Psychopharmacology

https://doi.org/10.1007/s00213-019-05289-x

REVIEW

Toward an animal model of borderline personality disorder

M. B. Corniquel 1 & H. W. Koenigsberg 1,2 & E. Likhtik 3,4

Received: 31 July 2018 / Accepted: 30 May 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Background Borderline personality disorder (BPD) is a pervasive psychiatric disorder characterized by emotion dysregulation,
impulsivity, impaired self-perceptions, and interpersonal relationships and currently affects 1–3% of the US population as
reported by Torgersen et al. (Arch Gen Psychiatry 58:590–596, Torgersen et al. 2001), Lenzenweger et al. (Biol Psychiatry
62:553–564, Lenzenweger et al. 2007), and Tomko et al. (J Personal Disord 28:734–750, Tomko et al. 2014). One major obstacle
to our understanding of the neural underpinnings of BPD is a lack of valid animal models that translate the key known features of
the disorder to a system that is amenable to study.
Objective To summarize the etiology, major symptoms, and symptom triggers of BPD and then propose a blueprint for building
an animal model of BPD by choosing key components of the disorder that can be implemented in rodents.
Results We identify the role of early life stress and subsequent mild stress in adulthood as contributing etiological factors and the
potential use of altered communication between frontal cortices and the amygdala in extinction and habituation, increased
impulsivity, dysregulation of the hypothalamic pituitary axis (HPA), and increased neuroinflammation as biological markers
of BPD. Building upon these features of BPD, we propose a two-hit animal model that uses maternal abandonment to alter
maturation of the HPA axis and mild secondary adult stress to evoke behavioral symptoms such as increased impulsivity and
impaired extinction, habituation, and social interactions.
Conclusion Through exploration of the etiology, symptom presentation, and altered neurological function, we propose an animal
model of BPD. We believe that a number of existing animal paradigms that model other mental health disorders should be
combined in a unique way to reflect the etiology, symptom presentation, and altered neurological function that is evident in BPD.
These model, when compared with available human data, will inform research and treatment in humans for better understanding
of systems from the micro-molecular level to more global physiology underlying BPD.

Keywords Borderline personality disorder . Early life stress . Arousal regulation

Challenges posed by borderline personality relationships, impulse control, and sense of self. This pattern
disorder symptomatology causes patients to present with extreme fears of abandonment,
emotional dysregulation, recurrent suicidal behaviors or ges-
Borderline personality disorder (BPD) is characterized by a tures, feelings of emptiness, and difficulty controlling anger
pervasive pattern of instability with regard to affect, (American Psychiatric Association 2013). Most research into
its prevalence has found that between 1 and 3% of community
This article belongs to a Special Issue on Translational Computational samples meet the criteria for BPD (Torgersen et al. 2001;
Psychopharmacology. Lenzenweger et al. 2007; Tomko et al. 2014). This prevalence
increases overall to levels of 9.3 to 12.3% within clinical out-
* E. Likhtik patient populations with some studies showing a rate as high
elikhtik@genectr.hunter.cuny.edu as 26.8% within inpatient communities (Koenigsberg et al.
1
1985; Fossati et al. 2000; Zimmerman et al. 2005).
Icahn School of Medicine at Mount Sinai, New York, NY, USA
Those with BPD have severe functional impairment in
2
James J Peters VA Medical Center, New York, NY, USA areas such as employment and interpersonal relationships
3
Hunter College, City University of New York, New York, NY, USA and on global assessments of functioning (Skodol et al.
4
The Graduate Center, City University of New York, New York, NY, 2002; Tomko et al. 2014). This severity in functional impair-
USA ment is worsened by the likelihood for suicide, as up to 10%

of the BPD population dies by suicide, a rate 50 times that of
the average population, with individuals on average
attempting suicide 3.3 times during their lifetime (Black
et al. 2004; Soloff and Chiappetta 2012).
Due to the severity of symptoms, those with BPD tend to
receive enormous amounts of psychiatric treatment even in
comparison with all other personality disorders (PDs).
Almost all BPD patients receive individual therapy and stand-
ing medications at some point in their lives, and many are
hospitalized multiple times. BPD patients begin using services
at a younger age than patients suffering from any other PD, for
example, antisocial or narcissistic personality disorder, and
most need some form of intervention in the late teens or early
twenties. Although treatment utilization decreases over time,
it remains significantly higher than in other PDs, incurring
high costs over a patient’s lifetime (Zanarini et al. 2001,
2015; Tomko et al. 2014). Several manualized psychother-
apies have been shown to be effective in treating BPD.
These include treatments focusing on developing skills for
emotion regulation, anticipating and coping with interpersonal
stresses and self-soothing (e.g., dialectical behavior therapy
(DBT); Rudge et al. 2017), using the real-time interpersonal
relationship with the therapist to identify maladaptive defen-
sive patterns and to reconstitute an integrated identity (e.g.,
transference focused psychotherapy (TFP); Yeomans and
Levy 2002), and enhancing the capacity to recognize the men-
tal states in self and others that underlie behavior (e.g.,
mentalization-based treatment (MBT); Fonagy and Bateman
2006). Medications, such as antidepressants (e.g., the selective
serotonin reuptake inhibitor fluoxetine), mood stabilizers
(e.g., the anticonvulsants divalproex Na and topiramate), and
second-generation antipsychotics (e.g., aripiprazole/
olanzapine), are minimally effective in the treatment of
BPD, but are often employed to treat specific features of
BPD (e.g., impulsive aggression and mood lability) or comor-
bid diagnoses, such as major depressive disorder or post-
traumatic stress disorder (Lieb et al. 2010).
Among outpatient psychiatric patients, borderline patients
are twice as likely to have three or more comorbid diagnoses
and nearly four times as likely to have four or more diagnoses
over their lifetimes. These comorbidities include major de-
pressive disorder (MDD), bipolar I or II (BP), panic disorder,
social and specific phobias, post-traumatic stress disorder
(PTSD), obsessive compulsive disorder (OCD), eating disor-
ders, substance use disorder, and somatoform disorder
(Zimmerman and Mattia 1999; Hall and Riedford 2017).
