Learning to cope with stress: psychobiological mechanisms of stress resilience

DOI 10.1515/revneuro-2012-0080 Rev. Neurosci. 2012; 23(5-6): 659–672

Simona Cabib * , Paolo Campus and Valentina Colelli

Learning to cope with stress: psychobiological mechanisms of stress resilience Abstract: Stress is the main non-genetic source of psy-

chopathology. Therefore, the identification of neurobio-

logical bases of resilience, the resistance to pathological

outcomes of stress, is a most relevant topic of research.

It is an accepted view that resilient individuals are those

who do not develop helplessness, or other depression-like

phenotypes, following a history of stress. In the present

review, we discuss the phenotypic differences between

mice of the inbred C57BL/6J and DBA/2J strains that could

be associated with the strain-specific resistance to help-

lessness observable in DBA/2J mice. The reviewed results

support the hypothesis that resilience to stress-promoted

helplessness develops through interactions between a

specific genetic makeup and a history of stress, and is

associated with an active coping style, a bias toward the

use of stimulus-response learning, and specific adap-

tive changes of mesoaccumbens dopamine transmission

under stress. Finally, evidence that compulsivity rep-

resents a side effect of the neuroadaptive processes fos-

tering resistance to develop depressive-like phenotypes

under stress is discussed.

Keywords: adrenal hormones; D2 dopamine recep-

tors; endophenotypes; fitness; habit-like responses;

hippocampus.

*Corresponding author: Simona Cabib, Department of Psychology

and CRIN, Sapienza University of Rome, via dei Marsi 78, I-00185

Rome, Italy, e-mail: [email protected]

Simona Cabib: Centro Europeo di Ricerca sul Cervello (CERC),

Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano, 64, I-00143

Rome, Italy

Paolo Campus: Department of Psychology and CRIN, Sapienza

University of Rome, via dei Marsi 78, I-00185 Rome, Italy

Valentina Colelli: Department of Psychology and CRIN, Sapienza

University of Rome, via dei Marsi 78, I-00185 Rome, Italy

Introduction Stress is the main non-genetic source of psychopathol-

ogy. Therefore, the identification of mechanisms capable

of moderating the pathogenic effects of stress is a major

goal of preclinical research. Recent studies focused on

resilience – the resistance to environmental risk experi-

ences shown by some individuals (Charney, 2004; Rutter,

2006; McEwen, 2007; Feder et al., 2009). Indeed, the path-

ogenic potential of stress experiences does not depend

solely on their severity: a large proportion of individuals

exposed to traumatic experiences do not show patho-

logical outcomes (Charney, 2004) and events appraised

as positive by most people can be pathogenic stressors.

Thus, either bereavement or marriage is a potentially

pathogenic experience (Paykel, 1997).

There is evidence from studies in humans and in

experimental animals that resilience can result from a

history of stress (the so-called steeling or immunizing

effects) (Rutter, 2006). The brain undergoes major plasti-

city events under stress challenge; these include genomic

and non-genomic changes and reorganization of neural

connectivity. Some of these events have been associated

with an increased risk for pathological outcomes, whereas

others seem involved in the development of resilience

(Krishnan et al., 2007; Dias-Ferreira et al., 2009; Mitra

et al., 2009; Shansky et al., 2009; Vialou et al., 2010). These

observations suggest the hypothesis that stress resilience

can emerge from neuroadaptive changes promoted by the

interaction between a stress history and a specific genetic

makeup; in other words, from specific gene-environment

(G × E) interactions.

Adult brain plasticity is associated with learning, and

there is evidence of a bidirectional relationship between

stress and learning in mature organisms. Stress can either

increase or reduce the persistence of long-term memo-

ries and can bias learning toward habitual responses

(Schwabe and Wolf, 2012; Schwabe et al., 2012). More-

over, the experience of being unable to remove, avoid, or

control a stressor facilitates subsequent fear conditioning

but renders organisms resistant to the extinction of an

acquired fear, whereas the experience of stress control has

opposite effects (Baratta et al., 2007; Amat et al., 2012).

Finally, coping strategies acquired through previous stress

experiences moderate the impact of a subsequent stress

challenge (Maier and Seligman, 1976; Maier and Watkins,

2010). These findings support the view that brain learn-

ing systems are a major target of stress neuroplasticity and

suggest that learning-associated neurophenotypes could

constrain neuroplastic outcomes of stress experiences.

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660 S. Cabib et al.: Learning to cope with stress

In the following pages, we will present evidences from a

mouse model of individual resistance to helplessness, a

known pathological outcome of stress experience, sup-

porting development of this phenotype through G × E

interactions promoting plasticity within specific learning

systems.

Stress, emotion, and coping Stress-related concepts suffer from their massive, and

usually inappropriate, utilization in common language.

Moreover, there is a diffuse, although repeatedly chal-

lenged, view that stress is anything increasing the phasic

levels of cortisol/corticosterone. Although a discussion of

these topics is beyond the goal of the present review (see

Koolhaas et al., 2011; Cabib and Puglisi-Allegra, 2012, for

recent reviews), some definitions are required.

