This is an ongoing assignment and will be worked on each week. This is what is required this week. I also picked to focus on Borderline Personality for my topic.Select the topic for your Critical Revi
D E B A T E Open Access
Borderline personality disorder and
childhood trauma: exploring the affected
biological systems and mechanisms
Nadia Cattane 1, Roberta Rossi 2, Mariangela Lanfredi 2and Annamaria Cattaneo 1,3,4*
Abstract
Background: According to several studies, the onset of the Borderline Personality Disorder (BPD) depends on the
combination between genetic and environmental factors (GxE), in particular between biological vulnerabilities and
the exposure to traumatic experiences during childhood. We have searched for studies reporting possible
alterations in several biological processes and brain morphological features in relation to childhood trauma
experiences and to BPD. We have also looked for epigenetic mechanisms as they could be mediators of the effects
of childhood trauma in BPD vulnerability.
Discussion: We prove the role of alterations in Hypothalamic-Pituitary-Adrenal (HPA) axis, in neurotrasmission, in
the endogenous opioid system and in neuroplasticity in the childhood trauma-associated vulnerability to develop
BPD; we also confirm the presence of morphological changes in several BPD brain areas and in particular in those
involved in stress response.
Summary: Not so many studies are available on epigenetic changes in BPD patients, although these mechanisms
are widely investigated in relation to stress-related disorders. A better comprehension of the biological and
epigenetic mechanisms, affected by childhood trauma and altered in BPD patients, could allow to identify “at high
risk ”subjects and to prevent or minimize the development of the disease later in life.
Keywords: Borderline personality disorder, Childhood trauma, HPA axis, Endogenous opioid system,
Neurotransmission, Neuroplasticity, Neuroimaging studies, Epigenetic mechanisms
Background
Borderline Personality Disorder (BPD) is a pervasive pat-
tern of emotional dysregulation, impulsiveness, unstable
sense of identity and difficult interpersonal relationships
[1]. The prevalence rates of BPD are between 0.2 –1.8%
in the general community, 15 –25% among psychiatric
inpatients and 10% of all psychiatric outpatients [2, 3].
Among the different aetiopathological theories that have
been proposed over years, the most supported is the one
proposed by Linehan in 1993 [4], which suggests that
BPD can be the result of the interactions between
biological and psychosocial factors [2], in particular be-
tween biologically based temperamental vulnerabilities
and adverse and traumatic experiences during childhood.
BPD is a disorder primarily characterized by emotion
dysregulation and indeed, patients with BPD show
heightened emotional sensitivity, inability to regulate in-
tense emotional responses, and a slow return to emo-
tional baseline. Linehan proposed also that the
development of BPD occurs within an invalidating devel-
opmental context characterized by intolerance toward
the expression of private emotional experiences during
childhood [4]. As a consequence, children exposed to
this adverse environment show inability to learn how to
understand, label, regulate, or tolerate emotional
responses and, conversely, they vacillate between emo-
tional inhibition and extreme emotional lability.
Recently, Hughes and colleagues [5] have proposed an
integration to the aethiopathogenetic model of BPD,
* Correspondence: [email protected] ; [email protected] Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio -Fatebenefratelli, via Pilastroni 4, Brescia, Italy3Stress, Psychiatry and Immunology Laboratory, Department of PsychologicalMedicine, Institute of Psychiatry, King ’s College London, 125 Coldharbour Lane, London SE5 9NU, UKFull list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Cattane et al. BMC Psychiatry (2017) 17:221 DOI 10.1186/s12888-017-1383-2 emphasizing the role played by a lack of social proximity
or responsiveness from relevant caregivers in the
development of BPD symptoms, which in turn impairs
the individual ’s emotion regulation. Affect regulation dif-
ficulties have been also proposed as key mediators in the
relationship between childhood trauma and BPD [6].
Several studies have shown that a diagnosis of BPD is
associated with child abuse and neglect more than any
other personality disorders [7, 8], with a range between
30 and 90% in BPD patients [7, 9].
Adverse childhood experiences are also related to BPD
symptom severity [9 –11]. In support to this, Widom and
collaborators [12] followed 500 children who had suf-
fered physical and sexual abuse and neglect and 396
matched controls, and they observed that significantly
more abused/neglected children met criteria for BPD in
adulthood in comparison to controls. However, the pres-
ence of a risk factor, such as adverse childhood events,
was not necessary or sufficient to explain the reason
why some individuals developed BPD symptoms in
adulthood, whereas others did not.
In a recent study, Martin-Blanco and collaborators
[10] have hypothesized that the interaction of childhood
trauma and temperamental traits could be associated
with the severity of BPD. In this regard, they have evalu-
ated the self-reported history of trauma, the psychobio-
logical temperamental traits and the severity of the BPD
symptoms in a cohort of 130 BPD patients. Data showed
a correlation only between childhood maltreatment and
sociability and no other correlation was observed. More-
over, the interaction between high neuroticism-anxiety
traits and the presence of severe emotional abuse was
associated with the severity of the disorder.
Symptom overlap has been reported between BPD
diagnosis and other disorders including Post-Traumatic
Stress Disorder (PTSD) and other axis I disorders [13].
Moreover, in recent decades, different nosographic de-
scriptions have been suggested to characterize the differ-
ent symptoms associated with trauma, like complex
Post-Traumatic Stress Disorder (cPTSD) [14], also
known as Disorders of Extreme Stress Not Otherwise
Specified (DESNOS) [15], which describes a clinical syn-
drome following an experience of interpersonal trau-
matic victimization and shares many similarities with
BPD, including pathological dissociation, somatizations,
dysregulation of emotions, altered central self and rela-
tional schemas. The definition of cPTSD therefore refers
to the experience of severe and/or prolonged traumatic
situations, and does not merely identify the effects of
devastating traumatic events (like violence or chronic
maltreatment), which fall under the category of PTSD or
Acute Stress Disorder. Indeed, exposure to particular
types of traumatic experiences may result in far more in-
sidious and crippling psychopathogenic disorders than
PTSD, compromising the sound development of attach-
ment behavior related systems and of the ability to
modulate emotions [16]. Recent research is currently try-
ing to determine whether cPTSD and BPD diagnosis in
comorbidity with PTSD are distinct or should both be
considered and named as trauma-related disorders [17]. A
recent review [18] has explored the mechanisms through
which childhood trauma is related to the development of
BPD in adulthood, and has discussed how interrelated fac-
tors (such as heritable personality traits, affect regulation
and dissociation, trauma symptoms) could be mediators
in the relationship between childhood trauma and BPD.
Based on all these findings, in the following para-
graphs we will discuss alterations in several neurobio-
logical systems and in brain morphology that can be
induced by exposure to early life adverse experiences
and that are also associated with BPD (see Table 1). We
will examine the impact of early stressful events on dif-
ferent biological systems and mechanisms, possibly iden-
tifying biomarkers that could be involved in BPD
vulnerability. This might allow to identify at high risk
BPD subjects earlier, and to develop intervention strat-
egies and programs.
