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Behavioral Medicine

ISSN: 0896-4289 (Print) 1940-4026 (Online) Journal homepage: http://www.tandfonline.com/loi/vbmd20

Adapting to Stress: Understanding the


Neurobiology of Resilience

Carlos Osrio, Thomas Probert, Edgar Jones, Allan H. Young & Ian Robbins

To cite this article: Carlos Osrio, Thomas Probert, Edgar Jones, Allan H. Young & Ian Robbins
(2016): Adapting to Stress: Understanding the Neurobiology of Resilience, Behavioral Medicine,
DOI: 10.1080/08964289.2016.1170661

To link to this article: http://dx.doi.org/10.1080/08964289.2016.1170661

Accepted author version posted online: 21


Apr 2016.
Published online: 21 Apr 2016.

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BEHAVIORAL MEDICINE
2016, VOL. 0, NO. 0, 116
http://dx.doi.org/10.1080/08964289.2016.1170661

Adapting to Stress: Understanding the Neurobiology of Resilience


rio, Thomas Probert, Edgar Jones, Allan H. Young, and Ian Robbins
Carlos Oso
Kings College London

ABSTRACT KEYWORDS
There is signicant variation in the way individuals react and respond to extreme stress and adversity. biological markers;
While some individuals develop psychiatric conditions such as posttraumatic stress disorder or major depression; PTSD; resilience;
depressive disorder, others recover from stressful experiences without displaying signicant symptoms of uncontrollable stress;
psychological ill-health, demonstrating stress-resilience. To understand why some individuals exhibit
characteristics of a resilient prole, the interplay between neurochemical, genetic, and epigenetic
processes over time needs to be explained. In this review, we examine the hormones, neuropeptides,
neurotransmitters, and neural circuits associated with resilience and vulnerability to stress-related
disorders. We debate how this increasing body of knowledge could also be useful in the creation of a
stress-resilient prole. Additionally, identication of the underlying neurobiological components related to
resilience may offer a contribution to improved approaches toward the prevention and treatment of
stress-related disorders.

Introduction
sympathetic nervous system (SNS), hypothalamic-pituitary-
Stress can be dened as a physiological and psychological adrenal (HPA) axis hormones, cytokines, and a number of
reaction of the body toward an event or situation, com- other systems.10,11
monly termed a stressor. The given stressor can be per- A physiological response to environmental stressors is
ceived broadly as either challenging or threatening.13 of evolutionary advantage as a function of the acute
Challenges that are perceived as exhilarating, while at the stress response, more commonly known as the ght-or-
same time being manageable, are normally classied as ight mechanism.12 However, if recovery is not accom-
positive and benecial to the individual, leading to panied by an adequate homeostatic response, the initial
accomplishment. However, threatening experiences, response could ultimately result in harmful after
which are perceived as irritating or imposing signicant effects.13 The prevailing effects of stress have been con-
danger, may result in short-term or long-term physiolog- ceptualized as the allostatic load, which represents the
ical and psychological ill health.4,5 physiological and psychological consequences of
The brain is the central organ responsible for the repeated chronic exposure to heightened neuroendocrine
stress response. It processes perceptual information for responses. In turn, the cumulative effect of these
potential threats and initiates a response. Second, it regu- responses can result in psychopathological conditions
lates the physiological and/or psychological responses such as posttraumatic stress disorder (PTSD) and major
that can either be adaptive or damaging to the individ- depressive disorder (MDD), among others.14,15
ual.4 Further, the brain is responsible for establishing a By examining how humans and animals adapt to
two-way communication between itself and the immune highly aversive environments, researchers have recently
and cardiovascular systems via endocrine and neural identied some of the neural, neurochemical, genetic,
mechanisms during the stress response.4,6 and epigenetic components that may characterize vul-
The adaptive physiological response to acute stress com- nerability, and conversely resilience, in individual
prises a process known as allostasis. This process performs responses.1618 This article assesses the role of these fac-
the function of maintaining the internal viability of the tors in relation to individuals who appear to show resil-
organism amid changing environmental conditions.79 In ience in the face of extreme or repeated traumatic
the short term, this is achieved by physiological changes in stressors. This review had three main objectives. First, to
the autonomic nervous system (ANS) through the understand the dynamic concept of stress and resilience

CONTACT Carlos Osorio carlos.m.osorio81@gmail.com Academic Department of Psychological Medicine; Institute of Psychiatry, Psychology and Neuro-
science, Kings College London, Weston Education Centre, 10 Cutcombe Road, SE5 9RJ, United Kingdom.
2016 Taylor & Francis Group, LLC
2 
C. OSORIO ET AL.

and what differentiates a resilient from a nonresilient condition but rather a constructive adaptation to adver-
individual; second, to identify the neurochemicals, sity and traumatic experience.19,22
genetic, and epigenetic mechanisms hypothesized as a The characterization of resilience is still difcult to
basis of resilience or vulnerability to a stress-related dis- conceptualize and operationalize, as it represents many
order. Third, to understand whether the ability to cope forms of successful adaptive biological, behavioral, and
with high levels of stress are inborn, inherited, and/or cognitive responses to traumatic events.21,23 As individu-
acquired through specic training (e.g., through a stress als exhibit a pattern of recuperation from life-threatening
inoculation process) or some combination of the previ- experiences, researchers have sometimes used the con-
ous. A comprehensive review of the current research and cept of resilience inappropriately. For example, other
introduction to the physical processes associated with adaptive responses to traumatic experiences such as
resilience is of interest and importance to the medical recovery from trauma can also be observed. The concept
community. of recovery from trauma indicates a trajectory in which
The literature search was conducted between February normal functioning temporarily gives way to a disrup-
2014 and June 2014. Relevant studies published in peer- tion through the manifestation of signicant psychiatric
reviewed journals were identied through electronic symptoms for a period of several months, followed by a
searches on PubMed, Web of Science, Embase, and Psy- slow but yet signicant recovery over months to levels of
cINFO databases. Key search terms to identify title and/or functioning prior to trauma.19,24 Therefore, while both
abstract included words such as stress OR resilience OR these responses are similar in the long-term, only the
adaptation OR allostasis OR allostatic load OR resilient ones exhibit a stable trajectory of healthy func-
PTSD OR depression combined with physiology OR tioning over time.19,24 In this review, we will only charac-
psychopathology OR neurochemistry OR neuropep- terize the biological stress responses known to be linked
tide OR neurotransmitters OR hormones OR neuro- with resilient phenotypes and how their enhanced neuro-
biological factors OR endocrine system OR sympathetic biological response is processed.
nervous system OR hypothalamic-pituitary-adrenal axis
OR central nervous system OR genes OR genetic OR
genetic variation OR epigenetic OR psychiatric disor- Neurochemical, genetic, epigenetic factors in
ders OR toxic. stress resilience
Neurochemical factors in stress resilience