Many of these disorders show some overlap in symptomatol-
ogy with BPD; however, the treatments for these disorders are
not effective for the majority of BPD patients. A major con-
tributing factor to the shortage of available targeted treatments
for BPD is our inadequate understanding of the neurobiolog-
ical mechanisms underlying this disorder. This problem is
exacerbated by the lack of translational animal models that
Psychopharmacology
are solely dedicated to creating a comprehensive understand-
ing of BPD.
Whereas there is significant comorbidity between BPD and
other disorders of emotion regulation (Table 1), BPD remains
diagnostically distinct and pharmacological treatments devel-
oped to ameliorate the respective symptoms of PTSD and
MDD remain marginally effective for treating BPD (Lieb
et al. 2010). In this review, we examine the etiology, presen-
tation, and current treatment of BPD and the variety of animal
models currently used to develop a neurobiological under-
standing of mood and emotion regulation. We then propose
a guideline for the creation of an animal model that draws
from existing paradigms but is dedicated specifically to BPD.
We will also draw upon the dimensional construct ap-
proach of the Research Domain Criteria (RDoC) framework
(https://www.nimh.nih.gov/research-priorities/rdoc/index.
shtml). We identify RDoC compatible domains of the model
such as negative valence systems, social processes, cognitive
control (e.g., impulsivity), and arousal regulatory system. This
strategy can foster the identification and study of specific
neurobiological phenotypes relevant to BPD (Insel et al.
2010; Willner and Belzung 2015).
Etiology of BPD
The role of child abuse and maternal abandonment
in BPD
While the etiology of BPD is unclear, many theories on the
formation of BPD have pointed to early childhood adversity
as a major contributing factor (Adler and Buie 1979; Kernberg
1985; Linehan 1993). Theories regarding the impact of child-
hood stress are corroborated by research showing that a large
proportion of patients with BPD report a history of child abuse
or neglect at a higher level than those with other personality
disorders (e.g., antisocial, narcissistic, avoidant, and depen-
dent). This research indicates a childhood marked by sexual
abuse or increased rates of emotional withdrawal, verbal or
emotional abuse, or neglect by the caregiver (Battle et al.
2004; Crowell et al. 2009; Zanarini 2000; Zanarini et al.
2006). The severity of the reported childhood abuse has also
been linked to increased impairment in cognitive and interper-
sonal symptoms of affected BPD patients (Zanarini et al.
2002). Whereas BPD patients without a history of child abuse
show a decrease in BPD-related symptoms with age, this pat-
tern is violated in patients with a history of early maternal
separation, resulting in high symptom severity throughout
the lifespan (Crawford et al. 2009).
Increased symptom presentation after early life stress
(ELS) may be attributed to accelerated development of the
connectivity between cortical regions, such as the frontal cor-
tices and the insula, with subcortical structures, such as the
Psychopharmacology
Table 1 Comparison of
symptoms between borderline Behavior/symptoms
personality disorder and disorders
with high comorbidity Unstable self-image
Poor impulse control
Affect instability
Unstable jobs/relationships
Suicidal behavior
Feelings of emptiness
Worries of abandonment
Dissociation/paranoia
amygdala and hippocampus (Callaghan et al. 2014; Gee et al.
2013). Animal work has shown that during development with
a non-abusive caregiver, the presence of the caregiver pre-
vents stimulus-evoked increases in corticosterone as well as
amygdala activation in the child, whereas early life abuse and
neglect by the caregiver negate these protective effects
(Santiago et al. 2017; Moriceau and Sullivan 2006; Tang
et al. 2014). During development, glucocorticoid fluctuation
helps calibrate hypothalamic-pituitary-adrenal (HPA) activa-
tion in response to external stress, whereas increased levels of
glucocorticoids in response to ELS enhance maturation (Tang
et al. 2014; Moriceau et al. 2004). Likewise, BPD patients
with a self-reported history of child abuse have higher plasma
adrenocorticotropic hormone (ACTH) and cortisol concentra-
tions when challenged with an injection of dexamethasone/
corticotropin-releasing factor (Kaufman et al. 2000; Rinne
et al. 2002; Teicher et al. 2003). Additionally, youths who
were institutionalized in childhood show higher amygdala re-
activity to threat than non-institutionalized youths and a more
adult-like pattern of communication between the prefrontal
cortex and the amygdala (Gee et al. 2013).
ELS as an etiology of BPD is a tractable approach for
animal models, and a number of ELS paradigms are already
in use. Animal models using ELS show that abuse in early life
dysregulates the stress response, modulates interneuron devel-
opment in the prefrontal cortex, and drives synaptic plasticity
in the threat response system at earlier time points (Roth et al.
2009; Goodwill et al. 2018).
Genetics of BPD: early stages of analysis
ELS is not the sole defining etiology of BPD, and not all who
experience ELS go on to develop BPD. Based on twin studies,
the genetic heritability of BPD is considered to be 0.40, mean-
ing that roughly 40% of the variability underlying BPD can be
accounted for by genetic contribution (Distel et al. 2007;
Kendler et al. 2008). As with other psychiatric disorders,
BPD is associated with a complex polygenetic background
that needs further investigation via genome-wide association
studies (GWAS) with large cohorts, as has been the case for
other psychiatric conditions (Bassir Nia et al. 2018; Power
BPD BD PTSD MDD Eating disorders Addiction
✔ ✔ ✔
✔ ✔ ✔ ✔
✔ ✔ ✔
✔ ✔ ✔ ✔
✔ ✔ ✔
✔ ✔
✔
✔ ✔
et al. 2017; Schizophrenia Psychiatric Genome-Wide
Association Study (GWAS) Consortium 2011). To date, there
is a relative dearth of large GWAS in BPD patients, with most
findings coming from small sample sizes (for an in-depth re-
view, see Bassir Nia et al. 2018). A handful of these studies
have been conducted thus far, with only one study using sub-
jects that met diagnostic criteria for BPD (Lubke et al. 2014;
Witt et al. 2017). Overall, genetic analyses of BPD have found
a small number of genes that reach significance, but these
findings lack specificity as the identified genes are involved
in enzymatic activity and exocytosis and play a role in a vari-
ety of mental health disorders including MDD, bipolar disor-
der, and schizophrenia (Witt et al. 2017; Schizophrenia
Psychiatric Genome-Wide Association Study (GWAS)
Consortium 2011; Ripke et al. 2013; Duan et al. 2014).