Discussion
Neurobiological mechanisms involved in BPD
BPD and the hypothalamic-pituitary-adrenal axis
The Hypothalamic-Pituitary-Adrenal (HPA) axis is one
of the neuroendocrine systems which mediate the
response of the body to stress. Although the stress re-
sponse mechanism is meant to maintain stability or
homeostasis, its long-term activation, as consequence of
chronic stress exposure, may have deleterious effects on
the body, increasing the risk for developing different
kinds of illnesses, including stress-related psychiatric
disorders.
In stress conditions, corticotropin-releasing factor
(CRF) and arginine vasopressin (AVP) are released from
the paraventricular nucleus (PVN) located in the hypo-
thalamus. These peptides travel through the pituitary
portal system and act synergistically to stimulate the re-
lease of the adrenocorticotropic hormone (ACTH) from
the corticotroph cells. Then, ACTH is transported
throughout the systemic circulation and binds to recep-
tors in the adrenal cortex of the adrenal gland, resulting
in the biosynthesis and release of cortisol [19]. Cortisol
can affect multiple organs and biological processes, such
as metabolism, growth, inflammation, cardiovascular
function, cognition, and behavior [20, 21], by binding to
specific receptors in the body and in several brain re-
gions, as the hypothalamus, anterior pituitary and medial
prefrontal cortex. The central and peripheral effects of
cortisol are mediated by two intracellular glucocorticoid
receptor subtypes: the high-affinity type I receptor or
Cattane et al. BMC Psychiatry (2017) 17:221 Page 2 of 14 Table 1 Summary of the papers cited in the review and showing alterations in different biological systems in BPD
Biological systems Authors Sample size Date of study Main Results
HPA axis Southwick et al. [ 26] 37 subjects with PTSD comorbid with BPD; 18 subjects only withPTSD
2003 Higher 24 h urinary cortisol levels in patients with PTSD compared topatients with PTSD and comorbid BPD.
Wingenfeld et al. [ 27] 21 female patients with BPD; 24 healthy female controls. 2007 Higher overnight urinary cortisol levels in BPD patients compared to controls.Very high cortisol levels were foundonly in BPD patients with a low numberof PTSD symptoms.
Rinne et al. [ 28] 39 BPD patients (24 with and 15 without sustained childhoodabuse and comorbid PTSD( n= 12) or MDD ( n= 11)); 11 control subjects
2002 Higher ACTH and cortisol levels in the blood of BPD females who hadexperienced childhood abuse duringthe DEX/CRH test.
Carvalho Fernando et al. [ 29] 32 female BPD patients; 32 healthy female 2013 Acute cortisol levels decreased the reaction time to target stimuli in bothBPD patients and controls.
Martin-Blanco et al. [ 30] 481 subjects with BPD; 442 controls 2016 Case-control study focusing on 47 SNPs in 10 HPA axis genes. An associationbetween polymorphic variants withinthe FKPB5 and the CRHR genes withthe diagnosis of BPD was shown. TwoFKBP5 SNPs were more frequentlyrepresented in patients with a historyof childhood trauma.
Neurotransmission Wagner et al. [ 42] 159 BPD patients 2009 Association between stressful events and low impulsivity in BPD patients.5-HTTLPR S-allele carriers showedhigher impulsivity scores when exposed to stressful events than LL omozygotes.
Wagner et al. [ 47] 112 female BPD patients 2010 COMT Val158Met SNP was associated with early life stressful events and impulsive aggression in female BPDpatients
Wagner et al. [ 48] 159 BPD patients 2010 The effect of COMT Val158Met SNP on the association between stressful lifeevents and impulsivity was not confirmed.
Tadic et al. [ 49] 161 Caucasian BPD patients; 156 healthy controls. 2009 The COMT Met158Met SNP was over-represented in BPD patients comparedto controls. No differences in 5-HTTLPRgenotype were found. An interactionbetween the COMT Met158 and the5-HTTLPR s-allele was observed.
Martin-Blanco et al. [ 50] 481 BPD subjects; 442 controls 2015 Genetic variants within COMT, DBH and SLC6A2 genes were associated with anenhanced risk to develop BPD
Endogenous Opioid System Kalin et al. [ 57] 8 infant rhesus monkeys (4 males and 4 females) 1988 The endogenous opioid system mediates separate-induced vocalizations andinfluences the HPA axis activation inrhesus monkeys using the mother-infantseparation paradigm.
Prossin et al. [ 61] 18 un-medicated female BPD patients; 14 female controls 2010 BPD patients had greater regional μ-opioid availability at baseline in the left necleusaccumbens, the hypothalamus and theright hippocampus/parahippocampusrelative to controls, showing anendogenous opioid system activation.
Neuroimaging studies Driessen et al. [ 36] 21 female BPD patients; 21 female controls 2000 Volume reduction in the hippocampus and in the amygdala in BPD patientscompared to controls.
Schmahl et al. [ 38] 25 unmedicated female patients with BPD (10 with and 15 withoutcomorbid PTSD);25 female controls
2009 Hippocampal volume reduction in patients with BPD and comorbid PTSDas compared to controls.
Cattane et al. BMC Psychiatry (2017) 17:221 Page 3 of 14 mineralcorticoid receptor (MR) and the low-affinity type
receptor or glucocorticoid receptor (GR). It has been
suggested that MRs have a high affinity for both cortisol
and aldosterone; they bind cortisol when it is detectable
at low concentrations. The GRs have a relatively low af-
finity for cortisol, but high affinity for dexamethasone
(DEX) [22]; moreover, they bind cortisol at high concen-
tration, reflecting what occurs in stress conditions.
The HPA axis is regulated by an auto-regulatory
mechanism mediated by cortisol itself, that is crucial in
the maintenance of the homeostatic functions of the
HPA axis. Indeed, when cortisol levels rise, as in
Table 1 Summary of the papers cited in the review and showing alterations in different biological systems in BPD (Continued)
Kreisel et al. [ 70] 39 BPD patients; 39 controls 2014 Smaller hippocampal volume in BPD patients with a lifetime history than those without comorbid PTSD.
Boen et al. [ 71] 18 women with BPD; 21 controls 2014 Two hippocampal structures (DG-CA4 and CA2 –3 subfields) were significantly smaller in patients with BPD than controls.
Kuhlmann et al. [ 73] 30 BPD patients; 33 controls 2013 Patients with BPD showed lower hippocampal volumes than controls, but higher volumes in the hypothalamus.
Rodrigues et al. [ 63] 124 BPD patients; 147 controls 2011 Both the left and the right sides of the hippocampus were reduced in BPD patients with PTSD when compared to controls.
Ruocco et al. [ 37] 205 BPD patients; 222 controls 2012 Bilateral volume reductions of the amygdala and hippocampus were not related to comorbid MDD, PTSD or substance usedisorders.