Understanding resilience to stress A signicant number of neurochemicals (e.g., neuropepti-


des, hormones, and neurotransmitters) are involved in
Concept of resilience the acute psychobiological response to stress. These
Resilience is the dynamic process through which an indi- neurochemicals have been investigated in relation to
vidual can adaptively overcome a stressful and/or trau- stress resilience, and conversely, to the risk of psychopa-
matic event(s), while maintaining relatively normal thology.10,16 According to several studies, these neuro-
physical and psychological function over time.1921 Addi- chemicals have been shown to be signicantly altered by
tionally, resilience is referred to as a two-dimensional stress and to perform an important functional interaction
construct. This implies that when an individual has been in the brain, by mediating the neural circuits and molecu-
subject to a stressor (such as exposure to a life-threatening lar pathways relevant to cognitive functioning, fear condi-
event), the experience has led to a positive adjustment. As tioning, regulation of reward, and social behavior.10,17 So
such, this bi-dimensional construct implies two evalua- far, some of the neurochemical components linked to
tions. The rst is about the signicance of risk or adversity stress resilience include constituents of the SNS, for exam-
associated with negative life conditions, and the second is ple norepinephrine (NE) and neuropeptide-Y (NPY) or
about how a positive adaptation is displayed through galanin, from the HPA Axis, corticotropin-releasing hor-
behavior on social competence or success at that specic mone (CRH), cortisol, dehydroepiandrosterone (DHEA),
life stage.22 In this context, individuals classied as stress and from other systems including the dopaminergic,
resilient are normally dened as exhibiting an enhanced serotonergic systems, brain-derived neurotropic factor
capacity of avoiding deleterious physiological and psy- (BDNF), or neurosteroidogenic enzymes.10,18,25
chological consequences as a result of exposure to
extreme stress, which could otherwise result in serious Sympathetic nervous system (SNS)
stress-related psychiatric disorders, such as PTSD or Under circumstances of potential danger, the human and
MDD.16,20 It is important to mention that resilience is not animal SNS will release neurochemical components such
conceptualized as the absence of a diagnosable psychiatric as epinephrine, the hormone responsible for the ght-
BEHAVIORAL MEDICINE 3

or-ight response, and NE in order to protect the organ- humans.29,3234 For example, studies with small rodents
ism from the perceived threat. However, danger response presenting PTSD-like behavior exhibit a signicant down-
varies from one individual to the other, and therefore regulation of NPY in various areas of the brain, particularly
stress responses can vary signicantly.12,26 the hippocampus and amygdala. Additionally, centrally
In cases where individuals exhibit an unusual hyper- administered NPY doses in these small rodents showed a
sensitive SNS response to stress, they can be subject to a reverse in these negative behaviors (such as lower predator-
higher risk of chronic anxiety, intrusive memories, fear, scent stress).35 Studies conducted on military personnel
hypervigilance, and in some cases be diagnosed as having participating in particularly stressful training, known as
PTSD.27 It is also recognized that the maintenance of an Survival, Evasion, Resistance, and Escape (SERE), com-
SNS response within a certain level of activation (not so pared highly resilient members of the US Special Forces
high to result in psychiatric symptoms however) has with their regular infantry counterparts. The Special Forces
been observed in highly resilient individual.28,29 participants were shown to produce higher concentrations
of NPY and exhibit an enhanced physical and psychologi-
Norepinephrine (NE). NE is a catecholamine present cal performance, followed by a reduced vulnerability to
within cells of the central (CNS) and peripheral nervous stress-induced anxiety and dissociation. These robust
system (PNS) and is known to work as a neurotransmit- increases of NE in the US Special Forces personnel were
ter during the stress response.27 NE is particularly noted followed by similar robust increases in the levels of
for its function in cognitive alertness and vigilant con- NPY.29,34
centration in individuals under stress.27 Under stressful In support of the importance of NPY as a mediating
circumstances, the organism will release NE from the factor in the stress response, one study compared a
brainstem nuclei and locus coeruleus. In turn, NE modu- healthy civilian control group to a group of military vet-
lates the ght-or-ight response along with epinephrine erans diagnosed as having PTSD. In a study comprised
by immediately increasing its heart rate, pressing the lib- of a rest stage and a stress stage, the ndings revealed
eration of glucose from energy stores and so increasing that the veteran group displayed lower levels of NPY in
blood stream-to-skeletal muscle and brain oxygen sup- each phase.36 Studies of veterans with PTSD showed that
ply.30 A higher activation of the NE system is known for they exhibited a signicant increase in NE levels, which
inhibiting functions in the prefrontal cortex, and there- was not positively accompanied by a signicant increase
fore promoting instinctual responses over more complex in their NPY levels. It is hypothesized that this main-
cognitive responses.30 tained symptoms of anxiety, hypervigilance, and intru-
Clinical evidence suggests that abnormal regulation of sive combat-related memories.27,36 Additionally, other
brain NE systems is observed in patients with PTSD, clinical studies have also shown that decreased concen-
through symptoms such as re-experiencing, hyper- trations of NPY in plasma and cerebrospinal uid were
arousal, tachycardia, increased diastolic blood pressure, observed in individuals with PTSD and MDD.37,38
and diaphoresis.27 However, studies that evaluated the In view of the current evidence, NPY can be seen as a
blockade of b-adrenergic receptors in the amygdala were novel molecular therapeutic target aimed to ameliorate
thought to ameliorate the development of aversive mem- and/or treat symptoms of PTSD. Indeed, a recent study
ories in human and animal studies.13,31 Thus, based on examining the properties of intranasal NPY in a single
these ndings, some authors suggested that a reduced prolonged stress animal model of PTSD showed reduc-
responsiveness of NE could be linked with resilience to ing anxiety-like behaviors, particularly when adminis-
stress.17 tered before the stress task.39 In term of human studies,
we are only aware of one approved by the US National
Neuropeptide-Y (NPY). NPY is a 36-amino acid neuro- Institutes of Health to investigate the safety and efcacy
peptide highly expressed in the mammalian brain and of intranasal NPY administration to individuals suffering
known to act as a neurotransmitter. It is produced in sev- from PTSD. At the time of writing this review the study
eral areas of the brain, such as the hypothalamus, and is was in the recruitment phase and as such results were
believed to have several important functions, including not available for inclusion.40
reducing anxiety, stress, pain perception, circadian
rhythms, and lowering blood pressure.27,32 Normally, NPY Galanin. Galanin is a 30-amino acid neuropeptide exis-
is released with NE when the SNS is highly activated. One tent in humans and encoded by the GAL gene, which is
of its main functions is to restrain the ongoing release of extensively expressed in the brain, and is known to have
NE and to prevent SNS overshoots.27,32 Numerous studies a signicant effect in the SNS response. While the func-
have proved the valuable function of NPY in mediating tional role of galanin is still vastly unknown, this neuro-
resilience and vulnerability to stress in both animals and peptide appears to have some neuroprotective activity in
4 
C. OSORIO ET AL.