Thus far, single candidate gene association studies have
seen small effect sizes with no associations surviving meta-
analysis or replication (Calati et al. 2013; Amad et al. 2014).
This remains true for specific genetic polymorphisms, as
many have been identified, particularly within the serotoner-
gic system; however, none is able to survive a meta-analytic
review (Calati et al. 2013).
One such polymorphism, the serotonin transporter-linked
polymorphic region (5-HTTLPR), located within the promot-
er region on chromosome 17, is worth mentioning due to its
role in impulsivity and stress reactivity more generally. The 5-
HTTLPR coding for the serotonin transporter is tri-allelic with
one shorter (S) and two longer (LA and LG) alleles. The LG
allele functions similarly in vitro to the S allele, and the two
are often combined into one S′ allele subtype, characterized by
less serotonin transporter expression compared with the LA
allele. As less serotonin transporter is expressed, serotonin is
cleared more slowly from the synapse for individuals with the
S′ allele (Collier et al. 1996). Although it has been widely
studied, meta-analyses have returned mixed results on the re-
lationship of the 5-HTTLPR to depressive and anxious traits
in response to stress, possibly due to varied diagnostic inven-
tory use, methods for assessing stress (i.e., questionnaires vs.
clinical interviews), the types of stressors included in the sam-
ple, and genotype characterization between studies (Risch
et al. 2009; Karg et al. 2011; Culverhouse et al. 2017; Bleys

et al. 2018; Middeldorp et al. 2007; Munafò et al. 2009;
Schinka et al. 2004; Sen et al. 2004). 5-HTTLPR has not been
shown to have an independent relationship with a risk of BPD
but is far more likely to function in a modulatory capacity for
other genes, possibly mediating the response to ELS (Ni et al.
2006; Pascual et al. 2008). For example, polymorphisms for a
longer version of 5-HTTLPR were associated with increased
impulsivity in BPD patients that suffered childhood abuse
(Wagner et al. 2009). Overall, although the role of genetics
is undeniable in the underpinnings of BPD, the lack of known
replicable and diagnostically specific genetic risk factors sug-
gests that at present this route is a poor candidate for a BPD-
specific animal model.
Daily life stress in adulthood and symptoms
of BPD
While genetic background and ELS can account for the de-
velopment of BPD, the onset of a particular symptom is typ-
ically preceded by a more temporally proximal stressful event.
Emotional instability in response to quotidian adult stress is an
integral aspect of BPD. Indeed, dialectical behavioral therapy
is one effective psychotherapy for BPD, which specifically
provides BPD patients with the tools to identify and manage
daily stress.
To test the contingency between a stressful event and emo-
tional state with symptom presentation, clinical researchers
use experience sampling, an approach where subjects report,
in real-time, their daily life experiences (including events,
emotions, perceptions, and symptoms) throughout the day
over a period of one or more days. As a result of this work,
BPD subjects were shown to be especially sensitive to daily
life stress, with minor stressors perceived as more intense by
BPD subjects relative to healthy controls, and their emotional
response likewise more intense (Berenson et al. 2011; Myin-
Germeys et al. 2005). Since BPD patients are particularly
reactive interpersonally, animal models distinguishing be-
tween social and non-social stresses may prove valuable.
Non-social stress
Patients with psychotic disorders exhibit increased symptoms
following minor daily life stress, and this tendency extends to
the stress-induced transient psychotic symptoms seen in BPD
(Myin-Germeys et al. 2005). In BPD patients, non-social
stress, such as a deadline or the memory of a past event, has
been associated with the onset of dissociative symptoms, para-
noia, and hallucinations (Glaser et al. 2010; Stiglmayr et al.
2008). Non-social stress has been modeled in animals by un-
predictable and uncontrollable administration of mild shocks
(Perova et al. 2015) or via unpredictable restraint stress
(Donaldson et al. 2014). Such non-social stress paradigms in
Psychopharmacology
animals can be used at reduced levels as minor stress triggers
in adulthood to study the onset of symptom presentation in
BPD (see BStress induction in modeling mental health
disorders^).
Social stress
Stressors based on social interactions, such as rejection or
abandonment, invalidation of one’s experiences, a perceived
interpersonal offense, or betrayal, have all been linked to the
symptom onset of BPD. Further, disappointment at having
one’s self-concept threatened and being offended have all
been associated with the onset of BPD symptoms. Perceived
rejection is associated with intense attempts to avoid abandon-
ment, relationship instability, uncertain self-image, impulsive
behavior, unstable mood, feelings of emptiness, dissociation,
and intense anger. While anger is a common response to re-
jection, those with BPD are thought to have a higher rejection
sensitivity and therefore respond more intensely to minor re-
jection (Berenson et al. 2011; Miskewicz et al. 2015). Being
alone, another social stressor, has also been linked to intense
efforts to avoid abandonment and impulsive behaviors
(Miskewicz et al. 2015). While many of these stressors are
difficult to reconstruct in an animal model, aloneness can be
replicated via social isolation and rejection via a mild form of
social defeat stress or introducing a new animal into an
established hierarchy (see BStress induction in modeling men-
tal health disorders^).
Anatomy and physiology of BPD
An assortment of neuroimaging techniques has been used to
study regional gray matter volume, white matter connectivity,
and functional connectivity (connectivity implied by the syn-
chronous neural activity of separate brain regions) in BPD
patients during specific behavioral tasks. Magnetic resonance
imaging (MRI) has revealed differences between healthy con-
trol subjects and BPD patients in regional brain volumes and
white matter integrity in fronto-limbic regions. BPD patients
have decreased gray matter volume of the anterior cingulate
cortex (ACC), the hippocampus, the medial prefrontal cortex
(mPFC), and the dorsolateral frontal cortex (dlPFC), while the
findings for the amygdala are mixed (Brambilla et al. 2004;
Denny et al. 2016; Hall et al. 2010; Kuhlmann et al. 2013;
Minzenberg et al. 2008). Studies using diffusion tensor imag-
ing show that BPD patients present with decreased fractional
anisotropy (an indicator of diminished axonal integrity or fiber
density) in the fornix, cingulum, corpus callosum, uncinate
fasciculus, and prefrontal white matter fasciculi (Carrasco
et al. 2012; New et al. 2013; Lischke et al. 2015; Whalley
et al. 2015; Gan et al. 2016). Lischke et al. (2015) and Gan
et al. (2016) also tested axial and radial diffusivity to gain a
Psychopharmacology
better understanding of the integrity of the white matter tracts.