Epigenetics Martin-Blanco et al. [ 88] 281 subjects with BPD 2014 An association between NR3C1 methylation levels and childhood trauma was found inblood samples of BPD patients.
Dammann et al. [ 89] 26 BPD patients; 11 controls 2011 An increase in the methylation levels of HTR2A,NR3C1,MAOA,MAOB and COMTwas found in BPD patients as comparedto controls.
Perroud et al. [ 91] 346 BD, BPD, and ADHD patients 2016 Differential 5-HT3AR methylation levels were associated with the severity ofchildhood trauma, mainly found in BPDpatients.
Teschler et al. [ 93] 24 female BPD patients; 11 female controls 2013 Genome-wide methylation analyses revealed increased methylation levels of several genes(APBA2,APBA3,GATA4,KCNQ1,MCF2,NINJ2,TAAR5) in blood of BPD female patientsand controls.
Prados et al. [ 94] 96 BPD subjects suffering from a high level of child adversity; 93subjects suffering from MDD andreporting a low rate of childmaltreatment
2015 Several CpGs within or near genes involved in inflammation and in neuronal excitabilitywere differentially methylated in BPD patientscompared to MDD patients or in relation tothe severity of childhood trauma.
Teschler et al. [ 95] 24 female BPD patients; 11 female controls 2016 A significant aberrant methylation of rDNA and PRIMA1 was revealed for BPD patients usingpyrosequencing. For the promoter of PRIMA1, theaverage methylation of six CpG sites was higher inBPD patients compared to controls. In contrast, themethylation levels of the rDNA promoter region andthe 5 ′ETS were significantly lower in patients with BPD compared to controls.
Neuroplasticity Koenigsberg et al. [ 109 ] 24 medication-free BPD patients; 18 healthy control subjects 2012 Decrease of PKC and BDNF protein levels in the blood of BPD patients.
Tadic et al. [ 49] 161 Caucasian BPD patients; 156 healthy controls. 2009 Association between HTR1B A-161 variant and the functional BDNF 196A allele in BPD patients.
Perroud et al. [ 90] 115 subjects with BPD; 52 controls 2013 Higher methylation levels in BDNF CpG exons I and IV in BPD patients than in controls. Higher BDNF proteinlevels in plasma of BPD patients than in controls.
Thaler et al. [ 92] 64 women with bulimia nervosa and comorbid BPD; 32 controls 2014 Hypermethylation within BDNF promoter region sites in women with bulimia nervosa and with a history ofBPD and/or trauma events.
Cattane et al. BMC Psychiatry (2017) 17:221 Page 4 of 14 response to stress, the MRs are saturated and, conse-
quently, cortisol binds the GRs, promoting a cascades of
events that represent the main transduction signals of
glucocorticoids in stress conditions.
So far, the HPA axis activity has been widely investi-
gated in the context of childhood trauma experiences
and findings support alterations in HPA axis in subjects
exposed to stress early in life. Indeed, several studies
have reported alterations in the cortisol circadian
rhythm and levels, indicating a deregulation of the HPA
axis responsiveness, due to childhood trauma experi-
ences, upon stress conditions [23 –25].
Despite the large amount of data on the HPA axis
functionality as consequence of exposure to stress early
in life, only a few studies have investigated possible alter-
ations of this axis in BPD patients. For example, higher
urinary cortisol levels have been found in BPD patients
compared to controls [26, 27].
Southwick and colleagues [26] found higher 24 h urinary
cortisol levels in patients with PTSD compared to patients
with PTSD and comorbid BPD, suggesting that these alter-
ations might reflect differences in the severity of PTSD
symptoms rather than factors related to BPD per se.
Another study [27] explored overnight urinary free
cortisol levels showing higher cortisol levels in BPD pa-
tients than in controls. A negative association between
cortisol and PTSD symptoms was also observed. More-
over, when BPD patients were divided according to the
presence of high or low number of PTSD symptoms,
very high cortisol levels were found only in BPD patients
with a low number of PTSD symptoms. Rinne and col-
laborators [28] found an exaggerated ACTH and cortisol
response during the DEX/CRH test in the blood of BPD
female subjects who had experienced childhood abuse.
Carvalho Fernando and colleagues [29] investigated the
effects of cortisol administration on response inhibition
of emotional stimuli in patients with BPD compared to
controls. They found that acute cortisol elevations
decreased the reaction time to target stimuli in both
BPD patients and controls, but they did not differ in task
performance.
Also genetic association studies support alterations in
HPA axis functionality in association with childhood
trauma exposure. Martin-Blanco and collaborators [30]
have investigated the contribution of genetic variants
within genes in the HPA axis, also in the context of child-
hood trauma exposures, in a sample of BPD patients and
controls. The authors performed a case-control study fo-
cusing on 47 SNPs in 10 HPA axis genes. Data showed an
association between polymorphic variants within the
FK506 Binding Protein 5 (FKBP5) and Corticotropin Re-
leasing Hormone Receptor (CRHR) genes with the diag-
nosis of BPD. In particular, two FKBP5 polymorphisms,
rs4713902 and rs9470079, showed significant association
with BPD. Stronger associations were found in patients
exposed to childhood trauma where the risk alleles of
other two FKBP5 polymorphisms, rs3798347-T and
rs10947563-A, were more frequently represented in
patients with a history of childhood physical abuse and
emotional neglect than in patients who had never experi-
enced these trauma and controls.
All these findings suggest an association between a
deregulated functionality of the HPA axis and childhood
trauma and highlight the involvement of this biological
system in the development of BPD.
BPD and neurotransmission
In addition to the presence of HPA axis dysfunction,
several studies have also proposed that childhood
trauma can affect glutamatergic, serotonergic, dopamin-
ergic and noradrenergic transmission, suggesting that
BPD is the result of alterations in several interacting
neurotransmitter systems [31, 32].
Glutamatergic and N-methyl-D-aspartate (NMDA)
neurotransmissions play a critical role in neurodevelop-
ment, synaptic plasticity, learning and memory [33, 34]
and alterations in all these processes have been involved
also in the vulnerability and pathophysiology of BPD
[35]. For example, neuroimaging studies in BPD patients
as compared to controls have consistently demonstrated
the presence of decreased synaptic density and volume
in several brain regions involved in spatial or autobio-
graphical memory and in the modulation of vigilance
and negative emotional states, such as hippocampus and
amygdala, which are also enriched in NMDA receptors
[36] (see also paragraph “BPD and neuroimaging stud-
ies ”). Moreover, early chronic stress and mistreatments
experienced during life by BPD patients have been found
able to impact dendritic arborization, thus contributing
to the development of morphological alterations associ-
ated with BPD symptoms [37, 38].
The serotonin transporter gene (5-HTTLPR) and its
related signaling in neurotransmission represent another
system involved in the pathogenesis of BPD [39 –42]. In
particular, a functional single nucleotide polymorphism
(SNP) within this gene (the 5-HTTLPR S/L SNP) has
been widely reported to be a modulator of early life
stressful events by several studies [43 –45]; interestingly,
it has been also associated with BPD symptoms [42, 46].
