et al. Neurobiology of resilience and implications for promoting resilience

activation to emotional facial anxiety, DHEAS, and cortisol: from a genetic rat depression model. fear conditioning. J. Neurosci. 24,
expressions in children and adoles- the MIPH Industrial Cohort Studies Neurosci. Lett. 451, 148–151. 4796–4806.
cents at risk for major depression. (MICS). Psychoneuroendocrinology Pietrzak, R. H., Johnson, D. C., Rende, R. (2012). Behavioral resilience
Am. J. Psychiatry 165, 90–98. 37, 929–936. Goldstein, M. B., Malley, J. C., in the post-genomic era: emerging
Moos, R. H., and Schaefer, J. A. (1993). Onur, O. A., Walter, H., Schlaepfer, Rivers, A. J., Morgan, C. A., et al. models linking genes with environ-
“Coping resources and processes: T. E., Rehme, A. K., Schmidt, (2010). Psychosocial buffers of trau- ment. Front. Hum. Neurosci. 6:50.
current concepts and measures,” in C., Keysers, C., et al. (2009). matic stress, depressive symptoms, doi: 10.3389/fnhum.2012.00050
Handbook of Stress, 2nd Edn. eds Noradrenergic enhancement of and psychosocial difficulties in Richardson, G. E. (2002). The metathe-
L. Goldberger and S. Breznitz (New amygdala responses to fear. Soc. veterans of Operations Enduring ory of resilience and resiliency.
York, NY: The Free Press), 234–257. Cogn. Affect. Neurosci. 4, 119–126. Freedom and Iraqi Freedom: the J. Clin. Psychol. 58, 307–321.
Morgan, C. A. 3rd., Rasmusson, A. Otte, C., Neylan, T. C., Pole, N., role of resilience, unit support, and Rusiecki, J. A., Chen, L., Srikantan, V.,
M., Wang, S., Hoyt, G., Hauger, Metzler, T., Best, S., Henn-Haase, postdeployment social support. Zhang, L., Yan, L., Polin, M. L., et al.
R. L., and Hazlett, G. (2002). C., et al. (2005). Association J. Affect. Disord. 120, 188–192. (2012). DNA methylation in repet-
Neuropeptide-Y, cortisol, and sub- between childhood trauma and Pizzagalli, D. A., Holmes, A. J., Dillon, itive elements and post-traumatic
jective distress in humans exposed catecholamine response to psy- D. G., Goetz, E. L., Birk, J. L., stress disorder: a case-control study
to acute stress: replication and chological stress in police academy Bogdan, R., et al. (2009). Reduced of US military service members.
extension of previous report. Biol. recruits. Biol. Psychiatry 57, 27–32. caudate and nucleus accumbens Epigenomics 4, 29–40.
Psychiatry 52, 136–142. Overmier, J. B., and Seligman, M. E. response to rewards in unmedicated Russo, S. J., Murrough, J. W., Han, M.
Morgan, C. A. 3rd., Southwick, S., (1967). Effects of inescapable shock individuals with major depressive H., Charney, D. S., and Nestler, E. J.
Hazlett, G., Rasmusson, A., Hoyt, upon subsequent escape and avoid- disorder. Am. J. Psychiatry 166, (2012). Neurobiology of resilience.
G., Zimolo, Z., et al. (2004). ance responding. J. Comp. Physiol. 702–710. Nat. Neurosci. 15, 1475–1484.
Relationships among plasma dehy- Psychol. 63, 28–33. Poulter, M. O., Du, L., Weaver, I. C., Rutter, M. (1993). Resilience: some
droepiandrosterone sulfate and Ozbay, F., Fitterling, H., Charney, D., Palkovits, M., Faludi, G., Merali, Z., conceptual considerations.
cortisol levels, symptoms of disso- and Southwick, S. (2008). Social et al. (2008). GABAA receptor pro- J. Adolesc. Health 14, 626–631,
ciation, and objective performance support and resilience to stress moter hypermethylation in suicide 690–696.
in humans exposed to acute stress. across the life span: a neurobiologic brain: implications for the involve- Rutter, M. (2012a). Annual research
Arch. Gen. Psychiatry 61, 819–825. framework. Curr. Psychiatry Rep. 10, ment of epigenetic processes. Biol. review: resilience: clinical
Morgan, C. A. 3rd., Wang, S., 304–310. Psychiatry 64, 645–652. implications. J. Child Psychol.
