Animal models for bipolar disorder: from bedside to the cage
Beyer and Freund Int J Bipolar Disord
Animal models for bipolar disorder: from bedside to the cage
Dominik K. E. Beyer 0
Nadja Freund 0
0 Experimental and Molecular Psychiatry, LWL University Hospital, Ruhr University Bochum , Universitätsstr. 150, 44801 Bochum , Germany
Bipolar disorder is characterized by recurrent manic and depressive episodes. Patients suffering from this disorder experience dramatic mood swings with a wide variety of typical behavioral facets, affecting overall activity, energy, sexual behavior, sense of self, self-esteem, circadian rhythm, cognition, and increased risk for suicide. Effective treatment options are limited and diagnosis can be complicated. To overcome these obstacles, a better understanding of the neurobiology underlying bipolar disorder is needed. Animal models can be useful tools in understanding brain mechanisms associated with certain behavior. The following review discusses several pathological aspects of humans suffering from bipolar disorder and compares these findings with insights obtained from several animal models mimicking diverse facets of its symptomatology. Various sections of the review concentrate on specific topics that are relevant in human patients, namely circadian rhythms, neurotransmitters, focusing on the dopaminergic system, stressful environment, and the immune system. We then explain how these areas have been manipulated to create animal models for the disorder. Even though several approaches have been conducted, there is still a lack of adequate animal models for bipolar disorder. Specifically, most animal models mimic only mania or depression and only a few include the cyclical nature of the human condition. Future studies could therefore focus on modeling both episodes in the same animal model to also have the possibility to investigate the switch from mania-like behavior to depressive-like behavior and vice versa. The use of viral tools and a focus on circadian rhythms and the immune system might make the creation of such animal models possible.
Translational; Human condition; Circadian rhythm; Dopamine; Immune system; Stress
Bipolar disorder (BD) is characterized by recurrent
episodes of manic and depressive states with intervening
episodes of euthymia (normal mood)
(Merikangas et al.
2007; Anderson et al. 2012; Phillips and Kupfer 2013)
The symptomatology of BD is very heterogenic and
heavily depends on the patient’s state. Throughout manic
episodes, people undergo euphoria, aggression, reduced
need for sleep, high reward seeking, hypersexuality, and
(Perry et al. 2010; Anderson et al. 2012;
Cheniaux et al. 2014)
. In contrast, a state of depression
includes anhedonia, increased sleep, reduced libido,
feeling tired, and a greater risk of suicide among other
(American Psychiatric Association 2013; Anderson
et al. 2012)
. In addition, BD patients suffer from
various cognitive deficits
(Martínez-Arán et al. 2004; Savitz
et al. 2005; Burdick et al. 2007; Goodwin et al. 2008)
Established treatments for BD include mood
stabilizers, such as lithium, anticonvulsants, like valproate,
and antipsychotics. Current treatments, however, are
not able to completely stabilize behavioral aberrations
or to recover cognitive deficits
(Grunze et al. 2013; van
Enkhuizen et al. 2015a)
. Lithium, the first line
medication for BD, is furthermore suspected to cause negative
side effects, including cognitive impairment
Wisniewski 2003; Holmes et al. 2008; Grunze et al. 2013)
Besides the lack of novel developed therapeutics
(Malkesman et al. 2009)
, current clinical criteria fail to
diagnose milder symptoms of BD and therefore it can take
years to finally diagnose this psychiatric disorder
(Merikangas et al. 2011)
. Improvement of treatment and
diagnosis options is crucial, particular given the high rate of
suicide attempts in patients with BD
(Novick et al. 2010)
A better understanding of cause and pathophysiology
of the disease is needed to archive these improvements.
Adequate animal models for BD will provide a useful tool
to advance the knowledge on the underlying
neurobiology of BD. Establishing animal models for psychiatric
disorders, however, is a difficult task
(Malkesman et al.