For example, Wagner and collaborators [42] investigated
the effects of 5-HTTLPR S/L SNP and of early life
stressful events on impulsivity, assessed by the Barratt
Impulsiveness Scale (BIS), in BPD patients. The authors
reported an association between the presence of stressful
events with lower BIS impulsivity scores, suggesting that
subjects who have experienced trauma, in particular sex-
ual abuse, may show a reduced impulsivity as a conse-
quence of the activation of coping mechanisms that
Cattane et al. BMC Psychiatry (2017) 17:221 Page 5 of 14 control behavior and social interaction. Further analyses
conducted by the same authors indicated that S-allele
carriers showed higher impulsivity scores when exposed
to early life stressful events as compared to LL omozy-
gotes, suggesting that patients with 5-HTTLPR S-allele
are more vulnerable to early life stress. These data high-
light the contribution of the serotonergic system on im-
pulsivity in BPD [42].
Another gene suggested to be a genetic risk factor for
BPD is represented by Catechol-O-methyltransferase
(COMT), an enzyme catalyzing the degradation of cate-
cholamines, including the neurotransmitters dopamine,
epinephrine, and norepinephrine; however, literature
data on the role of this gene are contrasting. In a first
study conducted by Wagner and collaborators [47], the
COMT Val 158 Met SNP has been found associated with
early life stressful events and impulsive aggression,
assessed by the Buss-Durkee-Hostility Inventory (BDHI)
sum score, in female BPD patients. In particular, the au-
thors identified that in COMT Val 158 Val carriers, but
not in Val/Met and Met/Met carriers, childhood sexual
abuse and the cumulative number of stressful events
were associated with lower BDHI impulsive aggression
scores. However, in another study conducted by the
same authors, the effect of the COMT Val 158 Met SNP
on the association between stressful life events and im-
pulsivity was not confirmed [48], probably due to the
small sample size. The same authors [49] also investi-
gated, in a group of BPD patients and controls, the role
of (i) the COMT Val 158 Met SNP, (ii) the 5-HTTLPR S/L
variant and (iii) their interaction as genetic vulnerability
factors for BPD. Data showed that the genotype COMT
Met 158 Met was over-represented in BPD patients than
in controls, whereas no differences in 5-HTTLPR geno-
type between BPD and controls were reported. In
addition, the COMT Met 158 Met genotype was signifi-
cantly over-represented in BPD patients carrying at least
one 5-HTTLPR S-allele and, interestingly, an interaction
between the COMT Met 158 and the 5-HTTLPR S-allele
was also observed. These results suggest an interactive
effect of COMT and 5-HTTLPR gene variants on the
vulnerability to develop BPD and, according to the au-
thors, highlight again the key role of the serotonergic
and dopaminergic system in the pathogenesis of BPD.
Martin-Blanco and collaborators [50] investigated the
possible involvement of the noradrenergic system in BDP
pathogenesis, by evaluating genetic variants within 4 nor-
adrenergic genes. In addition to COMT, the authors se-
lected Dopamine Beta-Hydroxylase (DBH), that acts
transforming dopamine into noradrenaline, Solute Carrier
Family 6 Member 2 (SLC6A2), a transporter responsible
for the reuptake of extracellular neurotransmitters, and
Adrenoceptor Beta 2 (ADRB2), that mediates the
catecholamine-induced activation of adenylate cyclase
through the action of G proteins. The authors ’findings in-
dicated that only genetic variants within 3 genes (COMT,
DBH and SLC6A2) were associated with an enhanced risk
to develop BPD.
These studies, taken together, show that alterations in
several neurotransmitter systems could be involved in
BPD pathogenesis; however, due to the small number of
available studies, further investigations are needed.
BPD and the endogenous opioid system
According to Bandelow and Schmahl ’s theory, a reduc-
tion in the sensitivity of the opioid receptors or in the
availability of endogenous opioids might constitute part
of the underlying pathophysiology of BPD [51].
Endogenous opioids mainly include three classes (en-
dorphins, enkephalins and dynorphins), which activate
three types of G protein-coupled receptors ( μ,δ, and κ
opioid receptors [52]). One of the most important en-
dogenous opioid is β-endorphin which is synthesized in
part in the arcuate nucleus of the hypothalamus and is
released into the blood, the spinal cord and in various
brain regions, including reward-related areas [53]. β-
endorphin is activated by a variety of stressors [54] and
induce euphoria and analgesic effects (for example dur-
ing childbirth and during positive experiences [55]).
The μ-opioid receptors appear to be more relevant for
the social and affective regulation associated with BPD,
suggesting that this system can contribute to the interper-
sonal vulnerabilities and intrapersonal pain of BPD. These
receptors are widely distributed throughout the human
Central Nervous System (CNS), with a particular density
in the basal ganglia, cortical structures, thalamic nuclei,
spinal cord, and specific nuclei in the brainstem [56].
The endogenous opioid system modulates responses
to acute and chronic stressful and noxious stimuli that
induce physical, emotional, or social pain. In animal
models, the endogenous opioid system has been
implicated in affiliative responses, emotion and stress
regulation, including stress-induced analgesia and
impulsive-like behavior [57]. Using the mother-infant
separation paradigm in rhesus monkeys, Kalin and col-
laborators [57] studied for the first time the role of the
opioid system in modulating the behavioural and neuro-
endocrine consequences of a brief occurring stressor.
The authors conducted several experiments where ani-
mals received morphine, an opioid agonist, naloxone, an
opioid antagonist or both to test the increase in
vocalization and the activation of the HPA axis in infant
primates separated or not from their mothers. The re-
sults showed that morphine significantly decreased
separation-induced vocalizations and locomotion with-
out affecting activity levels, whereas naloxone increased
separation-induced vocalizations and environmental ex-
ploration. When the two drugs were co-administered,
Cattane et al. BMC Psychiatry (2017) 17:221 Page 6 of 14 the effect of morphine was reversed only with the
0.1 mg/kg dose of naloxone. The authors also assessed
the effects of separation on neuroendocrine function
and tested whether activation of the opioid system may
attenuate these effects by measuring plasma concentra-
tions of ACTH and cortisol in infant rhesus monkeys
separated or not separated from their mothers, treated
with morphine or naloxone or co-treated with the two
drugs. Plasma ACTH and cortisol levels were higher in
infant rhesus monkeys separated from their mothers
compared to not separated ones, confirming the involve-
ment of the HPA axis during stress exposure. However,
only ACTH plasma levels were modulated by morphine
and by naloxone and by their interaction in the group of
infant separated by their mothers. These findings suggest
that the endogenous opioid system is involved in medi-
ating separation-induced vocalizations and influences
the HPA axis activation following a stress condition.