The present review deals with psychological stress-

ors, and the term stressor will indicate stimuli, experi-

ences, events, or problems appraised by the organism as

challenges demanding beyond its actual means (Folkman

et al., 1986a,b; Lazarus, 1993; Koolhaas et al., 2011). The

appraisal of a stressor is associated with very high levels of

emotional arousal and with a stereotypic pattern of physi-

ological responses such as increased release of cortico-

tropin-releasing hormone, adrenocorticotropic hormone,

and corticosterone/cortisol. These have profound effects

on peripheral systems and support the organisms in the

face of stressful challenges. However, they are dangerous

for the organisms ’ survival and well-being if sustained;

thus, once activated, they have to be terminated as soon

as possible (McEwen, 2007).

Coping responses develop from action-oriented and

intrapsychic efforts to manage the demands created by

stressors (Taylor and Stanton, 2007). They terminate or

moderate stress responses, preventing allostatic load

(McEwen, 2007), thus protecting the organisms against

most serious health threats. Therefore, coping responses

appraised as successful are acquired and consolidated to

be readily implemented in similar situations (Maier and

Seligman, 1976). There are two broad categories of coping

responses: those targeting the source of stress (problem-

focused) and those targeting the emotional arousal that

sustains stress responses (emotion-focused) (Folkman

et al., 1986b; Lazarus, 1993). The success of one or the

other type of coping depends on the stressor. Thus, when

stressors are susceptible to action (avoidable/control-

lable), problem-focused coping strategies are most suc-

cessful. However, when stress is promoted by problems or

events devoid of solution, unavoidable, or insensitive to

the subject ’ s action (unavoidable/uncontrollable stress-

ors), the only effective strategies are those aimed at regu-

lating emotional arousal (Austenfeld and Stanton, 2004;

Maier and Watkins, 2010).

Studies on the effects of psychogenic stressors have

demonstrated that experimental animals use different

strategies when dealing with controllable or uncontrolla-

ble stressors. Exposure to controllable stressors promotes

development and consolidation of specific defensive

responses (freezing, escape, avoidance, and species-

typical social displays), whereas uncontrollable stressors

promote helplessness: a condition characterized by the

absence of attempts at removing/avoiding the source of

stress. The two patterns of responding to stressful events

are known as active and passive coping and are strongly

reminiscent of human problem-focused and emotion-

focused coping (Drugan et al., 1985; Cabib and Puglisi-

Allegra, 1994; Anisman and Merali, 2001; Maier and

Watkins, 2005, 2010). Indeed, activation of brain opioid

receptors moderates emotional arousal and terminates

stress responses, and release of endogenous opioids is pro-

moted by uncontrollable but not by controllable stressors

(Maier et al., 1982; Drugan et al., 1985; Whitehouse et al.,

1985; Drolet et al., 2001; Ribeiro et al., 2005). Thus, in both

humans and non-human animals, passive coping is asso-

ciated with blunting stress-induced emotional arousal.

In summary, stressful events promote necessary but

unsustainable stress responses supported by very high

levels of emotional arousal. These responses can be ter-

minated by eliminating the stressor through the expres-

sion of active coping or reducing the emotional arousal

through passive coping. Finally, either type of coping is

adaptive depending on the degree of controllability of the

stressful condition.

Coping styles Because active and passive coping responses are effec-

tive in different stressful situations, flexible coping is to

be considered the healthiest strategy at the individual

level (Austenfeld and Stanton, 2004; Nes and Seger-

strom, 2008). Nonetheless, some individuals use passive

or active coping strategies preferentially, and naturali-

stic and experimental studies in different animal species

support the existence of true coping styles, i.e., the con-

sistent choice of one of the two coping strategies (Koolhaas

et al., 1999). There is evidence that coping styles depend

on genetic predisposition, and it has been proposed that


S. Cabib et al.: Learning to cope with stress 661

individual variance of this phenotype supports popula-

tion fitness in variable environments, a hypothesis tested

by selection studies in mice from wild populations (Kool-

haas et al., 2007).

Moreover, individual coping styles can result from

acquisition and consolidation of coping responses

through a history of stress. In animal models, both avoid-

ance/escape responses (active coping) and helplessness

(passive coping) are acquired even in single trials and

have lasting influences. Moreover, repeated experience

of uncontrollable stress promotes a form of persistent

and generalized helplessness, the learned helplessness,

whereas experiences of controllability promote resistance

to shift into passive coping in the presence of novel uncon-

trollable/unavoidable stressors (Maier and Seligman,

1976; Maier and Watkins, 2010). Finally, as previously sug-

gested, genetic predisposition and stress history can inter-

act to develop a stable coping style (Moffitt et al., 2006;

Rutter, 2006, 2008). Thus, low maternal care increases the

risk of developing helplessness in response to stress in

adult life, and the impact of the early environmental chal-

lenge is moderated by a polymorphism in the serotonin

transporter (5-HTT) (Carola et al., 2007).