the PNS and in the promotion of neurogenesis.41,42 Gala- synthesis of two steroid hormones, cortisol and DHEA, into
nin is known to have an effect on the cardiovascular and their stress response.52
sleep regulation, anxiety response, learning skills, mem- In several human and animal studies, resilience has
ory, and pain response control.43 Further to this, galanin been associated with the brains ability to moderate
is also known to be an inhibitory hyperpolarizing neuro- stress-induced increases in CRH and cortisol. This oper-
peptide, like NPY.44 ation occurs through an elaborate negative feedback sys-
A signicantly high percentage, approximately 80%, tem, which involves an optimal functioning and
of noradrenergic neurons located in the locus coeruleus equilibrium of mineralocorticoid and glucocorticoid
(situated in the nucleus of the pons) are involved in the receptors.53,54
physiological response to stress and panic and co-express
galanin.10,45 Galanin is normally released when NE is Corticotropin-releasing hormone (CRH). CRH is a 41-
highly activated. Consequently, its activity reduces the amino acid peptide hormone and neurotransmitter
ring action of the locus coeruleus.45,46 In rodent behav- encoded by the CRH gene and is known to play an
ioral studies, centrally administered galanin has been important role in the acute stress response. Particularly
known to modulate anxiety-like behaviors and when in increased arousal, motor activity and reduced reward
injected directly into the central nucleus of the amygdala; expectations and activated fear behaviors.55 CRH acts via
it was shown to block the negative effects of stress.47,48 the two receptors (CRH-1 and CRH-2), which are nor-
These ndings suggest that the noradrenergic response mally secreted by the paraventricular nucleus of the
to stress leads to the release of galanin into the central hypothalamus in response to stress.56 Studies that evalu-
nucleus of the amygdala as a protection against the anx- ated different concentration levels found that increased
iogenic effects of NE.10 Conversely, researchers who CRH concentrations have been associated with PTSD,
studied knockout mice galanin receptors found that MDD, and symptoms of fear and anxiety.5759 Con-
these animals showed increased anxiety-like behavior, versely, those individuals who displayed reduced CRH
leading to an augmented vulnerability to anxiety and iso- concentrations were normally found be to resilient
lation.11 According to these ndings, the response to individuals.10
stress noradrenergic response may be contingent on a CRH-1 and CRH-2 receptors are spread in the differ-
balance established between NE, NPY, and galanin ent areas of the brain. CRH-1 receptor is normally found
transmission.10 in the hippocampus, basolateral amygdala, and neocor-
Novel approaches to evaluate the enhanced therapeu- tex, while CRH-2 receptor is normally found in the dor-
tic characteristics of galanin are currently underway. For sal raphe, medial, and cortical nuclei of the amygdala
example, a study that evaluated small rodents exposed to and lateral septum.60 The CRH-1 signaling is known to
different sets of experiences and stress tasks revealed that play a role in the anxiogenic circuit and leads to anxiety-
both physical exercise and galanin therapy rodent groups like responses, while the CRH-2 controls the effects of
exhibit decreased anxiety-like behaviors, while the group CRH-1 signaling, and can either be anxiogenic or anxio-
of rodents deprived of exercise exhibit increased anxiety- lytic.6163 In rodent studies where they exhibited a de-
like behaviors. According to the authors, both physical ciency in the CRH-1 receptor, the animals displayed a
exercise and galanin therapy groups demonstrated reduced anxiety-like behavior and a diminished stress
increased levels of galanin.49 response. However, animals that exhibited a deciency
in the CRH-2 receptor showed augmented anxiety like-
Hypothalamic-pituitary-adrenal (HPA) axis behaviors and were hypersensitive to stress.6466. Accord-
A complex set of brain interactions between the hypothala- ing to these ndings, the triggering of the CRH-1 recep-
mus, the pituitary gland, and the adrenal gland known as tors are potentially linked with anxiety-like responses,
HPA axis play a crucial role in the human and animal stress while the triggering of the CRH-2 receptors are poten-
response.25,5052 Under an immediate threatening or stress- tially linked with anxiolytic-like responses. Although evi-
ful event, the hypothalamus releases a peptide hormone and dence exists highlighting the properties of CRH in
neurotransmitter known as CRH into the hypothalamic- animals, until now it has not been possible to examine
hypophyseal portal system (the connection between the the CRH-1 and CRH-2 receptors in humans.10
hypothalamus and anterior pituitary) to mediate its stress
response. The hypothalamic-hypophyseal portal system will Cortisol. Cortisol is a glucocorticoid that is part of the
then carry out the CRH into the anterior lobe of the pituitary class of the steroid hormones produced by the zona fasci-
where it will stimulate the production of another polypep- culata of the adrenal cortex. Its primary function is to
tide tropic hormone known as adrenocorticotropic hor- mobilize and replenish energy stores.67 Cortisol is also
mone (ACTH). In turn, the ACTH hormone stimulates the known to perform an important role in the stress
BEHAVIORAL MEDICINE 5