. Not only are the symptoms in patients with one
disorder often quite broad and variable between patients,
some symptoms used to diagnose psychiatric disorders in
humans are not even possible to asses in animals, such
as feelings of worthlessness or guilt
et al. 1998; Nestler and Hyman 2010)
. Given its cyclical
nature, BD is thereby especially hard to model
and Einat 2007, 2014)
. So far BD is mainly investigated
in separated animal models for either mania or
(Einat 2014; van Enkhuizen et al. 2015a)
. The animal
models mostly mimic some behavioral characteristics of
BD, which are more or less easy to measure, such as
overall locomotor activity, sexual behavior, aggression, risk
taking, and decision making
(Einat 2014; van Enkhuizen
et al. 2015a; Harrison et al. 2016; Sharma et al. 2016)
An animal model of BD in rodents, which models the
whole complexity of symptoms, might never be possible.
Nonetheless, it is still crucial to create and characterize
new models for BD, which consistently tighten the gap
between human pathophysiology and BD-like
symptoms in animals. Animal models are an indispensable
tool and a critical component in the preclinical research
field. They allow developing new treatment and diagnosis
options and therewith improving the lives of BD patients
and can therefore not be replaced. Ideally, an adequate
animal model of BD should include elements of the three
axes of validity: face, predictive, and construct validity.
Face validity indicates to which extent the model reflects
characteristics of the human disease. Predictive
validity refers to which degree the model will respond to an
efficient treatment in humans. Construct validity reflects
to which extent the model measures what it claims to be
(Einat 2014; Malkesman et al. 2009)
. The ideal
animal model should therefore comply with the following
requirements: (i) model BD-specific behavioral
abnormalities with ideally all its facets; (ii) consider the
cyclical nature of BD; (iii) be able to spontaneously switch
between both episodes (all face validity); (iv) respond
to current established treatment; and (v) due to the fact
that not all BD patients respond to medications
(Cipriani et al. 2011), reflect a distribution of responders and
nonresponders (both predictive validity)
This division would represent the result of clinical
trials and therefore a group effect of treatment should still
be observed. Additional prior determination of
individual, untreated baseline measurements will be required
to compare intra-individual differences before and after
treatment of the animals to later successfully separate
responders from nonresponders. It should furthermore
(vi) be affected by pharmacological, environmental, or
genetically manipulations in regard to the same
mechanisms that are involved in human patients (face validity).
To date, no such animal model for BD exists. However,
within the last couple of years several models were able
to at least address some of the above-mentioned
requirements and have therewith been able to improve our
understanding of the neurobiology underlying BD. In this
review, we will discuss various aspects that are affected in
patients with BD, namely circadian rhythm,
neurotransmitters focusing on the dopaminergic system,
environment, and immune system. Disruptions and influences
regarding these topics in patients will be compared to
findings in animal models and we will illustrate how
these findings have been used to develop animal models
for the disorder.
Aberrations of the sleep–wake cycle and circadian
rhythms belong to primary symptoms of patients
suffering from BD and are used as diagnostic criteria
(Gonzalez 2014; Kripke et al. 2009; McCarthy and Welsh 2012;
. Patients display irregularities in daily
biological rhythms including sleep, activity, body
temperature, hormonal secretions, cell regeneration, and
(Bunney and Potkin 2008; Goetze and Tölle
1987; McClung 2007; Salvatore and Tohen 2007; Souetre
et al. 1988; Takahashi et al. 2008)
. In addition,
psychotherapeutic treatment (interpersonal and social rhythm
therapy) with the aim of stabilizing and structuring daily
routines and thereby enabling a normalized sleep–wake
cycle is an effective therapeutic tool for mood
stabilization and can reduce the number of manic and depressive
(Frank et al. 2000, 2007; Miklowitz et al. 2007)
At the same time, mania can be induced by disruption of
(Bunney and Bunney 2000; McClung
. Circadian disruptions present in humans
suffering from BD suggest an involvement of circadian clock
genes in the pathogenesis of the disease
(Cosgrove et al.