Southwick, S. M., Rasmusson, Paez-Pereda, M., Hausch, F., and Price, L. H., Kao, H. T., Burgers, D. Psychiatry. doi: 10.1111/j.1469-
A., Hazlett, G., Hauger, R. L., et al. Holsboer, F. (2011). Corticotropin E., Carpenter, L. L., and Tyrka, A. 7610.2012.02615.x. [Epub ahead of
(2000). Plasma neuropeptide-Y releasing factor receptor antagonists R. (2013). Telomeres and early-life print].
concentrations in humans exposed for major depressive disorder. stress: an overview. Biol. Psychiatry Rutter, M. (2012b). Resilience
to military survival training. Biol. Expert Opin. Investig. Drugs 20, 73, 15–23. as a dynamic concept. Dev.
Psychiatry 47, 902–909. 519–535. Ptacek, R., Kuzelova, H., and Stefano, Psychopathol. 24, 335–344.
Morishima, Y., Schunk, D., Bruhin, A., Parker, K. J., Buckmaster, C. L., Justus, G. B. (2011). Dopamine D4 Sah, R., and Geracioti, T. D. (2012).
Ruff, C. C., and Fehr, E. (2012). K. R., Schatzberg, A. F., and Lyons, receptor gene DRD4 and its Neuropeptide Y and posttraumatic
Linking brain structure and activa- D. M. (2005). Mild early life stress association with psychiatric dis- stress disorder. Mol. Psychiatry. doi:
tion in temporoparietal junction to enhances prefrontal-dependent orders. Med. Sci. Monit. 17, 10.1038/mp.2012.101. [Epub ahead
explain the neurobiology of human response inhibition in monkeys. RA215–RA220. of print].
altruism. Neuron 75, 73–79. Biol. Psychiatry 57, 848–855. Quirk, G. J., and Mueller, D. (2008). Sah, R., Ekhator, N. N., Strawn, J. R.,
Murgatroyd, C., and Spengler, D. Parker, K. J., Buckmaster, C. L., Neural mechanisms of extinc- Sallee, F. R., Baker, D. G., Horn, P.
(2012). Genetic variation in the Schatzberg, A. F., and Lyons, D. M. tion learning and retrieval. S., et al. (2009). Low cerebrospinal
epigenetic machinery and mental (2004). Prospective investigation Neuropsychopharmacology 33, fluid neuropeptide Y concentra-
health. Curr. Psychiatry Rep. 14, of stress inoculation in young 56–72. tions in posttraumatic stress disor-
138–149. monkeys. Arch. Gen. Psychiatry 61, Radley, J. J., Kabbaj, M., Jacobson, L., der. Biol. Psychiatry 66, 705–707.
Murrough, J. W., and Charney, D. S. 933–941. Heydendael, W., Yehuda, R., and Sailer, U., Robinson, S., Fischmeister,
(2010). Cracking the moody brain: Paul, N. A., Stanton, S. J., Greeson, Herman, J. P. (2011). Stress risk F. P., Konig, D., Oppenauer, C.,
lifting the mood with ketamine. J. M., Smoski, M. J., and Wang, factors and stress-related pathol- Lueger-Schuster, B., et al. (2008).
Nat. Med. 16, 1384–1385. L. (2013). Psychological and neu- ogy: neuroplasticity, epigenetics Altered reward processing in the
Nemeroff, C. B., and Vale, W. W. ral mechanisms of trait mindfulness and endophenotypes. Stress 14, nucleus accumbens and mesial
(2005). The neurobiology of depres- in reducing depression vulnerabil- 481–497. prefrontal cortex of patients with
sion: inroads to treatment and new ity. Soc. Cogn. Affect. Neurosci. 8, Rakofsky, J. J., Ressler, K. J., and posttraumatic stress disorder.
drug discovery. J. Clin. Psychiatry 56–64. Dunlop, B. W. (2012). BDNF func- Neuropsychologia 46, 2836–2844.