Both studies found an increase in radial diffusivity, indicating
myelin degeneration rather than axonal injury in these tracts
(Song et al. 2002; Sun et al. 2006). These changes may be due
to a stress-related inflammatory response, a view that is sup-
ported by increased cytokine expression in BPD (Díaz-Marsá
et al. 2012).
When viewing emotionally valent images, BPD patients
have a hyperactive response in the amygdala and a hypoactive
response in frontal cortices such as the OFC and dorsolateral
prefrontal cortex (Baczkowski et al. 2017; Herpertz et al.
2001; Koenigsberg et al. 2009; Soloff et al. 2015; Soloff
et al. 2017). There is notable overlap between these findings
and changes observed in PTSD patients who present with
decreased ventral prefrontal cortical volume and resting state
activity, combined with hyperactivity in the ACC and amyg-
dala that has been repeatedly associated with poor extinction
learning and recall (Hayes et al. 2012; Stevens et al. 2013;
Marin et al. 2016). These findings suggest that we can draw
on animal models of PTSD, which have shown that during
successful extinction, activity in the ventral mPFC suppresses
fear via its communication with downstream targets, including
the amygdala, where the vmPFC is thought to shift the
excitatory-inhibitory balance toward inhibition, suppressing
amygdala output and defensive responding (Quirk et al.
2003; Rosenkranz and Grace 2001; Berretta et al. 2005; Cho
et al. 2013; Bukalo et al. 2015; Maren and Holmes 2016).
Thus, we would expect that decreased vmPFC volume should
result in diminished suppression of amygdala activity and
contribute to elevated autonomic and behavioral responses
associated with aversive experience (Likhtik et al. 2014;
Likhtik and Paz 2015; Maren and Holmes 2016).
In support of this data, BPD patients also show decreased
prefrontal function and amygdala hyperactivity that is coupled
with impaired extinction and lack of habituation to aversive
stimuli (Denny et al. 2018; Hazlett et al. 2012; Krause-Utz
et al. 2016; Schulze et al. 2016). For example, work using
fMRI during acquisition of differential fear conditioning in
female BPD patients shows that there is a lack of habituation
to an unpaired stimulus in the amygdala as well as increased
activity in the insula compared with healthy controls (Krause-
Utz et al. 2016). Likewise, during extinction of conditioned
stimuli, BPD patients show delayed recruitment of the pre-
frontal cortex coupled with continued amygdala activation to
unreinforced stimuli (Krause-Utz et al. 2016). BPD patients
also show a non-adapting amygdala response during novel
and repeated presentations of emotionally salient images
(Denny et al. 2018; Hazlett et al. 2012; Koenigsberg et al.
2014). Furthermore, during stressful situations, the inflicting
of pain can cause a decrease in amygdala activity associated
with a reduction of subjective anxiety for the patient
(Niedtfeld et al. 2010; Reitz et al. 2015). The replicated find-
ing of delayed extinction and impaired habituation in BPD
suggests that hyperactivity in the amygdala, insula, and ante-
rior cingulate cortex, combined with the hypoactive mPFC, is
a relevant behavioral and physiological marker for validating
an animal model of BPD.
Mapping current animal models of psychiatric
disorders onto BPD
Given that BPD patients display a constellation of behaviors
that are already modeled in animals for other mental health
disorders, including PTSD, MDD, and addiction (Table 1), we
draw upon relevant paradigms from these models (Table 2).
The tests are aimed at creating species-specific and etiologi-
cally relevant representations of pathological behaviors seen
in humans. We begin by outlining the relevant Btoolbox^ of
strategies that are currently used in animals to model PTSD,
MDD, and substance abuse, which can be adapted and
recombined for modeling BPD. Then, we propose a combina-
tion of paradigms that are most useful for representing BPD-
like behavior and physiology in animals. Importantly, the in-
terpretation of why a particular behavior occurs is often asso-
ciated with more abstract concepts such as reward processing,
impulsivity, and anxiety. These concepts, although fraught
with anthropomorphic categorizations, nonetheless allow for
investigation of brain-specific systems that are translationally
relevant and can lead to therapeutic and basic science
advances.
Currently, women are diagnosed with BPD in dispropor-
tionately higher numbers than men, a factor that may be more
attributable to clinical bias and the reported differences in
BPD expression rather than actual rates in the population.
For example, men are more likely to report impulsive aggres-
sion, while women report greater chronic emptiness, instabil-
ity, and self-mutilation (Hoertel et al. 2014; Sher et al. 2019).
Simultaneous work in human populations and in animal
models of BPD would provide more detailed information on
sex differences in behavioral responding (e.g., behavioral re-
sponse by social vs. asocial stressor, and will give novel in-
sights into the underlying neural mechanisms that drive BPD-
like behaviors in both sexes.
Stress induction in modeling mental health disorders
Given that PTSD is defined as a stress- and trauma-induced
disorder (American Psychiatric Association 2013) and MDD
is also stress-responsive, current animal models have been
developed to simulate highly stressful or traumatic events in
humans, in order to systematically explore the impact of stress
on behavior. Therefore, various forms of stress are considered
for incorporation into an animal model of BPD.