2016; Etain et al. 2011; Wirz-Justice 2006; McClung 2007;
Frank et al. 2000)
. Indeed, BD symptoms are correlated
with disruptions of the circadian rhythm and associated
with a polymorphism of the circadian locomotor output
cycles kaput (Clock) gene
(Benedetti et al. 2003; Logan
and McClung 2016; Serretti et al. 2003)
Targeting circadian rhythm genes to disrupt
mechanisms regulating the circadian rhythm has been widely
used to create animal models for BD
(McClung et al.
2005; Mukherjee et al. 2010; Roybal et al. 2007)
master pacemaker of the circadian rhythm is localized
in the suprachiasmatic nuclei and interconnects a
complex network of transcriptional–translational activation
and repression, resulting in an oscillating expression of
clock genes over a period of 24 h
(Takahashi et al. 2008)
Several diverse preparations of Clock manipulation were
used as animal models to study BD. The most common
model is the ClockΔ19 mutant mouse. These mice carry
a deletion at exon 19 of the Clock gene, resulting in a
dominant-negative protein, unable to activate
(King et al. 1997)
. Mutant mice exhibit mania-like
(Roybal et al. 2007)
and altered sleep patterns
. The disruption of CLOCK resulted
in lower immobility in the forced swim test, a greater
preference for rewarding stimuli, such as sucrose
solution and cocaine, a lower threshold within intra-cranial
self-stimulation at lower drug doses, lowered anxiety
levels, and less depressive-like behavior
(McClung et al.
2005; Roybal et al. 2007)
. In addition, the Clock mutant
mice exhibited deficits within the paired pulse
(van Enkhuizen et al. 2013b)
mutant mice were also tested in the behavioral pattern
monitor (BPM), a test to pattern and level of
locomotor activity, exploratory behavior, and novelty seeking
in humans and rodents
(Perry et al. 2009; Young et al.
. While BD patients show increased exploration
and goal-directed behavior, illustrated through linear and
(Logan and McClung 2016; Minassian
et al. 2011; Perry et al. 2009, 2010)
, the ClockΔ19 mutant
mice do not represent this specific exploration and
goaldirected behavior. They exhibit more circumscribed,
(Perry et al. 2009; van
Enkhuizen et al. 2013b)
. In summary, the ClockΔ19 mutant
mice resemble various but not all behavioral aspects of
BD mania in humans to its full extent. Another
manipulation of Clock, which resulted in BD-relevant behavior,
is the knock-down of CLOCK specifically in the ventral
tegmental area (VTA) of mice
(Mukherjee et al. 2010)
The knock-down of Clock expression resulted in
abnormal circadian rhythms, indicated by less robust activity in
dark phases and enhanced activity in resting phases, less
anxiety behavior, and increased locomotor activity in a
novel environment. Despite the observed hyperactivity in
a novel environment, the overall locomotor activity over
a period of 24 h, however, was reduced
(Mukherjee et al.
. In contrast to the previously observed
less-depression-like behavior of the ClockΔ19 mutant mice
et al. 2007)
, the CLOCK knock-down mice exhibited
increased depression-like behavior in the forced swim
and learned helplessness test and thereby express a mixed
state of mania- and depression-like behavior
et al. 2010)
. Mukherjee and colleagues postulated,
therefore, that CLOCK’s functioning in the VTA is required
for the regulation of mood-related behavior. This
hypothesis is supported by the fact that over-expression
of CLOCK in the VTA reduces hyperactivity and restores
anxiety-related behavior almost to wild-type level in the
ClockΔ19 mutant mice
(Roybal et al. 2007)
circadian rhythm in these animal models might create
a vulnerable state with a greater sensitivity for
addiction and mood disorders
(Logan et al. 2014; Logan and
. Commonly found in both Clock mice
models is an enhanced dopamine (DA) release from
neurons in the VTA, which is reflected, for example, in an
increased dopaminergic cell firing rate
(Coque et al. 2011;
McClung et al. 2005; Mukherjee et al. 2010; Roybal et al.