There is increasing hope to identify fragility factors

involved in G × E interactions responsible for psychopa-

thology by the use of genetically manipulated mice (Caspi

and Moffitt, 2006; Carola et al., 2007). The observation that

a phenotype is expressed by mice with a targeted genetic

alteration only following alteration of the early environ-

ment supports an interaction between these two factors

and suggests that the product of the altered genes plays

a main role in the neurobiological mediation of environ-

mental effects. However, G × E interactions responsible for

behavioral disturbances involve a large number of genes

each contributing to phenotypic variability to a very small

extent (Plomin and Davis, 2009; Plomin et al., 2009).

The possibility to measure or even detect the phenotypic

effects of individual manipulation of most of these genes

is virtually non-existent. Moreover, although early expe-

rience is especially formative for individuals, the brain

maintains a plasticity that can be the target of stressful

experiences through the lifetime (Szyf et al., 2008).

Comparative studies in inbred strains of mice repre-

sent a useful tool to identify polygenic influences in G × E

interactions (Cabib et al., 1997, 2000; Puglisi-Allegra and

Cabib, 1997; Alcaro et al., 2002; van der Veen et al., 2007,

2008a,b; Mozhui et al., 2010). Inbred mouse strains do

not offer the empirical precision that is the hallmark of

directed mutagenesis. Nonetheless, studies of the physio-

logy and behavior of inbred mice can facilitate the unbi-

ased discovery of biological and genetic correlations that

may help identify the genes and molecular mechanisms

mediating stress effects. Indeed, inbred strains have been

used for the creation of chromosome substitution strains

and recombinant inbred strains of mice, which provide

a permanent resource for studying the genetic control of

phenotypic variation (Williams et al., 2001; Singer et al.,

2005).

When compared with mice of the standard genetic

background C57BL/6J (C57), mice of the genetically unre-

lated inbred DBA/2J (DBA) strain show resistance to help-

lessness. Indeed, C57 mice show a much faster develop-

ment of helplessness in the forced swimming test (FST)

than DBA mice (Ventura et al., 2001). Moreover, C57 but

not DBA mice develop learned helplessness. Thus, expo-

sure to an inescapable shock reduces active swimming in

a Y maze up to 24 h after the experience in C57 mice but not

in DBA mice (Shanks and Anisman, 1988). Strain-specific

liability to development and consolidation of helpless

responses is also observable in social stress. Thus, in the

course of repeated confrontations with an aggressive resi-

dent, only C57 mice show progressive decrease of escape

attempts; moreover, when confronted with a non-aggres-

sive resident 24 h after being defeated, DBA mice show

defensive responses whereas mice of the C57 strain show

prevalent immobility/withdrawal (Siegfried et al., 1984;

Kulling et al., 1987). Finally, previous stress experiences

further reduce helplessness induced by a different uncon-

trollable/unavoidable stressor ( ‘ immunization ’ ) and

prevent retrieval of a consolidated helplessness in DBA

mice but not in mice of the inbred C57 strain (Alcaro et al.,

2002; Cabib et al., 2002; Mozhui et al., 2010). The latter

observation supports the view that resistance to helpless-

ness develops in DBA mice through G × E interactions.

The strain-specific resistance to helplessness shown

by DBA mice when compared with C57 mice supports the

use of phenotypic differences between these mouse strains

to investigate the mechanisms responsible for the develop-

ment of stress resilience. Indeed, it has been proposed that

an active coping style supports stress resilience because

clinical results indicate an association between emotion-

oriented coping strategies and higher levels of depressive

symptoms in clinical populations (Southwick et al., 2005).

Brain plasticity, learning systems, and stress hormones G × E interactions are generally described in terms of

genetic modulation of individual susceptibility/sensiti-

vity to environmental challenge. However, comparative



studies on anxiety-associated behavioral phenotypes and

hormonal stress responses in mice from the inbred DBA

and C57 strains have produced, at best, contrasting results

(Cabib et al., 1990, 1996; Rogers et al., 1999; Ryabinin et al.,

1999; Griebel et al., 2000; McNamara and Lenox, 2004;

Voikar et al., 2005; Mozhui et al., 2010). These findings

are in line with the observation that variations in coping

style do not correlate with variation in the amount of emo-

tional reactivity to stress in selection studies in mice from

wild populations (Koolhaas et al., 2007). Moreover, DBA

are more susceptible than C57 mice to stress-induced defi-

cits of brain self-stimulation (Zacharko et al., 1987) and to

stress-induced sensitization to the rewarding and psycho-

motor effects of addictive drugs (Cabib et al., 2000; van

der Veen et al., 2007).

The observations that strain-specific resistance to

helplessness in DBA mice is not associated with low

sensitivity to stress and that previous stress experience

increases resistance to helplessness in this strain of

mice support the hypothesis that resilience is the result

of a genotype-specific neuroadaptation to environmen-

tal challenges. Indeed, plastic events promoted by stress

experience show individual variability (Krishnan et al.,

2007; Mitra et al., 2009). In line with this hypothesis,

stress-induced expression changes in the brain of C57 and

DBA mice involve different genes (Mozhui et al., 2010),

and stressed DBA and C57 mice show opposite changes

in brain dopamine (DA) functioning (Cabib and Puglisi-

Allegra, 1991; Cabib et al., 1998; Ventura et al., 2002).