response by way of signicant increases in vigilance, neurocognitive performance on their outcomes.75,76


increased arousal, consolidation of memory, and selec- However, there has been a double-blind, placebo-con-
tive attention.68 While cortisol has an important regula- trolled trial study which found improved mood and
tory effect on the amygdala, hippocampus, and memory recollections after DHEA treatment in a sample
prefrontal cortex, the prolonged exposure to high levels of healthy young men. However, individuals in this latest
of cortisol in the organism proved to have signicant study were not exposed to any form of stress task.77
toxic effects, particularly in the neurodegeneration of the Nevertheless, studies evaluating these two steroid hor-
hippocampus, resulting in memory and learning de- mones reported that a reduced concentration of DHEA
cits.67 Studies that included cortisol supplementation in ratio-to-cortisol can be translated into a higher risk of
healthy individuals revealed that the repeated adminis- experiencing chronic fatigue syndrome, anxiety, anorexia
tration of cortisol led to signicant cognitive impair- nervosa, depression, schizophrenia, and PTSD.71 Yet,
ments, similar to those observed in patients diagnosed this pattern of ndings has not been observed thoroughly
with depression.69 It is also well documented that exces- in all PTSD studies, which in relation to each other show
sively low and high cortisol levels have been found in conicting results.78,79
individuals with a PTSD diagnosis.70 Recent ndings
suggest that in order to modulate the negative effects of Dopaminergic system, dopamine
cortisol, DHEA (which is also secreted with cortisol) Dopamine is a hormone and neurotransmitter impli-
serves a protective role, and is associated with cated in various neural functions including attention,
resilience.16 motivational behavior, and motor control. Dopamine is
also known to play an important role in the stress
Dehydroepiandrosterone (DHEA) and DHEA sulfate response.80 Stress inhibits the release of dopamine in the
ester (DHEA-S). DHEA and DHEA-S are two endoge- nucleus accumbens, an area mainly associated with the
nous hormones secreted by the adrenal cortex, and are reward pathway, and activates the release of dopamine in
known to be the most abundant circulating steroid hor- the medial prefrontal cortex, an area associated in com-
mones present in humans.7173 While their precise plex cognitive behavior, personality expression, decision
mechanisms of action are not completely understood, making, and moderating social behavior.10 A further
some studies suggest that DHEA and its derivative sul- study evaluated lesions of dopamine neurons in the
fate ester might serve in a variety of physiological aspects medial prefrontal cortex; the results suggested that
in the organism. These include control of fatness, min- reduced prefrontal cortical dopamine levels lead to the
eral metabolism, sexual functioning, anti-inammatory, maintenance of the fear response, an outcome normally
and antioxidant effects.7173 Further studies also hypoth- observed in individuals with PTSD.81 Conversely, studies
esized that DHEA may exert a protective response that identied high levels of dopamine release in the
against stress.71,72 medial prefrontal cortex resulted in cognitive
Several military studies highlighted the benecial impairment. Thus, the data suggest that there is an opti-
properties of DHEA and DHEA-S in supporting a pro- mal range for stress-induced increases in dopamine,
tective role. A number of studies were conducted on released in the medial prefrontal cortex that may facili-
healthy military personnel undergoing the SERE training tate advantageous behavioral responses. There has, until
school or the Combat Diver Qualication Course. The now, been little research concerning the function of
results showed that soldiers who performed better under dopamine in stress-related disorders.10
acute stress had a higher increased of DHEA or higher
DHEA-to-cortisol ratio in the blood. These soldiers also Serotonergic system, serotonin
showed a superior physical and psychological perfor- Serotonin is a monoamine neurotransmitter present in the
mance and reported fewer symptoms of dissociation.7173 CNS. It is known to have an effect on the regulation of
A further innovative study provided endogenous DHEA appetite, sleep, feelings of well-being, and happiness. Sero-
supplementation in a randomized, controlled, double- tonin is also known for its effects on mood and anxiety.
blind eld study. They used a treatment versus control The acute stress response is linked with the augmented
group, within a group of soldiers undergoing SERE train- serotonin turnover in different areas of the brain, particu-
ing. The study focused on higher salivary concentrations larly in the lateral hypothalamus, amygdala, prefrontal
of DHEA and DHEA-S as a result of DHEA treatment, cortex, and nucleus accumbens.18,30,82 The liberation of
none of the group differences resulted in a superior per- serotonin in the brain is known to have both anxiolytic
formance or in a reduction of dissociative symptoms.74 and anxiogenic effects, and this outcome is mediated by
In general, DHEA administration studies with humans which part of the forebrain and receptors are stimulated.
have failed to show any evidence of improved For example, stimulation of the serotonin 2A receptor
6 
C. OSORIO ET AL.