. This functional linkage between the
dopaminergic system (see “Dopaminergic pathways”) and aberrant
circadian rhythms connects two major pathways, which
may be involved in the pathogenesis of BD and are often
used as targets for the development of genetic or
environmental animal models for BD. This involvement of the
dopaminergic system supports the dopamine hypothesis
(Berk et al. 2007)
that hyper-dopaminergic transmission
might be responsible for mania in humans and therefore
also for mania-like behavior in animals.
Chronic lithium treatment was able to normalize
various aspects of aberrant behavior in the ClockΔ19 mutant
(Coque et al. 2011; Roybal et al. 2007)
therapeutic efficacy might be due to its properties to
lengthen the circadian period, which was observed across
(Klemfuss 1992; Kripke et al. 1978)
well-studied potential target of lithium’s action is the
inhibition of glycogen synthase kinase-3 beta (GSK-3β)
(Klein and Melton 1996; Serretti et al. 2009; but see also
Agam and Azab 2016)
. GSK-3β is involved in various
cell functions, like gene transcription, neurogenesis, and
apoptosis (Doble and Woodgett 2003). GSK-3β is also
able to regulate the circadian clock through
phosphorylation of CLOCK and nuclear receptor subfamily1, group
D, member1 (REV-ERBα)
(Bellet and Sassone-Corsi
2010; Besing et al. 2015; Martinek et al. 2001; Yin et al.
and thereby modulates the circadian rhythm
(Besing et al. 2015). Synthetic inhibition of GSK-3β was able
to mimic the effects of lithium and to prevent mania-like
behavior, such as amphetamine-induced hyperactivity, in
male C57BL/6J mice
(Kozikowski et al. 2007)
. In addition,
gsk-3β haploinsufficient mutant mice, lacking one copy of
the gene coding for GSK-3β, show the same behavioral
effects as lithium-treated mice
(O’Brien et al. 2004)
gsk3β haploinsufficiency reduces exploratory behavior and
immobility time in the forced swim test, comparable to
treatment with lithium in wild-type mice, without
affecting overall activity
(O’Brien et al. 2004)
manipulations of GSK-3β suggest that lithium’s therapeutic effect
as a mood stabilizer depends on inhibiting GSK-3β
(O’Brien et al. 2011)
. Once again a manipulation
of the circadian rhythm through transgenic mice
overexpressing GSK-3β resulted in mania-like behavior
(Prickaerts et al. 2006)
. The GSK-3β over-expressing
mice exhibited hyperactivity, reduced immobility in the
forced swim test, reduced habituation in the open field
test, and increased acoustic startle response
et al. 2006)
. Patients in manic episodes opposingly exhibit
reduced startle responses
(Perry et al. 2001)
. Due to the
nonspecific alterations of the dopaminergic system in the
GSK-3β over-expressing mice, which are also
recognizable in other psychiatric disorders, such as
schizophrenia and attention-deficit hyperactivity disorder (ADHD),
this animal model, however, lacks specificity for mania
et al. 2016
An additional target of the circadian rhythm, which
can be used to model BD-relevant behavior, is the
extracellular-signal-regulated kinase (ERK)
(Engel et al. 2008)
The ERK pathway mediates proliferation, differentiation,
and plasticity of neurons in the central nervous system
(Thomas and Huganir 2004)
. ERKs are also involved in
resetting the master pacemaker in the suprachiasmatic
nucleus via photic input
(Butcher et al. 2002; Coogan and
. Infusion of ERK inhibitor into the
suprachiasmatic nucleus of mice prevents the activity rhythms
shift, which is usually observed between light and dark
(Butcher et al. 2002)
. A knock-out of the gene
coding for ERK1 resulted in hyperactivity, enhanced
goaldirected activity, increased risk taking or impulsivity, and
increased reward-motivated behavior
(Engel et al. 2008)
In addition, the ERK1 pathway can be activated by lithium
and valproate, but only valproate, not lithium, was able to
reduce the behavioral abnormalities
(Engel et al. 2008)
The ERK pathway can in turn be activated by
neurotrophins. One of these neurotrophins might play a role in the
pathophysiology of BD, namely the brain-derived
neurotrophic factor (BDNF)
(Frey et al. 2013; Södersten et al.