Strain differences between DBA and C57 mice in

neuroplasticity were classically reported by studies on

hippocampus-dependent learning. Thus, impaired hip-

pocampal long-term potentiation, due to low protein

kinase C (PKC) levels, and reduced training-induced hip-

pocampal neurogenesis, CREB phosphorylation, and

72-kDa heat shock protein expression were reported in

DBA mice when compared with C57 (Matsuyama et al.,

1997; Kempermann and Gage, 2002; Ambrosini et al.,

2005; Sung et al., 2008). Impaired hippocampal plasticity

is considered responsible for the bias toward the use of

hippocampus-independent learning strategies characteri-

stic of DBA mice, in sharp contrast with the bias toward

the use of hippocampus-dependent learning typical of

C57 mice (Gerlai, 1998; Passino et al., 2002; Sung et al.,

2008). In addition, mice of the DBA strain do not require

a functioning hippocampus in different types of learning

tasks (Arns et al., 1999; Middei et al., 2004; Baarendse

et al., 2008).

However, the hypothesis of a strain-specific impair-

ment of hippocampal plasticity is challenged by some

observations. Thus, C57 rather than DBA mice show

stress-induced reduction of hippocampal PKC (McNamara

and Lenox, 2004); increased hippocampal PKC levels were

reported in DBA mice following 8 weeks of moderate-pace

treadmill running (5 days/week, 60 min/day) (Fordyce

and Wehner, 1993); and 43 days of free wheel running

increased adult hippocampal neurogenesis in mice of the

DBA strain but not in C57 mice (Clark et al., 2012). These

findings indicate a low learning-associated hippocampal

plasticity in DBA mice that could be the result rather than

the cause of a bias toward the use of hippocampus-inde-

pendent strategies.

The preferential use of hippocampus-dependent

or -independent learning strategies has also been reported

by studies in human subjects. Indeed, engagement of hip-

pocampus-dependent circuits in learning is a dimension

along which people vary (Hartley et al., 2003; Iaria et al.,

2003; Bohbot et al., 2007; Banner et al., 2011; Marchette

et al., 2011). Moreover, a recent study has associated this

variance to the Val66Met polymorphism of the brain-

derived neurotrophic factor ( BDNF ) gene (Banner et al.,

2011), a finding that supports genetic determinants of this

phenotype. However, acute stress experiences have been

shown to shift humans and experimental animals from

spatial (hippocampus-dependent) to stimulus-response

(hippocampus-independent) learning (Schwabe et al.,

2007; Dias-Ferreira et al., 2009; Packard, 2009; Schwabe

and Wolf, 2009), supporting a role for stress experience

in the promotion of individual bias toward the use of a

hippocampus-independent learning strategy. Finally, it

has been proposed that the relationship (either healthy

or pathological) between brain systems supporting hip-

pocampus-dependent and -independent learning is deter-

mined by interactions between an individual ’ s genetic

makeup, pre- and postnatal developmental events, and

accumulated experience through life (McDonald et al.,

2004); in other words, by life-long G × E interactions.

Stress hormones are main mediators of stress-induced

neuroplasticity and are involved in stress-induced bias

toward the use of hippocampus-independent strategies

(Sousa et al., 2008; Schwabe and Wolf, 2009; Schwabe

et al., 2010). Indirect evidence supports a role for these

hormones in strain-specific neuroadaptation to stress.

Behavioral sensitization, the increase of the psychomo-

tor stimulant effects of addictive drugs, is promoted by

repeated exposure to the drug as well as by exposure

to stressors. Moreover, it is supported by neuroplastic

events, which are partially dependent on stress hormones

(Marinelli and Piazza, 2002; Marinelli, 2007; Robin-

son and Kolb, 2004; Renthal et al., 2008; Thomas et al.,

2008). Mice of the DBA strain are more susceptible than

C57 mice to stress-induced behavioral sensitization to



psychostimulants (Badiani et al., 1992; Cabib et al., 2000),

and psychosti mulant-induced behavioral sensitization

is prevented by adrenalectomy in mice of the DBA strain

but not in C57 mice (de Jong et al., 2007). Moreover, both

repeated psychostimulant and repeated stress promote

strain-specific changes of DA receptors of the D2 type in

the meso-striatal system in these mouse strains (Puglisi-

Allegra and Cabib, 1997; Cabib et al., 1998; de Jong et al.,

2008). Finally, exogenous co-administration of corticos-

teroids and epinephrine, but not administration of each

one, reverses the strain-specific effects of adrenalectomy

on cocaine sensitization (de Jong et al., 2009) and mimics

the effects of stress on learning strategies in humans

(Schwabe and Wolf, 2009; Schwabe et al., 2010).