Table 2 Suggested symptom measures for inclusion in an animal model of BPD
Symptom Existing model? Measures
Unstable self-image X
Poor impulse control ✔ Delay discounting
Choice of small early vs. large later rewards
Choice of small frequent vs. large infrequent rewards
Affect instability ✔ Habituation to stimuli
Extinction acquisition
Extinction recall
Unstable jobs/relationships ✔ Social interaction test
3-chamber social interaction
Suicidal behavior X
Feelings of emptiness X
Worries of abandonment X
Dissociation/paranoia X
Early life stress ELS is an important component for a model of
BPD, as most BPD patients have undergone severe stress
early in life (see BThe role of child abuse and maternal aban-
donment in BPD^). In rodent models, ELS is typically caused
by altering the dam-pup relationship through bedding depri-
vation, maternal separation, or maternal deprivation. The bed-
ding deprivation approach stresses the dam via limited access
to bedding materials for nest building, which results in the
dam leaving the nest more often in search for materials and
increases the dam’s abusive behavior toward her pups (Rice
et al. 2008). The repertoire of abusive rodent behavior in-
cludes the dam dropping, dragging, roughly handling, or ig-
noring her pups; all of which are rarely seen in control condi-
tions (Ivy et al. 2008; Rice et al. 2008). In animal models
employing this approach to induce ELS, the pups grow up
to exhibit an increased corticosterone response to restraint
stress, show higher defensive freezing in tests of fear condi-
tioning, and more anxiety-like behavior in assays of innate
anxiety (e.g., ELS-exposed rats spend less time in the open
arms of an elevated plus maze test compared with rats that
were raised with adequate care; Dalle Molle et al. 2012;
Machado et al. 2013; Walker et al. 2017). Another form of
inducing ELS is maternal separation where the mother and
pups are separated for a short duration (3–6 h) over multiple
days or for a longer period (24 h) for only one session.
Notably, depriving pups of their mothers between postnatal
days 4 and 20 for an extended period of time (24 h) results
in a hyperreactive HPA axis in the pups, as assessed via in-
creased levels of corticosterone following stress (Banqueri
et al. 2017). Maternal separation is also associated with in-
creased innate anxiety in adulthood (Stanton et al. 1988;
Sampath et al. 2014; Sousa et al. 2014).
Social stress induction Social stress is an important factor in
BPD, as social stressors often trigger behavioral dysregulation
Psychopharmacology
RDoC
Domain: positive valence system
Construct: reward valuation
Domain: arousal/regulatory system, construct:
arousal
Domain: negative valence
Construct: acute threat (fear)
Domain: social processes
Constructs: affiliation, attachment
in BPD (see BSocial stress^). Animal models of social
stressors include social defeat stress or housing and social
instability stress. In the social defeat stress paradigm, the an-
imal (usually a mouse) is exposed to a larger aggressor who
will physically dominate it for a short time (~ 5 min). The
subordinate mouse is then housed in the presence of the ag-
gressor, while being separated by a divider to prevent physical
harm but can still see and smell the aggressor. This paradigm
is intensified by adding social instability in the form of
switching to a novel aggressor-cohabitant pairing on each
day of the paradigm (Golden et al. 2011). Other forms of
social stress include mild variable stress, whereby an animal’s
living environment is altered in new and unexpected ways
every day (including cage tilting, overcrowding, and shifted
light/dark cycles; Hodes et al. 2015; Menard et al. 2017).
Other examples of housing or social instability involve con-
sistently changing the subject’s cage mates or isolating the
subject from its cohort and housing it alone. Further, the more
molecular form of social stress is the predator scent stress
where a mouse is exposed to a predator smell, such as com-
ponents of fox or cat urine (Wang et al. 2018).
Non-social stress induction Variants of non-social stressors
have been used to model PTSD-like trauma and to induce
MDD-like behaviors. They may provide a different perspec-
tive on the influence of stress in BPD. Stress-enhanced fear
learning (SEFL) is incorporated in models of PTSD. This may
take the form of exposure to unpredictable shocks in order to
simulate a traumatic event (Rau and Fanselow 2009;
Rajbhandari et al. 2018). Notably, this protocol results in en-
hanced fear learning and resistance to extinction (Rau et al.
2005; Long and Fanselow 2012), which are two important
behavioral outcomes that overlap between PTSD and BPD.
Likewise, long-lasting learned helplessness is achieved by re-
peatedly exposing an animal to an uncontrollable and
Psychopharmacology
unpredictable stressor, such as many repeated presentations of
low-intensity foot shock (e.g., 360 shocks over two sessions),
followed by continued re-exposure to the stressful context
(Landgraf et al. 2015; Maier 2001). Notably, animals that
are exposed to the same number foot shocks but for whom
this stressor is controllable (e.g., they find a way to turn it off
through a lever press) do not develop depression-like symp-
toms to conditioned stimuli, suggesting the importance of
control over one’s environment in developing symptoms of
MDD (Baratta et al. 2007). Other forms of stress induction in
animal models include underwater trauma, which involves
placing a water-naïve rat or mouse into a container of water
that is deep enough to prevent the animal from standing and
submerging the animal into the water for roughly 30 s (Moore
et al. 2012). Another form of stress is restraint stress, in which
a mouse or rat is immobilized using an apparatus such as a
plastic restraint tube for 30 min to 2 h, a paradigm that also
leads to impaired extinction (Rahman et al. 2018).
By using a variety of stressors like a foot shock, restraint, or
underwater trauma and presenting them as a series of non-
repeating stressors at different times in the light-dark cycle
over several days, animals do not acclimate to the stressors
and show an MDD-like state of anhedonia. Recently, a two-hit
model, combining early life stress with social defeat in adult-
hood, was employed for the induction of depressive-like
symptoms (Peña et al. 2017). Another two-hit animal model
has been used to model schizophrenia, where the Bfirst hit^
refers to an in utero/neonatal immune reaction typically
brought on by molecules like lipopolysaccharide found in
gram-negative bacteria membranes (Bayer et al. 1999;
Maynard et al. 2001; Feigenson et al. 2014). However, the
two-hit approach that is more relevant for BPD does not rely
on an in utero manipulation but rather a combination of ELS
and mild daily stress in adults.
Behavioral measures utilized to examine stress
induction models of mental health disorders
Animal models of MDD incorporate behavioral measures
such as anhedonia, social withdrawal, decreased motivation
for obtaining reward, and behavioral despair (Peña et al. 2017;
Menard et al. 2017; Anacker et al. 2018). These depression-
like symptoms are operationalized in the sucrose preference
test (modeling anhedonia; Yan et al. 2010; Peña et al. 2017;
Menard et al. 2017), forced swim test/tail suspension test
(decreased movement is interpreted as loss of motivation or
behavioral despair; Nollet et al. 2013; Smolinsky et al. 2009),
and social interaction test (social withdrawal; Golden et al.