. BDNF haploinsufficient mice indeed exhibit
manialike behavior, including hyperactivity, increased
aggressive behavior, and appetite
(Kernie et al. 2000; Lyons et al.
. Interestingly, even untreated BDNF
haploinsufficient mice show reduced hippocampal volume and their
CA3 dendritic arborizations resembled stressed wild-type
mice, suggesting a role of BDNF in hippocampal dendritic
remodeling (Magariños et al. 2011).
One downstream target of the ERK signaling pathway
is B-cell lymphoma 2 (Bcl-2), which is involved in
neuronal development, plasticity, and degeneration
et al. 2004)
through inhibition of apoptosis
(Bold et al.
1999; Campani et al. 2001)
. Interestingly, lithium affects
the Bcl-2 levels, with chronic lithium treatment
increasing Bcl-2 levels in the brain of rats
(Chen et al. 1999;
Manji et al. 2000)
. Consistent with this effect of lithium is
that transgenic over-expression of Bcl-2 in mice prevents
(Bonfanti et al. 1996)
and acts protective
against deleterious stress-induced neuronal
(DeVries et al. 2001)
. Although BD is rather
associated with neuroplasticity deficits than neurodegenerative
, cell death might play a role in
the pathogenesis of BD
(Lee et al. 2002)
manipulation might also be related to anxiety as mice with an
additional Bcl-2 transgene, and therefore elevated Bcl-2
levels, exhibited less anxiety behavior
(Rondi-Reig et al.
1997; Rondi-Reig and Mariani 2002)
. On the other hand,
mice with a heterozygous knock-out of the Bcl-2 gene
exhibit Bcl-2 deficiency and increased anxiety
(Einat et al. 2005)
. In addition, Bcl-2 heterozygous
knock-out mice show some behaviors similar to mania,
including increased reward seeking and amphetamine
sensitization, and lithium pretreatment attenuated
sensitization in these animals
(Lien et al. 2008)
Another gene heavily involved in the regulation of
circadian rhythms is Dbp. It encodes for the albumin D
element-binding protein, a transcription factor that is
regulated by the CLOCK protein
(Ripperger et al. 2000;
Wuarin et al. 1992)
. Dbp expression is affected in patients
with BD and can furthermore be influenced by lithium
treatment (Kittel-Schneider et al. 2015). A
heterozygotous knock-out of DBP in mice induces a depressive-like
phenotype indicated by reduced locomotor activity and
diminished response to amphetamine. When exposed to
environmental stress (see “Environment: stressors”), DBP
knock-out mice show a switch in behavior and become
hyperactive. This switch, which to some extend
resembles the switch from depression to mania in BD patients,
can be prevented by the administration of valproate
(LeNiculescu et al. 2008).
But even stressors alone (e.g., sleep deprivation) can
disrupt the circadian clock resulting in changes of mood
and even the induction of mania in BD patients
et al. 1999; Malkoff-Schwartz et al. 1998; Wright 1993)
is therefore possible that sleep deprivation paradigms can
induce mania-like behavior in rodents. Indeed, wild-type
rats after typically 72 h of sleep deprivation exhibited
mania-like behavior, such as enhanced aggressive
behavior and hypersexuality
(Gessa et al. 1995; Hicks et al.
1979; Morden et al. 1968)
. But this behavioral phenotype
lasted only for about 30 min. In addition, chronic lithium
can reverse the mania-like behavior
(Gessa et al. 1995)
However, it should be noted that the disruption of
regular sleep requires the usage of techniques that cause
additional stress (i.e., immobilization, isolation, and the fear
and experience of falling into water)
(Logan and McClung
. Benedetti and colleagues used an improved
protocol to minimize these additional stressors and still found
mania-like behavior, such as increased locomotor
activity and aggressive behavior (Benedetti et al. 2008). These
results indicate that sleep deprivation alone is a sufficient
stressor to induce BD-relevant behavior.