In summary, the reviewed evidences support the

involvement of stress-induced neuroadaptation in the

development of strain-specific resistance to helplessness

by DBA mice. Moreover, they suggest that these neuroad-

aptive processes could be involved in the development of the

stable bias toward the use of hippocampus-independent

learning strategies that characterizes this mouse strain.

The nucleus accumbens in coping and learning Strain-specific adaptation of meso-accumbens DA trans-

mission to stress could be a relevant mechanism of resili-

ence in mice of the DBA strain. Indeed, DA transmission

in the nucleus accumbens (NAc) plays a major role in the

shift between active and passive coping (see Cabib and

Puglisi-Allegra, 2012, for a recent review). High levels

of NAc DA characterize the response to a controllable/

avoidable stressors and support active coping responses

by activating local D2 receptors. Instead, inhibition of DA

in the NAc characterizes the response to uncontrollable

stressors and is associated with the expression of help-

lessness. Mice of the inbred C57 strain are susceptible to

rapid reduction of DA in the NAc when under stress, and

this effect is prevented by a chronic antidepressant treat-

ment capable of reducing helpless responses. DBA mice,

instead, require prolonged exposure to an uncontrollable

stressor to show reduced NAc DA levels, and this resist-

ance is enhanced by a previous experience with a dif-

ferent stressor (Ventura et al., 2001, 2002; Alcaro et al.,

2002; Cabib et al., 2002). Moreover, the two strains differ

in meso-striatal D2 receptor functioning, depending on a

G × E interaction possibly modulating the alternative splic-

ing of the D2 gene (Puglisi-Allegra and Cabib, 1997; Cabib

et al., 1998; Colelli et al., 2010). Nevertheless, NAc DA is

required for different types of learning. In particular, acti-

vation of DA D2 receptors in the NAc is necessary for both

active and passive avoidance learning (Manag ò et al.,

2009; Boschen et al., 2012). As discussed, these types of

learning stabilize active coping strategies.

NAc integrates limbic and cortical inputs arising from

monosynaptic glutamatergic projections that originate in

the ventral subiculum of the hippocampus, basolateral

amygdala (BLA), and prefrontal cortex (Groenewegen

et al., 1987; O ’ Donnell and Grace, 1995; French and Tot-

terdell, 2003). Each of these regions is believed to supply

a different mode of input to the NAc, thus the interplay

between these different inputs is suggested to determine

the relative weight of discrete or contextual information

in associative learning. There is convincing evidence that

the interplay between cortical and limbic information is

modu lated by DA transmission in the two compartments

of the NAc: the shell (NAcS) and the core (NAcC). In rats,

excitotoxic lesions of the hippocampus or of the NAcS

prevent acquisition of place-reward association, whereas

lesions of the BLA or of the NAcC impair cue-reward asso-

ciation (Ito et al., 2006). In 6-hydroxydopamine-lesioned

rats, impairment in the discrimination of substituted

(non-spatial) or displaced (spatial) objects depends on

the extent of DA depletion in the NAcC and NAcS, respec-

tively (Nelson et al., 2012). Moreover, repeated intra-NAcS

amphetamine infusions significantly and selectively

enhance conditioned preference for a place associated

with a sweet reward. Instead, repeated intra-NAcC amphet-

amine infusions attenuate conditioned place preference,

whereas blockade of DA receptors in the NAcC facilitate

context-reward association (Ito and Hayen, 2012; Nelson

et al., 2012). These results support the view that two dis-

tinct and competing circuits involving the hippocampus

and the NAcS on one side and the BLA and the NAcC on

the other mediate the relative relevance of spatial/config-

ural and discrete/elemental information in learning pro-

cesses. It should be pointed out that DA outflow during

stressful events typically involves NAcS rather than NAcC;

D2 receptors mediating the expression of active coping are

located in the NAcS; and NAcS rather than NAcC is the site

of action of stress hormones activated by addictive drugs

(Wu et al., 1999; Marinelli and Piazza, 2002; Scornaiencki

et al., 2009). Therefore, learning circuits involving NAcS

could be central in stress-induced neuroplasticity.

NAc lesions have been reported to improve cue-fear

association and to impair context-fear association in C57

mice, thus mimicking the effects of hippocampal lesions.

In DBA mice, lesions of the hippocampus are ineffec-

tive on either context- or cue-elicited conditioned fear,

whereas NAc lesions impair both (Ammassari-Teule et al.,



2000b). These observations suggest a strain-specific

organization of learning circuits involving the NAc. In

line with this hypothesis, lesions targeting the NAcS have

been reported to facilitate latent inhibition in C57 mice

and to prevent it in mice of the DBA strain (Restivo et al.,

2002). Latent inhibition requires a preassociation of a ‘ to

be ’ conditioned stimulus (CS) with the absence of any

relevant experience. Lesions of the NAcS could facilitate

the preassociation between the CS and the absence of

consequences in C57 mice by removing the interference of

contextual information. Indeed, C57 mice acquire latent

inhibition only after prolonged preexposure to the CS

within the training context, in line with the hypothesis of

competition between context and discrete cues for associ-

ation (Ito and Hayen, 2012; Nelson et al., 2012). The obser-

vations that lesions of the entire NAc prevent context-fear

association, facilitate cue-fear association, and mimic the

effects of hippocampal lesions in C57 mice suggest a func-

tional predominance of the hippocampus-NAcS system in

this strain of mice. Also in DBA mice, the effects of selec-

tive NAcS and entire NAc lesions were similar. However,

both types of lesions reduced the associative strength of

discrete cues, as demonstrated by impairment of either

latent inhibition or CS-fear association, supporting a less

specific functional compartmentalization of the NAc in

this mouse strain.