In humans, regional endogenous opioid system activa-
tion has been associated with suppression of both sen-
sory and affective qualities of stressors and with trait
impulsivity [58 –60] whereas its regional deactivation has
been related to hyperalgesic responses and increases in
negative affect during stress [61]. The hypothesis is that
the activation of the μ-opioid receptors could have a
suppressive effect during emotional or physical chal-
lenges that threaten organism homeostasis.
Research has described regional alterations in the
function of the endogenous opioid system and μ-opioid
receptors in brain regions involved in emotion and stress
processing, decision making, and pain and neuroendo-
crine regulation. However, to date, there is only limited
evidence of alterations of endogenous opioid levels in
BPD patients. In an interesting study Prossin and collab-
orators [61] investigated the role of the endogenous opi-
oid system and μ-opioid receptors in emotion regulation
in un-medicated female BPD patients compared to fe-
male controls by using positron emission tomography
(PET) (see paragraph “BPD and neuroimaging studies ”
for details).
Comparing BPD patients to their matched controls,
the authors found significant differences in baseline re-
gional μ-opioid receptor concentrations in vivo, as well
as in this neurotransmitter system ’s response to a nega-
tive emotional challenge that can be related to some of
the clinical characteristics of BPD.
BPD and neuroimaging studies
Volumetric alterations in brain areas involved in stress
response
To date, several functional and structural in vivo neuro-
imaging studies have been performed in BPD patients,
detecting alterations mainly localized in the limbic cir-
cuit and in frontal cortex. These regions are related to
the distinctive clinical features of the disorder (i.e impul-
sivity, aggression, and emotional reactivity). The most
replicated result, confirmed in recent meta-analyses [37,
62, 63], is represented by the reduction in the volumes
of the hippocampus and the amygdala of BPD patients
compared to controls [36, 64 –69]. The robustness of this
finding seems to suggest that volumetric decreases in
these two brain areas could be specific for BPD and thus
useful as possible endophenotypes of illness. In 2000
Driessen and collaborators [36] performed the first mag-
netic resonance imaging volumetric measurement of the
hippocampus, amygdala, temporal lobes, and prosen-
cephalon in 21 female BPD patients and female controls,
reporting in BPD patients a volume reduction of the
16% in the hippocampus and of the 8% in the amygdala.
Moreover, hippocampal volumes were negatively corre-
lated with the extent and the duration of self-reported
early trauma, but only in the entire sample of BPD pa-
tients and controls.
The role of PTSD and trauma as comorbidity with BPD
on hippocampus and amygdala volumes has been object
of investigation but the results are still controversial.
Schmahl and colleagues [38] compared two groups of un-
medicated BPD female patients with and without comor-
bid PTSD and 25 female controls. They found reduced
hippocampal volumes only in patients with BPD and co-
morbid PTSD but not in BPD patients without a history
of PTSD as compared to controls. Similarly, Kreisel and
collaborators [70] investigated in details the hippocampal
structural volumes comparing 39 BPD patients with 39
matched controls, and, although no volume differences
were found between the two groups, patients with a life-
time history of PTSD had a smaller hippocampal volume
( 10,5%) than those without comorbid PTSD. Boen and
collaborators [71] investigated the volumes of the Cornu
Ammonis (CA) and the Dentate Gyrus (DG), two hippo-
campal structures prone to morphological changes [72] in
response to adverse environmental changes in a group of
18 women with BPD and 21 controls. The authors found
that the stress-vulnerable DG-CA4 and CA2 –3 subfields
were significantly smaller in patients with BPD than in
controls. However, they did not identify any significant
association between subfield volumes and reported child-
hood trauma.
In another interesting study, Kuhlmann and collabora-
tors [73] investigated alterations in the grey matter of
central stress-regulating structures, including hippocam-
pus, amygdala, anterior cingulate cortex and hypothal-
amus, in female patients with BPD and controls. The
authors also explored whether grey matter volume of
these four brain structures was associated with child-
hood trauma, reporting that patients with BPD showed
lower hippocampal volumes than healthy controls, but
higher volumes in the hypothalamus. Interestingly,
Cattane et al. BMC Psychiatry (2017) 17:221 Page 7 of 14 hypothalamic volume correlated positively with a history
of trauma in patients with BPD.
Two recent meta-analyses [37, 63] evaluated whether
the magnitude of hippocampus and amygdala volume
reductions may be associated with state-of-illness factors
and psychiatric disorders (i.e. PTSD) which often co-
occured with BPD. In the Rodrigues ’meta-analysis, the
authors included 7 articles with a total number of 124
patients and 147 controls. They showed that both the
left and the right sides of hippocampal volumes were re-
duced in BPD patients with PTSD when compared to
controls. The left hippocampal volume was not signifi-
cantly smaller in BPD patients without PTSD relative to
healthy controls and the right hippocampal volume was
reduced in patients with BPD without comorbid PTSD,
but to a lesser degree than in BPD patients with PTSD.
In contrast, the results reported by Ruocco ’s meta-
analysis [37] which included 11 studies with a total num-
ber of 205 BPD patients and 222 controls, revealed that
bilateral volume reductions of the amygdala and hippo-
campus were unrelated to comorbid Major Depressive
Disorder (MDD), PTSD, or substance use disorders.
Taken together, all these studies show that the main
brain regions involved in BPD are those associated to
stress and highlight the importance of classifying sub-
groups of patients with BPD, especially taking into ac-
count the presence of comorbidity with PTSD or of a
history of childhood trauma. Notwithstanding, the asso-
ciation between the volume reduction and the degree to
which childhood trauma could be responsible for these
changes remains unclear.
Endogenous opiod system alterations in brain regions
involved in stress response
Despite a large amount of data referred to volumetric
and morphological alterations in brain regions associated
to specific clinical features of BPD, not many neuroim-
aging studies have been conducted to investigate the role
of the endogenous opioid system in BPD. As previously
mentioned, Prossin and collaborators [61] measured the
in vivo availability of the μ-opioid receptors (non-dis-
placeable binding potential (BPND)) in a group of un-
medicated female BPD patients compared to female con-
trols by using PET and the selective radiotracer [11C]
carfentanil at baseline and during sustained sadness
states. Patients had greater regional μ-opioid BPND than
controls at baseline (neutral state) in the left nucleus ac-
cumbens, the hypothalamus, and the right hippocam-
pus/parahippocampus relative to comparison subjects,
showing an endogenous opioid system activation. As
suggested by the authors, differences between BPD pa-
tients and controls in baseline in vivo μ-opioid receptor
concentrations and in the endogenous opioid system re-
sponse to a negative emotional challenge can be related
to some of the clinical characteristics of BPD patients.
These findings show alterations in the function of the
endogenous opioid system and μ-opioid receptors in
brain regions involved in emotion and stress processing,
decision making, and pain and neuroendocrine regula-
tion, features also associated with BPD.