An additional possibility to affect the sleep–wake cycle
is the high-frequency stimulation of the lateral
hypothalamus, which resulted in mania-like behavior in rats
(Abulseoud et al. 2014)
. The hypothalamic stimulated
rats exhibited hyperactivity, such as increased
grooming, and reduced resting phases, as well as hypersexuality,
i.e., increased rearing and sexual self-stimulation. These
behavioral characteristics could be attenuated through
chronic lithium treatment.
Apart from the cycle of day and night, the changing of
seasons and the associated photoperiod length can
trigger changes in mood
(Young and Dulcis 2015)
a seasonal pattern of the episodes of BD was
identified in a proportion of patients (Schaffer et a
whereas depressive symptoms are more prevalent during
(Meesters and Gordijn 2016; Rosenthal
et al. 1984)
. This seasonal effect might be due to
shortening or lengthening of the day-lengths and the
associated received illumination. Modified illumination in rats
induced a switch in neurotransmitter expression. A long
day period of 19 h of light resulted in a switch from DA to
somatostatin expression in hypothalamic neurons after
1 week. The contrary effect was observed with a short
day period of 5 h light
(Dulcis et al. 2013)
. In addition,
a matching pattern of receptor expression was observed:
an increased expression of postsynaptic dopamine D2
receptors (D2R) was accompanied by the
presynaptic increase in dopaminergic interneurons
(Dulcis et al.
. Rats in the long day period exhibited more anxiety
behavior in the elevated plus maze and more
depressivelike behavior measured by increased immobile time in
the forced swim test, whereas animals in the short day
period displayed decreased anxiety-related behavior and
less immobile time
(Dulcis et al. 2013)
Disruption of the circadian rhythms has been widely
used to induce BD-like behavior, mainly mania-like
behavior (Table 1). Here it is to consider that the
manipulations have been mainly conducted in nocturnal animals
and results might not be comparable to mechanisms in
. Using diurnal rodent
animal models could be beneficial in this field of research
(Ashkenazy et al. 2009; Bilu et al. 2016; Einat et al. 2006;
Leach et al. 2013)
. Nevertheless, effects are quite robust
as various disruptions of one gene (i.e., Clock) as well as
targeting related pathways or environmentally influence
sleeping behavior result in similar effects
(McClung et al.
2005; Mukherjee et al. 2010; Prickaerts et al. 2006;
Roybal et al. 2007)
. Observations of depressive-like behavior
after manipulations of circadian rhythms are rare. We see
mixed behavior, some aspects of mania- and at the same
time depressive-like behavior, in the ClockΔ19 mutant
mouse (Mukherjee et al. 2010). Similarly, manipulation of
Bcl-2, a gene that has indirect connections with circadian
rhythm pathways, can induce both behavioral states
et al. 2008)
. Here it is important to note that elevated
levels of Bcl-2 are associated with decreased anxiety
(RondiReig et al. 1997; Rondi-Reig and Mariani 2002)
Bcl-2 deficiency increases anxiety (Einat et al. 2005). The
most promising model in terms of the cyclic
characteristic of BD is the manipulation of length of day. Here
we see depressive-like behavior when extending the day
period and (at least) less depressive-like behavior when
decreasing the day period
(Dulcis et al. 2013)
Sensitization models and neurotransmitters in general
Nearly 100 years ago, Kraepelin made the observation
that with an increasing number of episodes the course
of the illness worsens, the so-called sensitization model
(Kraepelin 1909; Post 1992)
. Later on behavioral
sensitization to psychostimulants in rodents was used to
resemble the shortening of interepisodic intervals during
the progression of BD in humans (Post 1990). Repeated
administration of the same dose of cocaine induced
hyperactivity and elevated stereotypy responses in rats
(Kilbey and Ellinwood 1977; Post 1990)
. A drug-high
state after the administration of psychostimulants was
furthermore associated with increased aggression
(Borison et al. 1978; Davies et al. 1974)
, a declined cognitive
(Fries et al. 2015; Rygula et al. 2015)
deficits in prepulse inhibition (PPI) (Zheng et al. 2013).