However, lesions of the entire NAc also prevented

context-fear association in DBA mice. Although problems

with lesion localization in the brain of mice from differ-

ent inbred strains cannot be ruled out, there is a differ-

ent and more interesting explanation for this set of data.

Indeed, it has been proposed that performance in the

‘ context ’ version of the fear-conditioning test may be

based on complex configural (hippocampal) learning, but

it can also be based on an elemental (non-hippocampal)

learning (Gerlai, 1998). Mice of the DBA strain could rely

on this elemental learning in contextual fear conditioning

explaining the impairing effects of NAc lesion in either the

‘ cue ’ or the ‘ context ’ version of the task. Indeed, C57 mice

perform better than DBA in tasks that require the forma-

tion of complex cognitive representations (configural),

whereas DBA mice have a strong predisposition to process

single elements (Ammassari-Teule et al., 2000a,b; Restivo

et al., 2002). Moreover, when compared with DBA mice,

C57 mice are relatively poor learners in tasks that require

discrimination of a discrete cue (Bovet et al., 1969; Izqui-

erdo et al., 2006), and DBA mice show better discrimina-

tion of a novel object than C57 mice although these are

more efficient in discriminating displaced objects (Cabib

et al., 2003; Orsini et al., 2004). Together, results of inac-

tivation studies indicate that a circuit involving both the

NAcS and the hippocampus mediates learning based on

complex configural information in C57 mice, as reported

in rats. Instead, the observation that inactivation of the

hippocampus spares all forms of learning whereas inacti-

vation of the NAcS or of the whole NAc impairs them sup-

ports the absence of this functional circuit in DBA mice.

In conclusion, the influences of G × E interactions on

NAc-centered circuits could be responsible for the coping

style, learning strategy, and stress-induced neuroplasti-

city that characterize DBA mice.

The cost of resilience As discussed, it has been proposed that an active coping

style supports stress resilience (Southwick et al., 2005).

However, findings from G × E studies suggest that resil-

ience can be better understood as a resistance to specific

stress outcomes rather than a general insensitivity to

stress. Indeed, negative childhood experiences increase

resistance to the development of depression and anxiety

in adulthood and increase the risk of developing anti-

social behavior in adolescence. The 5-HTT-LPR L allele

exerts a protective effect against the effects of early experi-

ences on depressive and anxiety phenotypes, whereas it is

high MAO A activity that protects against the development

of antisocial behavior in adolescence (Rutter, 2006; Carola

et al., 2007). Therefore, a bias toward active coping could

specifically increase resistance against pro-depressant

effects of adverse life events rather than promote general

stress resilience.

Moreover, in view of the main role of stress in the

development of a wide range of disturbances (Thompson

et al., 2004; Jones and Fernyhough, 2007; Gramotnev and

Gramotnev, 2011), an interpretation of resilience solely in

terms of low depression-like phenotypes can dangerously

underestimate other pathological outcomes of adapta-

tion to stress. In line with this view, chronic social stress

has been shown to protect organisms against the deve-

lopment of depressive-like responses at the expense of

central leptin functioning (Chuang et al., 2010). Similarly,

food restriction protects DBA mice against stabilization

of helpless responses (Alcaro et al., 2002) and promotes

strain-specific changes in the dynamics of leptin levels

(Gelegen et al., 2007). Moreover, helplessness-resistant,

food-restricted DBA mice express high levels of cage ste-

reotypies, sensitization to the psychomotor-stimulant

effects of amphetamine, and increased sensitivity to the

rewarding effects of the addictive drug – effects that are

either absent or reduced in food-restricted C57 mice (Cabib



and Bonaventura, 1997; Cabib et al., 2000) (see Figure 1

for a summary of the strain-specific effects of restricted

feeding). It is worth pointing out that strain-specific sen-

sitization to the behavioral effects of addictive drugs has

been reported in DBA mice following different types of

chronic/repeated stressful experiences (Badiani et al.,

1992; van der Veen et al., 2007). Finally, food-restricted

DBA mice develop compulsive wheel running, leading to

a dramatic loss of body weight and to death by starvation.

Instead, food-restricted C57 mice reduce their wheel acti-

vity, thus containing weight loss and reducing the risk of

starvation (Gelegen et al., 2007).