BPD and epigenetic mechanisms
The influence of environmental factors, such as child-
hood trauma, has been suggested to occur through
epigenetic mechanisms, which may underlie gene-
environment associated vulnerability to develop stress-
related disorders [74] including BPD where childhood
trauma history occurs in most of the patients (with a
range between 30 and 90%) [7, 9].
Among the most investigated epigenetic mechanisms
there are: (i) DNA methylation, which occurs at CG
dinucleotides (CpG) and can influence the spatial struc-
ture of the DNA and the binding or the repression of
specific DNA-binding proteins to the DNA [75], (ii) his-
tone modifications, which influence the condensation of
the DNA around histone proteins and regulate the ac-
cessibility of functional regions to transcriptional factors
[76] and (iii) post-transcriptional regulation by non-
coding RNAs such as microRNAs (miRNAs) [77].
All these epigenetic processes and, in particular,
changes in DNA methylation have been widely investi-
gated in the context of long-term negative effects of
early life stressful events. In non-human primates and in
rodents, several paradigms of stress early in life, includ-
ing maternal separation or prenatal stress have been as-
sociated with epigenetic alterations via DNA
methylation [78, 79]. For example, non-stressed dams
during pregnancy showed increased frequency of licking
and grooming in the first week of the puppies ’life that
were associated with changes in DNA methylation
within the promoter of genes, such as glucocorticoid re-
ceptor gene (NR3C1), known to be involved in behavior
and neurodevelopment.
The hypothesis is that the quality of maternal care, af-
fected by stress or depression in pregnancy and post-
partum [80, 81] could impact, through epigenetic mech-
anisms, on gene expression and behavioral traits that are
maintained throughout life [78].
Recently, McGowan and colleagues [79] examined
DNA methylation, histone acetylation and gene expres-
sion in a 7 million base pair region of chromosome 18
containing the NR3C1 gene in the hippocampus of adult
rat offspring, whose mothers differed in the frequency of
maternal care. The authors found that the adult off-
spring of high compared to low maternal care showed a
pattern of regions spanning the NR3C1 gene which were
differentially methylated and acetylated, highlighting the
idea that epigenetic changes, in the context of early life
Cattane et al. BMC Psychiatry (2017) 17:221 Page 8 of 14 stress, involve alterations in gene-networks rather than
in a single or few genes.
Similarly, studies in humans reported similar results as
those found in rodents, including the increased methyla-
tion levels within the NR3C1 promoter region in sub-
jects who reported a history of early life adverse events
[82 –84]. For example, in another interesting study,
McGowan and collaborators [82] found that in humans
the cytosine methylation levels of the NR3C1 promoter
were significantly increased in the postmortem hippo-
campus obtained from suicide victims with a history of
childhood abuse as compared with those from suicide
victims with no childhood abuse or with control sam-
ples. Decreased levels of NR3C1 mRNA were also identi-
fied, suggesting an effect of childhood abuse on NR3C1
methylation status and gene expression, independently
from suicide.
Several epigenetic studies have been also conducted in
control subjects characterized for a history of childhood
trauma compared to those with no childhood trauma. In
this context, Suderman and colleagues [85] have demon-
strated, by using a genome-wide promoter DNA methy-
lation approach, an abuse-associated hypermethylation
in 31 miRNAs in a sample of control adult males
exposed to childhood abuse. The hypermethylated state
for 6 of these miRNAs was consistent with an hypome-
thylation status of their target genes.
Reduced methylation levels of FKBP5 gene within
regions containing functional glucocorticoid responsive
elements (GRE) were also found in the blood of control
individuals exposed to childhood abuse when compared
to subjects without a history of trauma [86]. This de-
methylation was linked to increased stress-dependent
gene transcription followed by a long-term dysregulation
of the stress hormone system and a global effect on the
function of immune cells and brain areas associated with
stress regulation. Thus, according to the authors, the
changes in FKBP5 methylation levels might increase the
differential responsiveness of FKBP5 to GR activation
that can remain stable over time. Moreover, Labontè and
colleagues [87] have conducted a genome-wide study of
promoter methylation in the hippocampus of individuals
with a history of severe childhood abuse and control
subjects. Methylation profiles were then compared with
corresponding genome-wide gene expression profiles.
Among all the differentially methylated promoters, 248
showed hypermethylation whereas 114 demonstrated hy-
pomethylation and genes involved in cellular/neuronal
plasticity were among the most significantly differentially
methylated.
Despite the contribution of DNA methylation has been
extensively investigated in association with childhood
trauma in the context of pathologies related to stress,
studies on the possible involvement of epigenetic
mechanisms in BPD vulnerability are only at their birth.
Indeed, only few studies are available. In particular,
Martin-Blanco and colleagues, investigated the associ-
ation between NR3C1 methylation status, history of
childhood trauma and clinical severity in blood samples
of BPD subjects, showing an association between
NR3C1 methylation and childhood trauma, in the form
of physical abuse, and a trend towards significance for
emotional neglect [88]. Regarding NR3C1 methylation
and clinical severity, the authors also found a significant
association with self injurious behavior and previous
hospitalizations. All these findings support the hypoth-
esis that alterations in NR3C1 methylation can occur
early in life as consequence of stress exposure and can
persist up to adulthood where subjects with higher
NR3C1 methylation levels are also those with enhanced
vulnerability to develop BPD.
Above to DNA methylation changes within NR3C1,
hypo- or hyper-methylation within other genes have
been found to play a key role in mediating the impact of
early life stress on the development of stress-related dis-
orders, including BPD [89 –92]. For example, in a study
conducted by Dammann and colleagues [89] DNA
methylation pattern of 14 genes, selected because previ-
ously associated with BPD and other psychiatric disor-
ders, (COMT, Dopamine Transporter 1 (DAT1),
Gamma-Aminobutyric Acid Type A Receptor Alpha1
Subunit (GABRA1), G Protein Subunit Beta 3 (GNB3),
Glutamate Ionotropic Receptor NMDA Type Subunit 2B
(GRIN2B), 5-Hydroxytryptamine Receptor 1B (HTR1B),
5-Hydroxytryptamine Receptor 2A (HTR2A), Serotonin
Transporter 1 (5-HTT), Monoamine Oxidase A
(MAOA), Monoamine Oxidase B (MAOB), Nitric Oxide
Synthase 1 (NOS1), NR3C1, Tryptophan Hydroxylase 1
(TPH1) and Tyrosine Hydroxylase (TH)), was analyzed
in the whole blood of BPD patients and controls. An in-
crease in the methylation levels of HTR2A, NR3C1,
MAOA, MAOB and COMT was observed in BPD
patients as compared to controls, suggesting that an in-
creased methylation of CpG sites within these genes
may contribute to BPD aetiopathogenesis. Recently,
Perroud and colleagues [91] investigated the role of
childhood trauma on the methylation status of the
Serotonin 3A Receptor (5-HT 3AR), including several
CpGs located within or upstream this gene. They ana-
lyzed its association with clinical severity outcomes, also
in relation with a functional genetic SNP (rs1062613)
within 5-HT 3AR in adult patients with Bipolar Disorder,
BPD, and Attention Deficit Hyperactivity Disorder
(ADHD). The results showed that differential 5-HT 3AR
methylation status was dependent on the history of
childhood maltreatment and the clinical severity of the
psychiatric disorder; this association was not specifically
restricted to one specific psychiatric disorders
Cattane et al. BMC Psychiatry (2017) 17:221 Page 9 of 14 investigated by the authors, but was found in patients
who reported the higher severity indexes of childhood
maltreatment, mainly represented by BPD patients. In
particular, childhood physical abuse was associated with
higher 5-HT 3AR methylation levels, whereas childhood
emotional neglect was inversely correlated with CpG1 I
methylation levels. As suggested by the authors, these
results highlight the need to search for history of child-
hood maltreatment in patients suffering from psychiatric
disorders as these events could be associated with the
worse negative outcomes. Moreover, the authors found a
modulation of the 5HT 3AR methylation status by
rs1062613 at CpG2 III, where patients carrying the risk
CC genotype showed the highest levels of methylation at
CpG2 III. Since C allele has been also associated with a
lower expression levels of 5HT 3AR, the authors sug-
gested that increased methylation, due to exposure to
childhood maltreatment, could lead to a further decrease
in the expression of 5HT 3AR mRNA.