2011; Hodes et al. 2015). If a particular induction method
leads to increased anhedonia, weight loss, decreased self-
grooming, and social withdrawal, it is considered to be a par-
ticularly strong animal model of MDD. The most relevant of
these paradigms for modeling BPD is the social interaction
test, as unstable relationships are a cardinal feature of BPD
diagnosis (American Psychiatric Association 2013). PTSD-
like behavioral responses to stress include heightened anxiety,
sensitization to fear learning, and impaired extinction learning
(Rau et al. 2005; Long and Fanselow 2012; Maren and
Holmes 2016; Rahman et al. 2018). Of these, impaired extinc-
tion of conditioned fear and heightened anxiety are useful tests
for modeling BPD in animals. Likewise, stress exposure has
been associated with increased impulsivity in BPD patients
(Krause-Utz et al. 2016; Fields et al. 2014). Behavioral mea-
sures of impulsivity using delay discounting tasks in animals
have characterized a variety of traits that can model the BPD-
like endophenotype and are easily integrated with human
studies to define the neural mechanisms of impulsivity in
BPD. To validate animal models of BPD, we will focus on
measures of social interactions (mostly used in MDD re-
search), emotion regulation (used in MDD and PTSD re-
search), and impulsivity (often used in substance abuse re-
search), as the most appropriate outcomes for modeling
BPD-like symptoms.
Social interactions Social withdrawal is typically measured
with tests that assay changes in social interactions after stress
exposure (e.g., social defeat stress and chronic variable stress).
In this assay, a mouse is given the chance to explore either one
of two cups, one that contains a novel mouse and one that is
empty. Mice are social animals; however, a stressor typically
decreases the amount of time mice spend exploring other
mice, increasing exploration of the empty cup instead
(Menard et al. 2017; Peña et al. 2017; Hodes et al. 2015). In
this approach, the pre- to post-stress comparison controls for
individual differences in innate anxiety and sensitivity to so-
cial stimuli. In the case of BPD, the social interaction should
also be scored for social aggression in addition to social
avoidance.
Emotion regulation Emotion regulation is probed via re-
sponses to innately anxiogenic stimuli, behavioral responding
to stimuli that are conditioned to be associated with a threat-
ening versus a non-threatening outcome, and responses to
stimuli that undergo extinction of previously aversive associ-
ations. The former addresses emotional reactivity and the lat-
ter is one possible mechanism of emotional regulation, both of
which are dysregulated in BPD. Tests of innate anxiety reac-
tivity exploit exposure to anxiogenic environments or stimuli
that animals try to avoid in the wild (e.g., for rodents, this
includes large, empty, well-lit spaces and for primates, this
includes snakes). ELS, social stress, and non-social stress in-
crease innate anxiety on measures such as the open field and
EPM, collectively indicating that after stress animals decrease
exploration of innately anxiogenic environments (Machado
et al. 2013; Walker et al. 2017; Peña et al. 2017; Chattarji
et al. 2015). Tests of new learning about an aversive

conditioned stimulus (CS) typically rely on classical condi-
tioning by pairing a neutral stimulus (e.g., a light, tone, or
the context itself) with an aversive unconditioned stimulus
(US) (e.g., electric shock to the feet or an air puff to the
eye). Prior stress enhances fear expression upon re-exposure
to the context or to the stimulus that has been previously
associated with the physically aversive event (Rau et al.
2005; Chattarji et al. 2015). One form of emotion regulation
may be tested via acquisition and retention of extinction learn-
ing, where subjects learn that the previously paired CS no
longer predicts the US. The inability to extinguish CS-US
associations and difficulty in learning to distinguish stimuli
that predict threat from those that do not closely approximate
human behavior in PTSD where patients show persistently
high level of fear to trauma-associated cues, even long after
the cues stop being associated with the trauma (Marin et al.
2014, 2016; Rabinak et al. 2017). Notably, impaired acquisi-
tion and retention of extinction learning have been modeled in
animals via genetic modification as well as stress exposure
(Maren and Holmes 2016; Chauveau et al. 2012; Gunduz-
Cinar et al. 2018), which may provide a useful direction for
future work in genetic modeling of BPD. Thus, impairments
in extinction learning and retention are useful behavioral
markers of the emotional dysregulation seen in BPD.
Impulsivity BPD patients manifest impulsivity that is typically
self-damaging, such as risky sexual behavior, reckless driving,
binge eating, and excessive spending. Such behaviors reflect
immediate need for gratification without considering the con-
sequences and can be modeled by delay discounting tasks in
animals (Dalley and Robbins 2017). Animal and human ver-
sions of the delay discounting paradigm measure the propen-
sity to choose a small but immediate reward versus a larger
delayed reward, where the value of the larger reward becomes
discounted relative to smaller one by the longer delay before
receipt of the larger reward (Bailey et al. 2018). Likewise,
risky choice is a probabilistic form of discounting akin to
gambling, where the larger reward is less frequent and is there-
by associated with increased risk (Dalley and Robbins 2017).
Notably, damage to the nucleus accumbens core (in the ventral
striatum), the medial PFC/ OFC, and PFC-amygdala commu-
nication has been associated with increased risky choices
(Cardinal et al. 2001; St Onge and Floresco 2010; St Onge
et al. 2012; Stopper et al. 2014; Zeeb et al. 2015). In line with
this, recent work shows that BPD patients have decreased
ventral striatum activation during choices associated with loss
(Herbort et al. 2016), suggesting that there is overlap between
animal and human studies in this area. Furthermore, binge
eating is considered to be a type of impulsive behavior in
BPD, and therefore this behavioral assay could be considered
a secondary outcome measure in an animal model of BPD.
However, the effects of stress on food intake are not unidirec-
tional. Whereas chronic stress leads to anhedonia and weight
Psychopharmacology
loss, a factor that has been used to model MDD, combining
chronic stress with food restriction and re-feeding, was shown
to lead to binge-like eating behavior (Hagan et al. 2002; Artiga
et al. 2007). Furthermore, stress exposure via maternal sepa-
ration during pre-weaning in combination with social isolation
stress in juvenile rats was shown to increase bingeing-like
behavior (Jang 2011). Thus, food intake may be pursued as
an outcome measure for modeling BPD, but first we suggest
that a more detailed analysis of how stress affects feeding be
conducted.
Dimensional and categorical modeling
In this review, we first emphasize categorical modeling—
which is developing an animal model for the diagnostic cate-
gory of BPD. However, we also propose modeling dimen-
sions of BPD psychopathology that may cut across diagnoses.