66(Suppl. 7), 5–13. Pei, L., Li, S., Wang, M., Diwan, M., tion as a potential mediator of Sajdyk, T. J., Shekhar, A., and Gehlert,
Nestler, E. J., and Carlezon, W. A. Jr. Anisman, H., Fletcher, P. J., et al. bipolar disorder and post-traumatic D. R. (2004). Interactions between
(2006). The mesolimbic dopamine (2010). Uncoupling the dopamine stress disorder comorbidity. Mol. NPY and CRF in the amyg-
reward circuit in depression. Biol. D1-D2 receptor complex exerts Psychiatry 17, 22–35. dala to regulate emotionality.
Psychiatry 59, 1151–1159. antidepressant-like effects. Nat. Rasmusson, A. M., Schnurr, P. P., Neuropeptides 38, 225–234.
Numakawa, T., Suzuki, S., Kumamaru, Med. 16, 1393–1395. Zukowska, Z., Scioli, E., and Sanacora, G., Treccani, G., and Popoli,
E., Adachi, N., Richards, M., and Peters, J., Dieppa-Perea, L. M., Forman, D. E. (2010). Adaptation M. (2012). Towards a gluta-
Kunugi, H. (2010). BDNF func- Melendez, L. M., and Quirk, G. to extreme stress: post-traumatic mate hypothesis of depression:
tion and intracellular signaling in J. (2010). Induction of fear extinc- stress disorder, neuropeptide Y and an emerging frontier of neu-
neurons. Histol. Histopathol. 25, tion with hippocampal-infralimbic metabolic syndrome. Exp. Biol. ropsychopharmacology for mood
237–258. BDNF. Science 328, 1288–1290. Med. (Maywood) 235, 1150–1162. disorders. Neuropharmacology 62,
ó Hartaigh, B., Loerbroks, A., Thomas, Petersen, A., Wortwein, G., Gruber, S. Rattiner, L. M., Davis, M., French, C. 63–77.
G. N., Engeland, C. G., Hollands, H., El-Khoury, A., and Mathe, A. T., and Ressler, K. J. (2004). Brain- Sapienza, J. K., and Masten, A. S.
M. A., Fischer, J. E., et al. (2012). A. (2009). Nortriptyline mediates derived neurotrophic factor and (2011). Understanding and promot-
Age-dependent and -independent behavioral effects without affect- tyrosine kinase receptor B involve- ing resilience in children and youth.
associations between depression, ing hippocampal cytogenesis in ment in amygdala-dependent Curr. Opin. Psychiatry 24, 267–273.

Frontiers in Behavioral Neuroscience www.frontiersin.org February 2013 | Volume 7 | Article 10 | 14


Wu et al. Neurobiology of resilience and implications for promoting resilience

Scheier, M. F., Matthews, K. A., Owens, Staub, E., and Vollhardt, J. (2008). signatures of MAN2C1 are associ- populations. Arch. Gen. Psychiatry
J. F., Magovern, G. J. Sr., Lefebvre, Altruism born of suffering: the roots ated with PTSD. Dis. Markers 30, 66, 1201–1209.
R. C., Abbott, R. A., et al. (1989). of caring and helping after victim- 111–121. Yamada, K., and Nabeshima, T. (2003).
Dispositional optimism and recov- ization and other trauma. Am. J. Vaillant, G. E. (1992). The histor- Brain-derived neurotrophic fac-
ery from coronary artery bypass Orthopsychiatry 78, 267–280. ical origins and future potential tor/TrkB signaling in memory
surgery: the beneficial effects on Stewart, D. E., and Yuen, T. (2011). of Sigmund Freud’s concept of processes. J. Pharmacol. Sci. 91,
physical and psychological well- A systematic review of resilience in the mechanisms of defence. Int. J. 267–270.
being. J. Pers. Soc. Psychol. 57, the physically ill. Psychosomatics 52, Psychoanal. 19, 35–50. Yehuda, R., Brand, S., and Yang, R.