Aiming to identify novel genes that may exhibit aber-
rant DNA methylation frequencies in BPD patients,
Teschler and collaborators [93] performed a genome-
wide methylation analysis in the blood of BPD female
patients and female controls. The authors reported in-
creased methylation levels of several genes, including
neuronal adaptor proteins (Amyloid Beta Precursor
Protein Binding Family A Member 2 (APBA2) and
Amyloid Beta Precursor Protein Binding Family A Mem-
ber 3 (APBA3)), zinc-finger transcription factors (GATA
Binding Protein 4 (GATA4)), voltage-gated potassium
channel gene (Potassium Voltage-Gated Channel Sub-
family Q Member 1 (KCNQ1)), guanine nucleotide ex-
change factors (Proto-Oncogene MCF-2 (MCF2)),
adhesion molecules (Ninjurin 2 (NINJ2)) and G protein-
coupled receptors (Trace Amine Associated Receptor 5
(TAAR5)) in BPD samples compared to controls. Simi-
larly, using a whole-genome methylation approach, Pra-
dos and colleagues [94] analyzed the global DNA
methylation status in the peripheral blood leukocytes of
BPD patients with a history of childhood adversity and
also in patients with MDD characterized by a low rate of
childhood maltreatment. Contrary to Teschler [93], who
used control subjects as reference group, in this study
the authors used MDD subjects, most of them suicide
attempters, thus controlling not only for MDD but also
for a history of suicide. The authors also assessed pos-
sible correlations between methylation signatures and
the severity of childhood maltreatment. Data showed
that several CpGs within or near genes involved in in-
flammatory processes (Interleukin 17 Receptor A
(IL17RA)), regulation of gene expression (miR124 –3)
and neuronal excitability and development/maintenance
of the nervous system (Potassium Voltage-Gated Chan-
nel Subfamily Q Member 2 (KCNQ2)) were differentially
methylated, either in BPD compared with MDD or in re-
lation to the severity of childhood maltreatment.
In a more recent study, Teschler and collaborators
[95] have analyzed also DNA methylation patterns of the
ribosomal RNA gene (rDNA promoter region and 5 ′-ex-
ternal transcribed spacer/5 ′ETS) and the promoter of
the proline rich membrane anchor 1 gene (PRIMA1) in
peripheral blood samples of female BPD patients and
controls. The authors have identified a significant aber-
rant methylation of rDNA and PRIMA1 in the group of
BPD patients. Specifically, the average methylation of 6
CpG sites in the promoter of PRIMA1 was 1.6-fold
higher in BPD patients compared to controls. In con-
trast, the methylation levels of the rDNA promoter re-
gion and the 5 ′ETS were significantly lower (0.9-fold) in
patients with BPD compared to controls. Furthermore,
decreased methylation levels were found for nine CpGs
located in the rDNA promoter region and for 4 CpGs at
the 5 ′ETS in peripheral blood of patients compared to
controls. These results suggest that aberrant methylation
of rDNA and PRIMA1 could be associated with the
pathogenesis of BPD.
Taken together, all these studies reveal a complex
interplay between BPD, early-life stressful adversities and
epigenetic signatures.
BPD and neuroplasticity (the role of BDNF)
Neuroplasticity refers to brain-related mechanisms
associated with the ability of the brain to perceive, adapt
and respond to a variety of internal and external stimuli
[96, 97], including stress.
The exposure to acute stressful challenges can induce
several beneficial and protective effects for the body,
which responds to almost any sudden, unexpected events
by releasing chemical mediators –i.e. catecholamines that
increase heart rate and blood pressure –and help the in-
dividual to cope with the situation [20, 98 –101]. However,
a chronic exposure to stress and thus a chronic exposure
to glucocorticoids can have negative and persistent effects
on the body, including altered metabolism, altered im-
munity, enhanced inflammation, cognitive deficits, and
also an enhanced vulnerability for psychiatric disorders
and for medical conditions such as cardiovascular disease,
metabolic disorders and cancer [102, 103].
Neurotrophic factors, and in particular the neurotro-
phin Brain-Derived Neurotrophic Factor (BDNF), have
been identified as key mediators of stress on neuronal
connectivity, dendritic arborization, synaptic plasticity
and neurogenesis [104 –107]. Since its crucial role in
brain development and brain plasticity, BDNF has been
widely investigated also in several psychiatric diseases,
including BPD [108].
For example, Koenigsberg and colleagues [109] found
a decrease of Protein Kinase C (PKC) isoenzyme, which
Cattane et al. BMC Psychiatry (2017) 17:221 Page 10 of 14 is a molecule downstream the activation of BDNF, and
BDNF protein levels in the blood of BPD patients, sug-
gesting an alteration of BDNF signaling and conse-
quently of neuroplasticity-related mechanisms in BPD.
In another study, Tadic and collaborators [49] investi-
gated the association between BPD and genetic variants
within HTR1B and BDNF genes. Although data showed
no significant differences in genotype or haplotype dis-
tribution for both HTR1B and BDNF variants between
BPD patients and controls, logistic regression analyses
revealed an association between the HTR1B A-161 vari-
ant and the functional BDNF 196A allele in BPD.