In this approach, domains of psychopathology relevant to
BPD can be studied independently across diagnoses. This
approach offers the opportunity to identify important
endophenotypes, to understand component mechanisms of
psychopathology (and their relationships to normal function),
and to target treatment to specific dysfunctions. The NIMH
has articulated such an approach in its Research Domain
Criteria (RDoC) program. Each strategy has its strengths and
weaknesses. The categorical approach tracks current clinical
practice, in which treatments are selected based on the specific
diagnosed disorder or its predominant symptoms. In this re-
gard, our proposal to develop an animal model for BPD af-
fords the possibility of developing specific treatments for this
disorder and addresses the dearth of animal models for BPD,
whereas such models exist (as described above) for depres-
sion, PTSD, and substance use among others. The
transdiagnostic dimensional approach may more closely ex-
pose underlying biological mechanisms. While our principal
focus here is upon strategies to design models of the BPD
diagnosis per se, below we describe approaches to model in-
dividual BPD dimensions. We believe that a combination of
categorical and dimensional modeling will have the greatest
yield in informing us about BPD psychopathology and treat-
ment approaches.
Building an animal model of BPD
We propose an animal model of BPD that integrates stress
induction and behavioral outcomes that have proven useful
in modeling other mental health disorders, combined in a
manner that has face and construct validity that is specific to
BPD. We propose that the model is further validated by how
well it recapitulates known pathophysiology of BPD
(BAnatomy and physiology of BPD^). Given that there is
Psychopharmacology
currently no BPD-specific pharmacological treatment, phar-
macologic validation is not currently possible.
A two-hit model: early life stress followed by mild
adult stress
In light of the current lack of knowledge regarding the genetic
underpinnings of BPD, efforts to incorporate genetics into the
model would be premature. We suggest an etiologic model
that combines ELS, seen to be prevalent in BPD (see BThe
role of child abuse and maternal abandonment in BPD^), with
stress exposure in adulthood (i.e., a two-hit model), analogous
to the observed development of BPD (see BDaily life stress in
adulthood and symptoms of BPD^ and Fig. 1). As described
in BStress induction in modeling mental health disorders,^
currently existing ELS paradigms for the pre-weaning period
simulate early life etiology of BPD in rodents. These include
early maternal separation, the creation of a mother that mis-
treats or neglects her pups by introducing insufficient bedding,
or other environmental stressors that increase corticosterone
levels in the pups (Opendak et al. 2017; Flannery et al. 2017;
Goodwill et al. 2018). Following ELS, and once the animal
has reached adulthood, a mildly stressful version of a variety
of stress paradigms can be used to mimic conditions that lead
to the symptom onset in BPD. The adult stressors may come
from social stress paradigms, such as chronic mild variable
stress, social isolation, or brief social defeat stress (Nollet
et al. 2013; Menard et al. 2017; Peña et al. 2017).
Alternatively, ELS may be combined with a non-social stress-
or, such as repeated and unpredictable restraint stress, shock-
evoked stress (e.g., SEFL), or food restriction (Perova et al.
2015; Rajbhandari et al. 2018; Donaldson et al. 2014).
Etiology Mild Adult Stressor
(Day 0-21) (Day 60+)
One of the following One of the following
• • Mild variable stress
Maternal Separation
• • Restraint stress
Low Bedding
• Mild social defeat stress
• Neglectful/ mistreating
• Social Isolation
mother
Fig. 1 A suggested layout for an animal model dedicated to the study of
BPD. The timeline refers to development of mice and confers a model
with early life stress as the etiology established pre-weaning, followed by
mild stress administration in adulthood, and outcome measures
immediately after the trigger. We suggest several possibilities for
inducing early life stress and mild adult stress. The suggested methods
for stress induction and outcome testing are a guide, and the specific
constellation of chosen tests will depend on each researcher’s interests.
Individual parameters within each paradigm (e.g., length or
frequency of stress exposure) can be adjusted for mild levels
of stress that do not affect behavioral performance in healthy,
non-ELS controls.
Laboratory outcome measures for model validation
To best match the time course of the symptom onset in BPD,
behavioral measures should be conducted immediately post-
exposure to the minor adult stressor (Miskewicz et al. 2015;
Fig. 1). Furthermore, we would expect that re-testing for the
same behavioral outcomes at time points that are further re-
moved from the mild stress would demonstrate normalized
behavior, as this is the time course of symptoms seen in pa-
tients with BPD. However, we would expect to see that an-
other exposure to mild stress will once again reinstate the
tested maladaptive responses. Broad categories of BPD symp-
toms that lend themselves to animal modeling include affect
instability, poor impulse control, and unstable relationships
(BBehavioral measures utilized to examine stress induction
models of mental health disorders,^ Table 2). Below, we out-
line a series of behavioral and physiological measures that we
suggest to model BPD. For each type of behavioral test, we
indicate the associated RDoC area (Table 2). We suggest that
for the animal model of BPD to be valid, that behavior on the
social interaction test and at least one of the other proposed
paradigms shows maladaptive responses to mild stress and
recapitulates BPD-like physiology. This approach is in line
with the current practices outlined in DSM-V (American
Psychiatric Association 2013), where a patient must demon-
strate disrupted interpersonal communication and pathologi-
cal personality traits for a diagnosis of BDP.
Outcome Tests
(immediately post trigger)
Behavior
Social interaction/ 3-chamber Sociability test
and at least 1 of the following:
• Fear extinction consolidation (recall)
• Habituation
• Delay Discounting
Physiology
• Blood Corticosterone Levels
• Cytokine Expression
• Activity in prefrontal - amygdala, nucleus
accumbens/ ventral striatum circuits
For the most accurate behavioral model of clinical BPD, we recommend
that deficits in a test of social interaction or the 3-chamber sociability test
are established along with a deficit in at least one of the following behav-
ioral measures: fear extinction consolidation, habituation, and delay
discounting (see BLaboratory outcome measures for model validation^).