These results suggest that the strain-specific adapta-

tion to chronic stressful experiences that characterizes

mice of the inbred DBA strain increases their resistance

to helplessness but renders these mice liable to com-

pulsive behavior. In line with this hypothesis, DBA mice

present endophenotypes associated with liability to com-

pulsion-like responses. Endophenotypes are measurable,

heritable traits theoretically situated in an intermediate

position between the clinical phenotype and the disease-

susceptibility genotype, which are proposed to be more

directly related to genetic risk (Gottesman and Hanson,

2005; Ersche et al., 2010; Fineberg et al., 2010). In the case

of compulsion-associated disturbances, including addic-

tion, most likely endophenotypes are impulsivity and low

striatal DA D2 receptors (Denys et al., 2004; Everitt et al.,

2008; Volkow et al., 2009; Ersche et al., 2010; Fineberg

et al., 2010). When compared with C57, DBA mice are char-

acterized by both phenotypes (Puglisi-Allegra and Cabib,

1997; Cabib et al., 1998; Patel et al., 2006; Colelli et al.,

2010; Loos et al., 2010; Pinkston and Lamb, 2011). There-

fore, development of compulsion-associated phenotypes

by stressed DBA mice could reproduce the effects of life

events on individuals characterized by a specific genetic

liability.

It has been proposed that compulsive responses

engage a dorsolateral striatum (putamen)-centered circuit

involved in the acquisition and expression of stimulus-

bound habit-like responses. Indeed, human and animal

studies support the view that compulsions are associ-

ated with pathological neuroplasticity within this circuit

(Everitt and Robbins, 2005; Fineberg et al., 2011; Gillan

et al., 2011). Habit learning is normally developed through

extensive instrumental training (overtraining), leading to

a progressive shift from goal-directed responses (flexible,

dependent on goal value and contingencies) to habitual

responses (rather inflexible, independent of goals and

contingencies). It has been proposed that the shift from

goal-directed to habit-like responses is dependent on a

progressive replacement of ventromedial striatal circuits

by dorsolateral striatal systems in the control of behavior

(Dickinson, 1985; Balleine and Dickinson, 1998; Robbins

et al., 2008; Belin et al., 2009). Finally, reciprocal connec-

tions between the NAc and mesencephalic DA cells consti-

tute a relevant initial station of this process (Belin et al.,

2009).

There is consistent evidence that stress, stress hor-

mones, and sensitizing treatments with psychostimulant

drugs share the ability to prompt a rapid shift into habit

learning in moderately trained organisms by influencing

plasticity within corticostriatal circuits. Thus, in a dual-

solution water cross maze, rats show a progressive shift

from a place (go to a target location) to a response stra-

tegy (make a specific body turn) to reach the escape plat-

form with increased training. However, an acute stressful

experience prompts the use of the response strategy by

moderately trained rats (Packard, 2009). Similarly, in a

learning task that allowed differentiating spatial from

habit-like learning strategies, stressed participants used

the latter strategy significantly more often than controls

(Kim et al., 2001; Schwabe et al., 2007). The latter effect

was mimicked by pharmacological costimulation of glu-

cocorticoids and noradrenergic activity, but not selective

stimulation of each one (Schwabe et al., 2010). Moreover,

a chronic stressful experience fosters the development of

a stable bias toward habit learning and opposite struc-

tural plasticity within the frontal cortex and the dorsal

striatum in the rats (Dias-Ferreira et al., 2009), and similar

neuroplastic changes are promoted by a protracted expo-

sure to exogenous corticosterone (Sousa et al., 2008).

Finally, it has been shown that chronic exposure to a

psychostimulant drug capable of promoting behavio-

ral sensitization fosters a rapid shift to habit learning in

moderately trained rats (Nelson and Killcross, 2006). As

previously discussed, stress hormones are involved in

psychostimulant-induced neuroplasticity (Marinelli and

Piazza, 2002); thus, they could be responsible, at least

in part, for the increased habitual responding following

sensitization.

On the basis of the previously discussed strain differ-

ences between DBA and C57 mice, one could expect differ-

ences in their liability to shift into habit learning following

stress. This hypothesis has never been tested; however,

there is some indirect support. It has been reported that

either C57 or DBA mice use a spatial strategy to a similar

extent in the appetitive version of a Barnes maze, but DBA

mice abandon the spatial strategy in a negative version of

the same task (Youn et al., 2012). Moreover, a temporary

experience of restricted feeding improves the detection of

configural changes by C57 mice and of elemental changes

by DBA mice (Orsini et al., 2004).