Several different psychostimulants were administrated
to induce mania-like behavior. Apart from cocaine, the
used substances were amphetamine
(Frey et al. 2006)
lisdexamfetamine dimesylate (
Macêdo et al. 2013
fenproporex in rats
(Rezin et al. 2014)
, and alpha-lipoid acid
(Macêdo et al. 2012)
and GBR12909 in mice
et al. 2015)
. All these substances resulted in mania-like
behavior, which could be attenuated by mood stabilizers
e or lithium (Sharma et al. 2016
Withdrawal from psychostimulants is accompanied by
depressive-like behavior or at least an anhedonic state
measured as reduced sexual behavior
(Barr et al. 1999)
elevated thresholds in self-stimulation
(Markou and Koob
1991; Wise and Munn 1995)
, reduced activity
et al. 1991)
, decreased sucrose consumption
, increased negative contrast
, and increased anxiety
. Immobility time in the forced swim test,
however, depends on the administered does of
amphetamine as well as the training procedure and was reported
to be reduced during amphetamine withdrawal
(Schindler et al. 1994)
but also to be increas
(MarszalekGrabska et al. 2016
). Withdrawal furthermore induces
supersensitivity of serotoninergic neurons (Baumann and
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Rothman 1998), a transient decrease in norepinephrine
(NE) in the hypothalamus, and a reduction in
responsiveness to amphetamine in terms of DA concentrations in
caudate-putamen and nucleus accumbens
(Paulson et al.
. Even a switch in behavior has been shown in the
same animal model. Anhedonic symptoms after
withdrawal stabilize after a while
(Paulson et al. 1991; Wise
and Munn 1995)
. Morphine pretreated rats,
furthermore, show a switch in β-endorphin-induced locomotor
activity from being hyper-responsive to hypo-responsive
when going through withdrawl (Schwartz et al. 1982).
The administration of psychostimulants affects
several neurotransmitter systems which is in line with the
fact that a number of neurotransmitters are affected in
patients with BD
(Barchas and Altemus 1999;
. Similarly, other pathways, e.g., the
phosphoinositide cycle have been reported to be involved in
BD and are targeted by treatment options for the
(Agam et al. 2002)
. A comprehensive overview of all
these neurotransmitters and pathways would go beyond
the scope of this review; therefore, we will give a brief
overview on neurotransmitters and then focus on the
dopaminergic system in “Dopaminergic pathways.”
The cholinergic system seems to be predominantly
involved in depressive-like symptoms in humans and
animals. Manipulation of the cholinergic system through
administration of arecoline, a direct agonist of
cholinergic receptors, induced depression in both healthy
controls and unmedicated euthymic BD patients
(Nurnberger et al. 1983)
. Furthermore, affective disorder
patients undergo exaggerated depressive responses to
cholinergic agents compared to control groups. This
hypersensitivity to cholinergic manipulations supports
the hypothesis of a cholinergic imbalance during
(van Enkhuizen et al. 2015b; Janowsky et al.
. Further evidence for the involvement of
acetylcholine in BD comes from neuroimaging studies, where
physostigmine, a cholinesterase inhibitor, resulted in
elevated acetylcholine levels in the brain, counteracted
mania, and induced depressive-like symptoms in both
control and patients with affective disorders
et al. 2013; Janowsky et al. 1972; Janowsky et al. 1974)
Also reduced β2 nicotinic acetylcholine receptor
availability was observed in depressed BD patients compared
to healthy and euthymic individuals (Hannestad et al.
2013). The brains of depressed patients contain elevated
levels of choline, the precursor of acetylcholine
(Steingard et al. 2000)
, supporting a hypercholinergic state
during depressive episodes
(van Enkhuizen et al. 2015b)
Animal models confirm the involvement of the
cholinergic system in depression. The α7 nicotinic acetylcholine
receptor agonist SSR180711 shows antidepressant-like
effects in mice, indicated by reduced immobility time in
the forced swim test
(Andreasen et al. 2012)
Interestingly, behaviorally effective doses of SSR180711
inhibited in part the serotonin reuptake
(Andreasen et al.