results in anxiogenic effects, while the stimulation of the ALLO involve the role of stress in the HPA Axis dysregu-
serotonin 1A are anxiolytic and potentially associated lation.95,96 Acute stress produces an increase in ALLO
with adaptive reactions to stressful occurrences.83,84 Two levels, which negatively modulates the stress-induced
additional serotonin receptors, particularly the serotonin HPA Axis activation, thus aiding the recovery of physio-
1B and 2C receptors, have also been studied and though logical homeostasis after a stressful stimuli.97,98 For
to be associated with adaptive reactions to stressful example, in a study of small rodents, forced-swimming
circumstances.30 stress induced a time-dependent increase in the amount
of ALLO and progesterone, both in the plasma and in
Brain-derived neurotropic factor (BDNF) brain areas such as cerebral cortex, hypothalamus, and
BDNF is a protein encoded by the BDNF gene and is part plasma by producing protection against the damaging
of the neurotrophin family of growth factors.85,86 This effects of stressors.97 Nevertheless, other studies investi-
neurotropic factor works in specic neurons of the CNS gating chronic stress response highlight a signicant
and PNS, and is known for supporting the survival of reduction in the ALLO concentration levels. This sug-
existing neurons, by stimulating the growth and differenti- gests that chronic stress may alter ALLO synthesis and
ation of new neurons and synapses.87,88 BDNF is lead to a dysregulation in the HPA Axis.98 In a recent
expressed in several regions of the brain such as the study of small rodents, chronic stress was associated with
amygdala, prefrontal cortex, hippocampus, and basal fore- a signicant reduction in endogenous ALLO levels and
brain, and is implied in anxiety and mood disorders.18 an increased risk of anxiety-like behaviors and depres-
Numerous studies have reported that a down-regula- sion.98 The exogenous administration of ALLO from the
tion of BDNF in the hippocampus has been observed in onset of isolation-induced chronic stress and a period of
small rodents exposed to various types of stressors and chronic stress was able to reduce the occurrence of anxi-
in depressed patients who successfully committed sui- ety-like behaviors and depression, and regulate the HPA
cide.89,90 According to some authors, hippocampal Axis dysfunction.95 Based on these ndings, it appears
BDNF expression may have a signicant inuence in that ALLO is a key regulator of physiological functions
both stress resilience and risk of psychiatric problems. 18 and potentially important variable in resilience.
BDNF acts through the BDNF-tyrosine kinase B
(BDNF-TrkB) receptor. According to some human and
Early genetic factors in stress resilience
animal studies that evaluated the BDNF-TrkB pathway,
this receptor was related with PTSD symptomatology.91 Genetics is the process of trait inheritance through the
Conversely, those studies which administered antide- sharing of molecular structure and function of genes, gene
pressants found an increase in BDNF-TrkB receptors in behavior and distribution, variation, and change among
the hippocampus and prefrontal cortex and a potential similar or related organisms.99 Genetic factors play a very
role to hippocampal neurogenesis.92 However, this evi- signicant function in the determination of an individuals
dence was not observed in all BDNF-TrkB studies.18 response to stress and therefore regulate his or her risk or
resilience to a psychiatric condition.17,18 Indeed, studies
Neurosteroidogenic enzymes, allopregnanolone developed with identical twins have projected an overall
(ALLO) heritability rate of 32% to 38% in PTSD cases.100 Some
ALLO is a cholesterol-derived neuroactive steroid pres- studies considering individuals deoxyribonucleic acid
ent in the CNS that is synthesized from progesterone, a (DNA) genetic make-up and their particular history of
steroid hormone, in a two-step pathway, by action of the exposure to environmental stressors found that stress regu-
5a-reductase and 3a-hydroxysteroid dehydrogenase lation response could be signicantly affected by geneti-
enzymes, both steroidogenic enzymes.93,94 In particular, cally modied differences in reactivity of the SNS, of the
certain 3a-reduced metabolites of progesterone such as CNS through the HPA Axis, the noradrenergic and dopa-
ALLO are potent positive allosteric modulators of the minergic system, the serotonergic system, and the
Gama-Aminobutyric Acid (GABAA) receptor, particu- BDNF.17,18,100 We should mention here that this area is still
larly known for being the chief inhibitory neurotransmit- largely unexplained and particularly unknown.101
ter in the vertebrate CNS.93,94
Stress increases ALLO levels in the brain to concen- Sympathetic nervous system (SNS) related genes
trations that can activate the GABAA receptors, and Regulation of the SNS can also be affected by genetic fac-
according to several studies, ALLO might have potential tors. Demonstrating the fundamental role of SNS reactiv-
pharmacologic properties, particularly anticonvulsant ity is a study that evaluated the genetically modied
and anxiolytic actions.94,95 New hypotheses concerning variation of SNS activity in a group of healthy individuals,
the putative anxiolytic and antidepressant properties of found that a polymorphism in the alpha adrenergic-2
BEHAVIORAL MEDICINE 7

receptor gene appears to be considerably linked with their modulation of the glucocorticoid receptor activity and
autonomic hyper-responsiveness.102 Further, another signaling, and predicted the severity of the onset of
study found that during stress exposure, NPY levels were depression and PTSD symptoms in adult with childhood
disturbed by polymorphism in the gene encoding of the trauma.111,112
NPY molecule.103 This suggests that the association
between the noradrenergic system (NE) and stressor Noradrenergic and dopaminergic genes system
might be mediated by different alpha-2 adrenergic recep- Another polymorphism that has been associated with vul-
tors subtypes. Consequently, when researchers evaluated nerability to a psychiatric condition is found in the gene that
the effects of mice knocked out by the alpha-2A adrener- codes catechol-o-methyltransferase (COMT), an enzyme
gic receptor, their ndings suggested this receptor dis- degraded in the noradrenergic and dopaminergic sys-
played stress-protective functions. Opposing these tems.113 The COMT Val158Met polymorphism has been
ndings other studies have shown the alpha-2C adrener- studied in relation to stress and psychiatric disorders, sug-
gic receptor was involved in stress susceptibility.101,104 gesting an association with cases of PTSD.113 For example,
The SNS response to stress may also be disturbed by in a human study evaluating traumatic load, diagnosis of
changes in the NPY-gene.17,18 Supporting this evidence, PTSD and COMT Val158Met polymorphism, results
a study found that two NPY haplotypes have been asso- showed that a gene environment interaction among the
ciated with increased vulnerability to anxiety symptoms human COMT Val158 Met polymorphism and the magni-
after experiencing severe adversity during youth.105 tude of traumatic events experienced increased the risk of
Another study evaluated the effects of NPY genetic developing PTSD.114 Another study was developed with a
expression on emotions and stress resilience and revealed sample of Vietnam and Gulf War veterans who experienced
that the presence of lower haplotype-driven NPY expres- signicant amounts of operational stress. Its ndings also
sion was predictive of diminished resilience, assessed by suggested that COMT Val158Met polymorphism moder-
the presence of a higher emotional-induced activation of ated the effect of PTSD-related processes on right anterior
the amygdala in the brain.106 Still, the long term variant cingulate cortex volume.115
of the NPY encoding gene was related to a reduced Polymorphisms in the dopaminergic receptor genes
PTSD susceptibility and negative emotional states in have also been associated in the risk of developing
depression.106,107 depression and PTSD. According to a study that evalu-
ated the Dopamine Transporter gene polymorphism
Hypothalamic-pituitary-adrenal (HPA) axis-related (DAT1), the results suggest that this gene contributed
genes signicantly to a susceptibility to PTSD in those individ-
Changes in genes that control HPA Axis reactivity uals with a previous history of trauma.116 Additionally,
appear to contribute signicantly to modications in bio- studies that evaluated the Dopamine receptor gene D2
logically based stress response systems and inuence polymorphism (DRD2) suggest that determined DRD2
resilience or vulnerability to psychiatric conditions.100,108 signaling explained part of personality traits related to
Polymorphisms (mutation in the genotype) and haplo- emotion processing as well as individuals variability in
types (combination of DNA sequences) in two key genes specic brain responses to emotionally relevant
of the HPA axis include the corticotropin-releasing-hor- inputs.117 Another study that evaluated the Dopamine
mone receptor 1 gene (CRHR1 gene) and the FK506- receptor gene D4 polymorphism (DRD4) showed that
binding protein 5 gene (FKBP5), both potentially known this polymorphism inuenced vulnerability to stress and
for interacting with early life trauma (childhood mal- trauma and a signicant higher risk of developing a case
treatment or abuse) and predictive of later life stress- of PTSD.118
related psychiatric conditions.108 A signicant number of
studies have examined CRHR1 gene variation in PTSD Serotonergic gene system
and MDD in individuals exposed to life-threatening cir- Several studies assessing the polymorphic trait characteris-
cumstances. For example, the genetic marker spanning tics of the serotonin transporter gene, through the effects
the CRHR1 receptor gene rs110402 has been associated of gene multiplied by environment interactions, have pro-
with cortisol levels and the developing of depression in moted advances in the area of stress-related disorders.18
adult males who experienced trauma during their child- For example, in studies that evaluated the interaction
hood.109 Other studies found protective effects of the between stress and the polymorphism in the promoter
CRHR1 TAT haplotype rs7209436, rs110402, rs242924 region of the serotonin transporter gene (5-HTTLPR),
genetic markers in adults who have been victims of results showed the presence of the shorter allele of 5-
childhood maltreatment.110 Concerning the FKBP5 gene, HTTLPR linked with an increased risk for depression and
studies have shown the involvement of this gene in the PTSD.119,120 Conversely, human studies evaluating the
8 
C. OSORIO ET AL.