Physiology measures have expected outcomes based on previous findings
(see BBuilding an animal model of BPD^). Repeated mild stressor out-
come measures are appropriate

Use of the social interaction test to assess social instability
in an animal model of BPD
Domain (social processes) and construct (affiliation and at-
tachment) Impairments in interpersonal functioning are a car-
dinal symptom for a BDP diagnosis. To model unstable rela-
tionships, we propose tests of social interaction in dyads and
groups to compare animal behavior pre- and post- minor stress
triggers, in order to assess interaction patterns such as
exploration/sniffing and attack/biting, as well as the three-
chamber paradigm to test whether animals will choose a com-
partment with a familiar or a novel animal. In the animal
model of BPD, we would expect that rodents show signs of
decreased social exploration after mild adult stress relative to
their own pre-stress levels, and we would expect an increase in
aggressive rodent behavior, such as increased instances of
attacks and biting in dyad interactions.
Use of habituation and extinction to assess analogs
of emotion regulation in an animal model of BDP
Habituation: domain (arousal and regulatory systems)
and construct (arousal)
Extinction: domain (negative valence) and construct (acute
threat (fear)) To determine the extent to which the animal
model captures a phenotype related to affect instability in
BPD, we propose assessing fear extinction and startle habitu-
ation, both of which are affect-related processes that are mea-
surable in animal models by commonly used experimental
paradigms. BPD patients show affect instability, which may
be assessed by impaired extinction and enhanced fear condi-
tioned learning (BAnatomy and physiology of BPD^).
Maladaptive extinction learning, as observed in BPD patients,
is the inability to properly consolidate extinction of the defen-
sive response to stimuli that are continuously presented with-
out the previously accompanying aversive CS. We expect the
same impairments in consolidation of extinction learning in
animals that are revealed during the test of extinction recall.
This behavioral approach can be readily combined with an
investigation of the physiological and molecular mechanisms
of extinction failure.
One well-studied aspect of BPD physiology in humans is
the dysregulated communication between frontal cortices and
the amygdala during habituation and extinction (Koenigsberg
et al. 2014; see BAnatomy and physiology of BPD^). In keep-
ing with this, simultaneous physiological recordings in the
prefrontal-amygdala circuit during extinction and habituation
in animal models of BPD should demonstrate increased amyg-
dala activity during habituation and extinction recall, along
with diminished CS-driven prefrontal activation. Likewise,
based on human work, a lack of stimulus habituation is pre-
dicted to be associated with continuous activation of the
Psychopharmacology
amygdala (Koenigsberg et al. 2014; Schulze et al. 2016;
Krause-Utz et al. 2016; Hazlett et al. 2012). Furthermore,
studies in BPD patients show that stress-induced self-inflic-
tion of pain downregulates the amygdala (Niedtfeld et al.
2010; Reitz et al. 2015), suggesting that this reaction to stress
may be worth exploring in an animal model as a method of
validation. In this regard, following a stressful event, such as
social isolation, the rodent amygdala response to a mild form
of injury, such as the tail flick or hot plate tests (Illich et al.
1995) should be monitored. The predicted outcome based on
observations from work in humans would be that the stressed
animals show faster latency pain responses and higher amyg-
dala activation. These behavioral analyses can be combined
with simultaneous multi-site physiological recordings, immu-
nohistochemistry, or imaging, to evaluate activity within the
PFC and amygdala circuit. Likewise, manipulation of PFC-
amygdala communication (e.g., via optogenetics) is predicted
to either impair extinction recall, if PFC input to the amygdala
is inhibited, or improve it, if PFC input to the amygdala is
excited. For tests of habituation, amygdala silencing is pre-
dicted to repair the response.
Use of delay discounting to assess impulse control
in an animal model of BPD
Impulse control: domain (positive valence system) and con-
struct (reward valuation) Impulsive behavior is one of the core
symptoms of BPD. To measure impulse control, we propose
delayed discounting tests that use choice preference for small-
er, more immediate versus larger delayed rewards and risky
choice paradigms that assess choice for smaller and frequently
occurring rewards versus larger but infrequent rewards
(Table 2). Whereas in non-stressed controls we expect to see
behavior that follows low-risk options, we expect that our
BPD-like animals will be equally likely to prefer the risky as
the non-risky options (Endrass et al. 2016). Physiology and
imaging of circuit-level activity during delay discounting
tasks are predicted to show decreased dorsal and medial ante-
rior cortex activity (St Onge and Floresco 2010; St Onge et al.
2012; Zeeb et al. 2015) and decreased activity in the nucleus
accumbens core (Herbort et al. 2016; Cardinal et al. 2001). We
would also expect decreased PFC-amygdala communication
(Churchwell et al. 2009).
Hormone and cytokine expression to assess physiological
responses in an animal model of BPD
In conjunction with the behavioral tests we have outlined,
physiological measures such as ACTH, corticosterone levels,
and cytokine expression should assay stress-related activation
and inflammation in control and stressed animals pre- and
post-mild stress exposure. We propose that the BPD-like ani-
mal’s cytokine and stress hormone levels will be increased
Psychopharmacology
relative to no-stress controls (Rinne et al. 2002; Teicher et al.
2003; Díaz-Marsá et al. 2012).
Controls
There are multiple points of control that should be used in an
animal model of BPD. First, there are built-in controls for each
behavioral paradigm described here, whether using pups from
non-stressed mothers to control for ELS or unstressed animals
in adulthood to control for the BPD-like symptom onset.
Second, our approach also allows for comparisons between
groups that have a background of ELS in the absence of fur-
ther stress, thereby controlling for the effects of ELS alone on
behavior and physiology, and animals that have undergone
ELS in addition to mild stress in adulthood and developed
BPD-like symptoms. Third, this approach is readily amenable
to comparison between the sexes in order to identify whether
female subjects are more susceptible to developing BPD-like
symptoms than males.
Conclusion
It is our hope that we can make significant progress in under-
standing the molecular and physiological mechanisms that are
specific to BPD by isolating the etiology and symptoms that
are tractable with currently established paradigms in animals.
Important information regarding network communication and
local activity will emerge from physiological recordings or
imaging conducted during behavior and in the slice.
Likewise, these approaches will give greater insights into the
specifics of BPD-like HPA dysregulation such as glucocorti-
coid receptor expression or cellular changes across the PFC-
amygdala-striatal network. The validation of outcomes based
on available human data will pave the way for making new
discoveries from the micro-molecular level to more global
physiology that will better inform research and treatment in
humans.
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