Importantly, several findings have also documented epi-
genetic modifications on BDNF gene in patients with
BPD ,suggesting that childhood maltreatment in BPD pa-
tients can cause long term epigenetic alterations of genes
crucially involved in brain functions and neurodevelop-
ment, including BDNF, and that these alterations may
contribute to enhanced vulnerability to develop BPD path-
ology. In this regard, Perroud and collaborators [90] mea-
sured the percentage of methylation at BDNF CpG exons
I and IV and also plasma BDNF protein levels in subjects
with BPD and controls. The authors reported significantly
higher methylation status in both CpG regions in patients
than in controls, with the number of childhood trauma
exposures associated with the high levels of BDNF methy-
lation. Moreover, BPD patients had significantly higher
BDNF plasma protein levels than controls, but this in-
crease was not associated with changes in BDNF methyla-
tion status. More recently, Thaler and collaborators [92]
analyzed DNA methylation patterns in the promoter re-
gion of BDNF gene in women with bulimia nervosa and
with history of BPD and/or trauma events. They reported
that bulimia nervosa was associated per se with an hyper-
methylation within BDNF promoter region sites. This was
particularly evident when co-occurring with childhood
abuse or BPD.
Overall, these studies support the hypothesis that child-
hood trauma could be associated with changes in BDNF
epigenetic signature, that in turn could contribute to alter
cognitive functions in BPD patients. Indeed, higher levels
of gene methylation are commonly accompanied by a re-
duced gene expression. Thus higher BDNF methylation
levels should determine reduced expression of BDNF gene
and reduced BDNF mRNA levels are widely observed in
patients with psychiatric diseases [110 –112].
Conclusions
Up to now, neither a specific gene variant or biological
mechanism has been exclusively associated with BPD,
but the onset of this disorder has been suggested to
depend on the combination of a vulnerable genetic back-
ground with adverse environmental factors during
childhood.
Among the biological systems found involved in BPD
pathogenesis and particularly affected by childhood
trauma events, there are: the HPA axis, the neurotrans-
mission mechanisms, the endogenous opioid system and
the neuroplasticity. In line with the involvement of these
processes, neuroimaging studies in BPD patients have
shown volume reductions in the hippocampus and amyg-
dala, both brain regions mainly involved in stress
responses, cognition, memory and emotion regulation and
an increase in the μ-opioid receptors in the same areas.
Among the environmental factors, early life stressful
events, in particular childhood trauma, have been pro-
posed to negatively impact brain development through
epigenetic mechanisms. Although a complex interplay
between BPD, early-life stressful adversities and epigen-
etic signatures has been suggested, further investigations
are needed in order to better understand the role of gen-
etic background and traumatic events during childhood
in the onset of BPD. A better comprehension of these
interactions could allow to identify at risk subjects, who
could be treated with preventive therapies, such as psy-
chotherapy, and to prevent or minimize the develop-
ment of the disease later in life.
Abbreviations 5-HT 3AR: Serotonin 3A Receptor; 5-HTT: Serotonin Transporter 1; 5-HTTLPR: Serotonin transporter gene; ACTH: Adrenocortico tropic Hormone; ADHD: Attention Deficit Hyperactivity Disorder; ADRB2: Adrenocep tor Beta 2; APBA2: Amyloid Beta Precursor Protein Binding Family A Member 2; APBA3: Amyloid Beta Precursor Protein Binding Family A Member 3; AVP: Arginine Vasopressin; BDHI: Buss-Durkee-Hostility Inventory; BDNF: Brain-Derived Neurotrophic Factor; BIS: Barratt Impulsiveness Scale; BPD: Borderline Personality Disorder; CA: Cornu Ammonis; CNS: Central NervousSystem; COMT: Catechol-O-methyltransferase; CpG: CG dinucleotides;cPTSD: complex Post-Traumatic Stress Disor der; CRF: Corticotropin-Releasing Factor; CRHR: Corticotropin Releasing Hormone Receptor; DAT1: Dopamine Transporter 1; DBH: Dopamine Beta-Hydroxylase; DESNOS: Disorders of Extreme Stress NotOtherwise Specified; DEX: Dexamethasone; DG: Dentate Gyrus; FKBP5: FK506 BindingProtein 5; GABRA1: Gamma-Aminobutyric Acid Type A Receptor Alpha1 Subunit; GATA4: GATA Binding Protein 4; GNB3: G Protein Subunit Beta 3; GR: Glucocorticoid Receptor; GRE: Glucocorticoid Responsive Elements; GRIN2B: Glutamate IonotropicReceptor NMDA Type Subunit 2B; HPA axis: Hypothalamic-Pituitary-Adrenal axis;HTR1B: 5-Hydroxytryptamine Receptor 1B; HTR2A: 5-Hydroxytryptamine Receptor 2A; IL17RA: Interleukin 17 Receptor A; KCNQ1: Potassium Voltage-Gated Channel Sub- family Q Member 1; KCNQ2: Potassium Voltage-Gated Channel Subfamily Q Member2; MAOA: Monoamine Oxidase A; MAOB: Monoamine Oxidase B; MCF2: Proto-Oncogene MCF-2; MDD: Major Depressi ve Disorder; miRNAs: microRNAs; MR: Mineralcorticoid Receptor; NINJ2: Ninjurin 2; NMDA: N-methyl-D-aspartate; NOS1: Nitric Oxide Synthase 1; NR3C1: Glucocorticoid receptor gene; PET: PositronEmission Tomography; PKC: Protein Kina se C; PRIMA1: Prolin Rich Membrane Anchor 1; PTSD: Post-Traumatic Stres s Disorder; PVN: Paraventricu lar Nucleus; SLC6A2: Solute Carrier Family 6 Member 2; SNP: Single nucleotide polymorphism; TAAR5: Trace Amine Associated Receptor 5; TH: Tyrosine Hydroxylase; TPH1: TryptophanHydroxylase 1
Acknowledgements Not applicable.
Funding This work was supported by an Eranet-Neuron Grant to A.C. (Inflame-Dproject) and by funding from the Italian Ministry of Health (MoH) to A.C.
Availability of data and materials The data supporting the conclusions of this article are included within thearticle.
Cattane et al. BMC Psychiatry (2017) 17:221 Page 11 of 14 Authors ’contributions N.C. managed the literature searches and wrote the first draft of the manuscript. R.R. and M.L. managed the literature searches and completed the manuscript.A.C. revised and approved the final version of the manuscript. All authors gavetheir scientific contribution and have approved the final manuscript.
Competing interests All the authors declare that they have no conflicts of interest.All the authors certify that the submission is an original work and it is not under review at any other journal.
Consent for publication Not applicable- as the submitted manuscript is a review.
Ethics approval and consent to participate Not applicable- as the submitted manuscript is a review.
Author details1Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio - Fatebenefratelli, via Pilastroni 4, Brescia, Italy. 2Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio - Fatebenefratelli, via Pilastroni 4, Brescia, Italy.3Stress, Psychiatry and Immunology Laboratory, Department of PsychologicalMedicine, Institute of Psychiatry, King ’s College London, 125 Coldharbour Lane, London SE5 9NU, UK. 4Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King ’s College London, 125 Coldharbour Lane, London SE5 9NU, UK.
Received: 7 February 2017 Accepted: 6 June 2017
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