presence of the long allele of the 5-HTTLPR found a posi- the epigenetics of the regulation of stress focuses on at least
tive association with self-reported emotional resilience.121 two distinct aspects of stress-induced epigenetic pathology
or resilience. This is through mechanisms such as DNA
Brain-derived neurotropic factor (BDNF) genes methylation or histone methylation, and/or acetyla-
Recent scientic evidence suggests that BDNF Val66- tion.129,130 Although there has been recent progress toward
Met polymorphism may be potentially linked with understanding the epigenetic regulation of stress and how
the modulation of the stress reactivity in such mechanisms contribute to susceptibility and resilience
humans.122,123 For example, a study that evaluated the to stress-related disorders, careful interpretation is required
BDNF Val66Met polymorphism in a group of healthy as this area remains largely unexplained.129
university students found that the BDNF Val66Met
carriers were more susceptible for anxiety symptoms DNA methylation
and exhibited an increased cortisol stress response in DNA methylation is a biochemical process known for
face of stressful events.123 Two further studies also altering the expression of genes in cells when cells divide
identied an association between this polymorphic and differentiate. It is also known to be factor in the neu-
gene and cases of depression and anxiety. A clinical ral development of the organism and is potentially linked
study found that depressed patients with the BDNF to psychiatric disorders.130 A series of studies have
Val66 Met polymorphism exhibited higher rates of already linked the biochemical process of DNA methyla-
chronic MDD.124 Another study found that the tion to psychiatric conditions.129,130 Post-mortem studies
BDNF Val66Met polymorphism interacted with early of suicide victims with a history of childhood abuse
life stress to predict anxiety and depression.125 found that increased DNA methylation of a specic exon
Most of the evidence gathered in this area does not 17 glucocorticoid receptor (NR3C1) gene expression pro-
support a positive association between BDNF Val66Met moter in the hippocampus decreased hippocampal GR
polymorphism and stress-related disorders, particularly expression. This in comparison with other postmortem
MDD and/or PTSD.126,127 For example, a meta-analysis victims of sudden or accidental death without history of
that evaluated the association between BDNF Val66Met childhood abuse.133 Another human study aimed to
polymorphism and depressed (MDD) individuals did compare the expression of DNA methyltransferase
not nd an association between these two variables.126 (DNMT) messenger Ribonucleic Acid (mRNA) between
Another meta-analysis that evaluated the same polymor- individuals who committed suicide and had a MDD
phism with anxiety disorders also did not nd an associ- diagnosis with individuals who died suddenly as a result
ation between the variables.128 A further meta-analysis of other causes other than suicide. The rst ones had sig-
did not found an association with PTSD.127 nicant alterations in the DNMT gene transcripts
expression in brain areas including the frontopolar cor-
tex, amygdala and the paraventricular nucleus of the hip-
Epigenetic factors in stress resilience
pocampus.134 Thus, this study shown that DNMT-3B
Epigenetics corresponds to the functional alterations in the expression was augmented in areas like the frontopolar
chromatin structure that trigger long-lasting modications cortex, previously known to be linked with an increase in
in gene expression without creating changes in the DNA DNA methylation of the g-aminobutyric acid (GABA)
sequence.129,130 These functional alterations help to regulate (A) receptor alpha-1 subunit promoter region.18,134
the phenotype and gene expression of an individual using Additionally, another study aimed to evaluate the effect
mechanisms such as DNA methylation and histone methyl- of gene expression and PTSD-associated methylation in
ation and acetylation, among others.17,18 Recent research 33 candidate genes. Their ndings suggested that higher
with monozygotic twin studies have determined that during DNA methylation of Mannosidase Alpha Class 2C
the lifetime of these individuals, there is a meaningful and Member 1 (MAN2C1) shown to relate with higher expo-
profound accumulation of epigenetic differences that could sure to potentially traumatic situations and predictive of
be explained by distinctive life development events and/or PTSD.135 Nevertheless, the precise role of MAN2C1 in
stressful experiences.131 In fact, various studies have shown the stress response remains unclear.136
that hardship and adversity experienced during youth can
result in persistent epigenetic marks in the genome that alter Histone methylation and acetylation
gene expression and induce both neural and behavioral Histone methylation is a biochemical process through
changes across adulthood.132 These epigenetic modications which a methyl group is shifted into amino acids of histone
are known to be implicated in social and maternal behavior, protein in chromosomes.132 As a mechanism, histone meth-
learning and memory decits, depression, and PTSD symp- ylation is linked with stimulation of the neural pathways
tomatology.129,130 Recent advances in our understanding of and potentially for its function in learning and long-term
BEHAVIORAL MEDICINE 9