1024–1040. 199–209. Vythilingam, M., Nelson, E. E., K. (2006). Plasma neuropeptide Y
Schlaepfer, T. E., Cohen, M. X., Strawn, J. R., and Geracioti, T. D. Scaramozza, M., Waldeck, T., concentrations in combat exposed
Frick, C., Kosel, M., Brodesser, Jr. (2008). Noradrenergic dysfunc- Hazlett, G., Southwick, S. M., veterans: relationship to trauma
D., Axmacher, N., et al. (2008). tion and the psychopharmacology et al. (2009). Reward circuitry in exposure, recovery from PTSD, and
Deep brain stimulation to reward of posttraumatic stress disorder. resilience to severe trauma: an fMRI coping. Biol. Psychiatry 59, 660–663.
circuitry alleviates anhedonia Depress. Anxiety 25, 260–271. investigation of resilient special Zhang, K., Rao, F., Pablo Miramontes-
in refractory major depression. Strome, E. M., Wheler, G. H., forces soldiers. Psychiatry Res. 172, Gonzalez, J., Hightower, C. M.,
Neuropsychopharmacology 33, Higley, J. D., Loriaux, D. L., 75–77. Vaught, B., Chen, Y., et al. (2012).
368–377. Suomi, S. J., and Doudet, D. J. Warner, L. M., Schwarzer, R., Schuz, Neuropeptide, Y (NPY): genetic
Schmidt, U., Holsboer, F., and Rein, (2002). Intracerebroventricular B., Wurm, S., and Tesch-Romer, variation in the human promoter
T. (2011). Epigenetic aspects of corticotropin-releasing factor C. (2012). Health-specific optimism alters glucocorticoid signaling,
posttraumatic stress disorder. Dis. increases limbic glucose metabolism mediates between objective and per- yielding increased NPY secretion
Markers 30, 77–87. and has social context-dependent ceived physical functioning in older and stress responses. J. Am. Coll.
Segman, R. H., Cooper-Kazaz, R., behavioral effects in nonhuman adults. J. Behav. Med. 35, 400–406. Cardiol. 60, 1678–1689.
Macciardi, F., Goltser, T., Halfon, primates. Proc. Natl. Acad. Sci. Weaver, I. C., Cervoni, N., Champagne, Zhou, Z., Zhu, G., Hariri, A. R.,
Y., Dobroborski, T., et al. (2002). U.S.A. 99, 15749–15754. F. A., D’Alessio, A. C., Sharma, S., Enoch, M. A., Scott, D., Sinha,
Association between the dopamine Sun, H., Kennedy, P. J., and Nestler, Seckl, J. R., et al. (2004). Epigenetic R., et al. (2008). Genetic variation
transporter gene and posttraumatic E. J. (2013). Epigenetics of the programming by maternal behavior. in human NPY expression affects
stress disorder. Mol. Psychiatry 7, depressed brain: role of histone Nat. Neurosci. 7, 847–854. stress response and emotion. Nature
903–907. acetylation and methylation. Werner, E. E. (2012). Children and war: 452, 997–1001.
Seligman, M. E., and Maier, S. F. (1967). Neuropsychopharmacology 38, risk, resilience, and recovery. Dev. Zimmerman, J. M., and Maren, S.
Failure to escape traumatic shock. 124–137. Psychopathol. 24, 553–558. (2010). NMDA receptor antago-
J. Exp. Psychol. 74, 1–9. Taliaz, D., Loya, A., Gersner, R., Wethington, H. R., Hahn, R. A., nism in the basolateral but not
Shin, L. M., and Liberzon, I. (2010). Haramati, S., Chen, A., and Zangen, Fuqua-Whitley, D. S., Sipe, T. A., central amygdala blocks the extinc-
The neurocircuitry of fear, stress, A. (2011). Resilience to chronic Crosby, A. E., Johnson, R. L., et al. tion of Pavlovian fear condition-
and anxiety disorders. Neuro- stress is mediated by hippocampal (2008). The effectiveness of inter- ing in rats. Eur. J. Neurosci. 31,
psychopharmacology 35, 169–191. brain-derived neurotrophic factor. ventions to reduce psychological 1664–1670.
Skelton, K., Ressler, K. J., Norrholm, J. Neurosci. 31, 4475–4483. harm from traumatic events among Zimmermann, P., Bruckl, T., Nocon,
S. D., Jovanovic, T., and Bradley- Taylor, S. E., and Stanton, A. L. (2007). children and adolescents: a system- A., Pfister, H., Binder, E. B., Uhr, M.,
Davino, B. (2012). PTSD and gene Coping resources, coping processes, atic review. Am. J. Prev. Med. 35, et al. (2011). Interaction of FKBP5
variants: new pathways and new and mental health. Annu. Rev. Clin. 287–313. gene variants and adverse life events
thinking. Neuropharmacology 62, Psychol. 3, 377–401. Winter, B., Breitenstein, C., Mooren, in predicting depression onset:
628–637. Thompson, R. W., Arnkoff, D. B., and F. C., Voelker, K., Fobker, M., results from a 10-year prospective
Smith, B. W., Ortiz, J. A., Steffen, Glass, C. R. (2011). Conceptualizing Lechtermann, A., et al. (2007). High community study. Am. J. Psychiatry