180A

B

C

D

C57BL/6DBA/2

160140120100

Imm

obili

ty (m

in)

80604020

0

0

Sample

Sample

Test

Test

0

05

1015202530

40 §

§

§

§

35

10

20

30

40

50

60

Dis

crim

inat

ion

inde

x(te

st-s

ampl

e ex

plor

atio

n)D

iscr

imin

atio

n in

dex

(nov

el-s

ampl

ed e

xplo

ratio

n)

1020304050

Per

cent

cha

ges

from

free

-feed

ing

60708090

100

Naive Experienced

Forced swimming test

Conditioned place preference

Sal 0.5Amphetamine (mg/kg)

Spatial novelty

Food

Novel object

Nfood

Food Nfood

1

Exp+Nfood

Figure 1 A summary of the strain-specific effects of a temporary reduction of food availability (12 – 14 days ending 48 h before behavioral

experiments). (A) Helplessness (mean immobility duration ± SEM) expressed in a 5-min FST by mice exposed for the first time to the stressful

experience (Na ï ve), mice with experiences of the stressful situation (10 min, 14 days earlier: Experienced), and by mice that were exposed to

FST for 10 min 24 h before the start of 12 days of food restriction (Exp+NFood). Data were published in Alcaro et al. (2002). (B) Conditioned

preference for a context repeatedly associated with amphetamine (mean % changes ± SEM from preference expressed by free-fed mice)

shown by mice exposed to 14 days of food restriction 48 h before the drug-context pairing. Data were published in Cabib et al. (2002).

(C) Discrimination of displaced objects (mean differences ± SEM between exploration of the displaced objects on the test session and on

the last sampling session) by mice exposed to 14 days of food restriction 48 h before the sampling session and free-fed mice. Data were

published in Orsini et al. (2004). (D) Discrimination of a novel object (mean differences ± SEM) between exploration of the novel and the

sampled object by mice exposed to 14 days of food restriction 48 h before the sampling session and free-fed mice. Data were published in

Orsini et al. (2004). * p < 0.05 vs. DBA. §p < 0.05 vs. free-feeding.



Conclusions The evidences reviewed indicate that mice of the inbred

DBA strain are characterized by a bias toward the use of

active coping and a resistance to develop helplessness

under stress. These phenotypes are strain specific, indicat-

ing dependence on genetic makeup; however, resistance to

helplessness increases following chronic or repeated stress-

ful experiences in this strain of mice but not in mice of the

inbred C57 strain, supporting a G × E interaction. Because

resistance to helplessness is considered the marker of stress

resilience, the neurobiological processes involved in the

G × E interaction responsible for resistance to helplessness in

DBA mice could represent important moderators of patho-

logical outcomes of stress experience. The review of the

results obtained by comparative studies in mice of the two

strains points to mesoaccumbens DA functioning and stress

hormone-induced neuroplasticity within the meso-cortico-

limbic circuits as the neurobological bases of resilience.

Finally, the evidences reviewed suggest that geno-

type-specific neurodapative changes associated with

resilience to stress-induced helplessness in mice of the

DBA strain could render this mouse strain most suscepti-

ble to compulsive-like phenotypes. Indeed, mice from this

inbred strain show endophenotypes associated with com-

pulsion liability and express compulsion-like phenotypes

following stress experiences. This finding does not support

the view that resilience to a specific stress outcome indi-

cates resistance to stress nor the hypothesis that active

coping supports resilience whereas passive coping is a

source of pathological outcomes.

It has been proposed that individual variability

in coping strategies is maintained within populations

because it supports population fitness in variable environ-

mental conditions (Koolhaas et al., 2007). The opposite

extreme phenotypes expressed by stressed DBA and C57

mice could play such a role. A life history of uncontrol-

lable stressful events can predict environmental changes

dangerous for population survival. In these situations,

allostasis, individual neuroadaptive changes regulated by

G × E interactions, and extreme phenotypes can increase

population fitness (Meylan et al., 2012). Dispersion is a

highly adaptive way of dealing with dangerous ecological

alterations, and proneness to develop compulsive active

coping under persistent stressful conditions could foster

successful dispersion of part of the endangered popula-

tion. In contrast, a strong bias toward the use of passive

coping strategies would protect part of the population

against the risks of migration, leading to successful out-

comes if the dangerous ecological change is temporary.

Received May 30, 2012; accepted October 7, 2012

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Simona Cabib is a full Professor of the Department of Psychology,

University of Rome “Sapienza”. She has an MA degree in

Philosophy from University of Naples Federico II°, Italy; an MA

degree in Education from Columbia University, NY USA; and a PhD in

Neurosciences from University L. Pasteur, Strasbourg, France. Her

fields of research are stress-promoted neuroplasticity, with special

emphasis on the brain dopamine systems, and neurobiological

mechanisms of gene-environment interactions in the mature brain.

Paolo Campus is a student of the PhD program Behavioral

Neuroscience of “Sapienza” University of Rome. He has an MA

in Cognitive Neurosciences and is preparing a dissertation on

strain-specific effects of restricted feeding on behavioral and neural

responses to stress challenge in mice.

Valentina Colelli is currently a Post-Doctoral Fellow of the

Department of Psychology of University of Rome “Sapienza”. She

has an MA in Cognitive Neuroscience and a PhD in Psychobiology

and Psychopharmacology from University of Rome “Sapienza”. She

investigates neural phenotypes promoted by gene-environment

interactions in mice including splicing activity of dopamine D2Rs

and system-specific expression of different transcription factors.


Learning to cope with stress: psychobiological mechanisms of stress resilience

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