memory.137 Scientic studies have already showed that rodents was linked with more depression-like behav-
female rats have different behavioral patterns of interaction iors.132 However, animal studies with the histone deacety-
with their offspring. While some mother rats exhibit lase 5 (HDAC5) suggest a protective effect in the nucleus
increased levels of nurturing behaviors (such as nursing, accumbens. For example, a study with small rodents sub-
licking, grooming), others do not.138 These different nurtur- jected to chronic social defeat stress exhibited a reduction
ing behaviors have a signicant impact, where offspring of in the HDAC5 expression, while chronic antidepressant
high-nurturing mothers are known for exhibiting less fear- treatment led to an increased HDAC5 expression. Thus,
fulness, anxiety, reduced corticosterone responses to stress, lacking of HDAC5 expression increased depressive-like
increased central benzodiazepine receptor density in the behaviors when compared with controls.143
amygdala and locus coeruleus, and higher quantities of glu-
cocorticoid receptors (GR) gene promoter in the hippocam-
Developmental factors and stress resilience over
pus.138,139 Interestingly, superior hippocampal GR
the life cycle
expressions in the offspring are thought to be mediated by
the transcription factor Nerve Growth Factor-Inducible The accrued scientic evidence also suggests that environ-
protein A (NGFI-A).139 For example, in a study where off- mental stress over the life cycle can be extremely impor-
spring rats received low levels of nurturing care from their tant in explaining an individuals risk to a stress-related
mothers exhibited an augmented methylation of the GR psychiatric injury, and conversely, stress resilience.144,145
gene promoter at the NGFI-A binding site in the hippocam- Human and animal studies suggest that severe stressful
pus.139 Thus, lower levels of GR expression in the hippo- experiences during early life can negatively affect the
campus led to several traits in adulthood, including higher development of stress response system and cause
levels of corticosterone (both before and after stress expo- long-lasting ill-health.109,145147 Strong, frequent, and
sure), and higher levels of anxiety-like behaviors. Thus, these prolonged activation of the stress response system during
differences observed in methylation appear the rst weeks of childhood has been labelled toxic stress (e.g., physical/
life and continue into their adulthood.139 emotional abuse, chronic neglect, constant exposure to
Histone acetylation is the biochemical process by violence). This can disturb the normal development of the
which the lysine for the histone core is acetylated as part brain and other systems and increase the risk of stress-
of gene regulation.140 According to some rodent studies, related disorders in adulthood. Thus, the higher number
histone acetylation has been observed in several regions of of stressful and/or adverse experiences encountered in
the hippocampus after exposure to acute stress, which childhood the higher risk of these individuals to develop
could potentially lead to its role in memory formation cognitive, emotional, and development problems. 148 In
and stress response.132 Scientic evidence that histone fact, studies that evaluated parental neglect and abusive
acetylation could have a signicant role in depression was behavior toward children during the early weeks of life
found through studies showing that the intracerebral and found fewer stress management skills, lower self-indepen-
systemic administration of several histone deacetylase dence, and higher levels of anxiety and stress. This was
inhibitors, either alone or combined with antidepressants, reected in increased HPA axis and CNS activity when
where results showed, in a variety of animal models, the same individuals were subjected to stressors in later
improved antidepressant responses.132 Another animal life.147 Additionally, these early life stressor experiences
study revealed that histone acetylation (H3K14ac) is led to hyper-functioning of NE system, reduction in the
briey reduced and then augmented in the nucleus hippocampal volume, and amygdala responsiveness to
accumbens (a central region of the limbic system) after negative facial expressions.149,150
chronic social defeat stress, where this action was reected Research in human and animal models suggest that
by a decrease in histone deacetylase 2 (HDAC2). Support- certain factors can play an exceptionally important role in
ing this evidence, another study also found similar effects determining whether an early traumatic experience can
in the nucleus accumbens of depressed humans who have result in vulnerability or resilience to a psychiatric disor-
been evaluated postmortem.141 They highlighted that his- der. One of the factors known to play an important role in
tone acetylation has an important function in the develop- these circumstances is the degree of control that an indi-
ment of stress and depression.141,142 Additionally, another vidual has over the stressor. Another factor is the possibil-
study supported the impact of histone acetylation in ani- ity of changing the situation.11,18 It is already known that
mal models by providing evidence that overexpression of when individuals are led to believe that they are unable to
dominant negative HDAC2 in the nucleus accumbens change stressful circumstances, learned helplessness
resulted in antidepressant-like behaviors, compared to occurs.151 Learned helplessness is a mental state where an
controls. However, an overexpression of a similar version individual, after experiencing ongoing adverse stimuli
of the HDAC2 (strongly related with chromatin) in small considered painful or unpleasant, becomes incapable and/
10 
C. OSORIO ET AL.