L. E., Tooley, E. M., Wiggins, K. mindfulness and acceptance as com- impact running improves learn- 168, 1107–1116.
T., Yeater, E. A., et al. (2011). ponents of psychological resilience ing. Neurobiol. Learn. Mem. 87,
Mindfulness is associated with to trauma. Trauma. Violence Abuse 597–609. Conflict of Interest Statement: The
fewer PTSD symptoms, depressive 12, 220–235. Wittert, G. A., Livesey, J. H., Espiner, authors declare that the research
symptoms, physical symptoms, Troy, A. S., Wilhelm, F. H., Shallcross, E. A., and Donald, R. A. (1996). was conducted in the absence of any
and alcohol problems in urban A. J., and Mauss, I. B. (2010). Adaptation of the hypothalamopi- commercial or financial relationships
firefighters. J. Consult. Clin. Psychol. Seeing the silver lining: cogni- tuitary adrenal axis to chronic exer- that could be construed as a potential
79, 613–617. tive reappraisal ability moderates cise stress in humans. Med. Sci. conflict of interest.
Snow-Turek, A. L., Norris, M. P., and the relationship between stress and Sports Exerc. 28, 1015–1019.
Tan, G. (1996). Active and passive depressive symptoms. Emotion 10, Wong, A. H., and Liu, F. (2012). Received: 17 December 2012; accepted:
coping strategies in chronic pain 783–795. Uncoupling the dopamine D1-D2 30 January 2013; published online: 15
patients. Pain 64, 455–462. Tsai, J., Harpaz-Rotem, I., Pietrzak, R. receptor complex: a novel target February 2013.
Solomon, Z., Karni, G., Yuval, N., and H., and Southwick, S. M. (2012). for antidepressant treatment. Clin. Citation: Wu G, Feder A, Cohen H, Kim
Abraham, O. (1995). Coping with The role of coping, resilience, and Pharmacol. Ther. 91, 298–302. JJ, Calderon S, Charney DS and Mathé
war captivity: the role of sensation social support in mediating the rela- Wu, G., Feder, A., Wegener, G., Bailey, AA (2013) Understanding resilience.
seeking. Eur. J. Pers. 9, 57–70. tion between PTSD and social func- C., Saxena, S., Charney, D., et al. Front. Behav. Neurosci. 7:10. doi:
Southwick, S. M., and Charney, D. S. tioning in veterans returning from (2011). Central functions of neu- 10.3389/fnbeh.2013.00010
(2012). The science of resilience: Iraq and Afghanistan. Psychiatry 75, ropeptide Y in mood and anxiety Copyright © 2013 Wu, Feder, Cohen,
implications for the prevention and 135–149. disorders. Expert Opin. Ther. Targets Kim, Calderon, Charney and Mathé.
treatment of depression. Science Tsankova, N., Renthal, W., Kumar, A., 15, 1317–1331. This is an open-access article dis-
338, 79–82. and Nestler, E. J. (2007). Epigenetic Xie, P., Kranzler, H. R., Poling, J., tributed under the terms of the Creative
Southwick, S. M., Vythilingam, M., regulation in psychiatric disorders. Stein, M. B., Anton, R. F., Brady, Commons Attribution License, which
and Charney, D. S. (2005). The Nat. Rev. Neurosci. 8, 355–367. K., et al. (2009). Interactive effect permits use, distribution and reproduc-
psychobiology of depression and Uddin, M., Galea, S., Chang, S. C., of stressful life events and the tion in other forums, provided the origi-
resilience to stress: implications for Aiello, A. E., Wildman, D. E., serotonin transporter 5-HTTLPR nal authors and source are credited and
prevention and treatment. Annu. De Los Santos, R., et al. (2011). genotype on posttraumatic stress subject to any copyright notices concern-
Rev. Clin. Psychol. 1, 255–291. Gene expression and methylation disorder diagnosis in 2 independent ing any third-party graphics etc.

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