or unwilling to avoid consequent encounters with the signicant number of neurochemical elements (such as
given stimuli. Even if there is the possibility of avoiding it, NPY, DHEA, CRH, galanin, ALLO) have been linked to the
because they have learnt by experience that the stressor acute stress response and can be associated with resilience to
cannot be controlled or avoided.152 This has been stress.10,11,45,94 Each specic pathway and neurochemical
conrmed through a classic study involving dogs exposed element conveyed some protection or promoted resilience
to erratic shocks.151 In studies with animals subjected to when facing stress. However, none of these neurobiological
shocks that could be avoided by behavioral modication, effects was highly signicant as inconsistencies were
learned helplessness seemed not to occur.153 Thus, evi- reported regarding neuro-protective effects.
dence indicates that individuals may learn resilience As some researchers have highlighted, the neurobio-
through experience and hardship, in particular by devel- logical concept of resilience cannot be regarded as the
oping qualities that facilitate appropriate coping strategies, interaction of a single neurochemical element but rather
adaptation, and recovery from stress.101 Studies also the interaction of multiple neurochemical elements
suggest that it may be possible to inoculate individuals within a complex network of cells in the human
against the negative effects of exposure to high levels of brain.45,159 In fact, a study that evaluated the negative
stress.154,155 This concept, termed stress inoculation, cumulative effects of multiple physiological dysregula-
happens when an individual acquires an adaptive stress tions showed that when considering any of the biological
response to the negative effects of following stressors. markers individually, a decline in health status was not
Stress inoculation is thus seen as a form of immunity found to have any predictive value. Instead, when all
against similar stressors which might occur in the future, markers were considered, they predicted an accentuated
essentially being analogous to vaccine induced immunity cognitive decline and a change in cardiovascular activ-
against disease.156 ity.5,45 If a similar model were applied to stress-resilient
Particularly, animal studies tend to support the stress- individuals, by combining neurochemistry and its known
inoculation concept and show that early-life exposure to components to confer protection and including high-lev-
stressful events may protect against some of future nega- els of NPY, galanin, DHEA, ALLO, and the low levels of
tive effects of stress.100 One study evaluated the contribu- CRH activation, we may come closer to identifying a
tion of early stressors in the emotional stability of small neurobiological prole of stress-resilient individuals.45
rodents. The researchers randomly exposed a group of The same strategy may also be observed of genetic and
infant rats to intermittent foot shocks, sufcient to elicit epigenetic traits.
evasive movements, as a stress task, alongside a control Further complication arises in relating neurobiological
group that did not experience shock. When they sub- processes to psychological states under the overarching
jected the same two groups of rodents to a new stressful concept of resilience. For example, a particular neuro-
situation, those that had been intermittently subjected to chemical may be found to be co-present with psychologi-
stress displayed an enhanced coping response and a cal symptoms of stress or resilience however this co-
lower emotional response.157,158 presence may not be sufcient to establish direction of
causation. Meaning its presence may conceivably be a
cause or conversely a response to intrusive symptomology.
Discussion
Indeed the relation that holds between the neurobiology
The neural mechanisms that underlie resilience to and psychology of resilience represents a signicant obsta-
stress are extremely complex, involving the interac- cle that will need to be addressed in future research.
tion of neurobiologic, genetic, and epigenetic compo- This review focuses on the underlying neurochemical
nents, together with the environment.10,16,17 While and physiological processes associated with resilience. As
genetic factors interact with neurobiological and epi- such we did not include literature concerning the impor-
genetic factors thereby affecting the biological charac- tant psychological factors and character traits related to
teristics and regulation of neurochemical receptors, the subject. However, it should be noted that active cop-
environmental factors produce epigenetic alterations ing strategies, humor, hardiness, and extraversion can
in individuals, inuencing resilience to stress or risk promote resilience through fostering feelings of mastery,
of a psychiatric condition.1618 While not part of this commitment, and competence as well as the ability to
review, other factors such as personality, tempera- help others through bonding. Importantly, the propen-
ment, physical tness, and social support also play a sity of resilient individuals to express positive emotions,
pivotal role in resilience. in relation to negative events, enables them to control
Our growing understanding of resilience leads us to con- their anxiety and fears.101 A signicant number of stud-
sider how we could establish a resilient prole by examining ies have also indicated positive social support has an
the complexity of interacting factors. We rst noted that a important factor in maintaining physical and
BEHAVIORAL MEDICINE 11

psychological well-being. These studies found that higher hormones related to resilience, an example being
levels of social support are able to reduce and/or attenu- increased levels of DHEA measured in individuals who
ate the impact of PTSD and/or MDD.159,160 Additionally, demonstrated greater physical and psychological perfor-
there is an emerging literature which also suggests that a mance under stress. However a further human study
positive social support environment can moderate indi- showed DHEA supplementation did not manifest in any
vidual environmental and genetic vulnerabilities and observable advantage. While neurobiological insights
increase their resilience.161 into a resilient prole are being gained the creation of
Further, encountering and overcoming stress-induc- one remains at the moment elusive, without recourse to
ing situations may have a benecial effect on the life the psychological domain.
cycle, in particular over ones perception of control and The benets of improved neurochemistry on psycho-
sense of stress mastery. However, as different individuals logical performance through prophylactic supplementa-
have different stress thresholds, a stressor that may pro- tion is a topic of fascination and one that will continue to
mote resilience in one individual could result in be explored. As it is, however, we should remain aware of
increased vulnerability in another individual. The line an example from history which illustrates this area of
between learned helplessness and stress inoculation is a research also has the potential to be mishandled with
ne one because of the variability of individuals in their negative consequence when applied.168 The use of prophy-
biological, psychological, and social competences.16 lactic drugs that target the CNS may reduce fatigue and
Choosing to focus on the neurobiological domain for enhance psychological resilience; however it can also inter-
signs of resilience entailed a neglecting of the psychological fere with the individuals moral judgement and mood.168
and social domains. As we understand them, the neurobio-
logical, genetic, epigenetic, and environmental signs of resil-
Conclusion
ience are akin to variables.162 In better understanding these
variables and the relation they stand in to each other we will In conclusion, the promotion of resilience and
begin to see a more complete picture of the neurobiology of prevention of psychopathology are of fundamental
resilience emerge. As research continues, facilitated by concern to the medical community. Moving forward and
advancing technology, our understanding will continue to building on the important insights gained from the
deepen. In turn this will enable the creation of more com- current research, an interdisciplinary approach combin-
prehensive prole of a stress resilient individual. ing neurobiological, genetic, epigenetic, and personality
The notion of a stress resilient prole will be of use to traits, as well community and group interactions, may
those who operate in high-stress environments. First, in work to facilitate the development of a stress-resilient
relation to the successful completion of the given task prole. This in turn would be signicant step toward the
and secondly in relation to the individuals post-task prevention and treatment of stress-related psychiatric
physical and psychological well-being. Initial steps in conditions such as PTSD or MDD.
this area have been taken in studies investigating mem-
bers of the US and Belgian Special Forces Units.29,163166
The United Kingdom is yet to conduct resilience related Funding
neurobiological research within its military population, AHY receives support from the National Institute for Health
this, despite having a tradition of epidemiological Research (NIHR) Mental Health Biomedical Research Centre
research in military mental health.167 at South London and Maudsley NHS Foundation Trust and
While understanding in the neurobiological domain is Kings College London.
advancing, this review has shown that the mechanism of
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