. Another subtype-selective nicotinic acetylcholine
receptor agonist acts antidepressive-like by reversing the
escape deficits in the learned helplessness paradigm in
(Ferguson et al. 2000)
. Furthermore, nicotine
attenuates anhedonia-like behavior in rats
(Andreasen et al.
and depressive-like behavior in mice
and Redrobe 2009)
. The withdrawal of chronic nicotine
administration induces depressive-like behavior in mice,
measured as increased immobility time in the force swim
(Roni and Rahman 2014)
. Another manipulation
of the cholinergic system is the inhibition of
acetylcholinesterase, which is degrading acetylcholine. This
inhibition induces depressive- and anxiety-like behavior in
mice (Mineur et al. 2013). Interestingly, both lithium and
valproate increase the activity of acetylcholinesterase in
the brain of rats
(Varela et al. 2013)
The catecholaminergic system on the other hand is
mainly involved in mania-like symptoms in humans as
well as in animals. Elevated levels of both DA and NE
could be observed in BD rapid cycling
(Juckel et al. 2000)
and normal cycling patients
(Berk et al. 2007)
antidepressants increase synaptic catecholamine
et al. 2008; Tanda et al. 1994)
levels. Furthermore, as
already mentioned above the psychostimulant
amphetamine increases synaptic DA and NE levels through
inhibition or reversing the corresponding reuptake
mechanisms or elevated DA efflux
(Berk et al. 2007;
Raiteri et al. 1975; Schaeffer et al. 1976; Sulzer et al. 2005)
Amphetamine not only induces mania-like behavior
in animals but also causes manic symptoms in healthy
humans and BD patients, such as decreased need for
sleep, elevated mood, drive and energy and attention,
sleep, sexual behavior, sensorimotor function, learning
and memory are affected
(Asghar et al. 2003; Berk et al.
2007; Corp et al. 2014; Cousins et al. 2009; Jacobs and
Silverstone 1986; Nurnberger et al. 1982; Peet and Peters
1995; Seiden et al. 1993)
. These behavioral effects of
amphetamine administration are not only a simple
consequence of increased neurotransmitter levels but it is
more likely that a disturbance of the homeostatic
mechanisms, controlling the catecholamine levels, plays a key
role for this dramatic mood shift
(Anand et al. 1999; van
Enkhuizen et al. 2015b; Young and Dulcis 2015)
Comparable to the animal models psychotherapeutics, such as
lithium and valproate, can also attenuate the
amphetamine mania-relevant behavior in humans
1974; Silverstone et al. 1980; Van Kammen and Murphy
Several neurotransmitters are affected in BD and
together with the high comorbidity of BD with substance
(Kessler et al. 1997; Regier et al. 1990;
Salloum et al. 2005)
sensitization models have some face
validity. They have for a long time also been the only BD
animal models that show both phases, mania and
depression, in the same animal model
(Kato et al. 2007)
. On the
other hand, the fact that psychostimulants act on
numerous pathways hampers the investigation of the
neurobiology underlying the observed behavioral changes.
Therefore, more recent models for BD try to focus on
one neurotransmitter system, primarily the
dopaminergic system. Its involvement in BD and manipulations
in animal models will be discussed in “Dopaminergic
Another limitation of the psychostimulant induced
animal models for BD mania is that only a few simple
aspects of human mania, like hyperactivity, are mimicked
and even the amphetamine-induced hyperactivity is not
specific for BD
(Logan and McClung 2016; Rygula et al.
Evidence from both human and animal studies
suggests that BD is caused by an impaired
(Berk et al. 2007)
. Clinical observations
revealed that DA is altered in both episodes of BD. Thus,
the dopamine hypothesis, claiming that dopaminergic
transmission is disturbed depending on the mood phase,
is one of the most promising hypotheses for the
pathophysiology of BD
(Berk et al. 2007)
. Manic episodes are
associated with hyperdopaminergia. Increased
dopaminergic transmission then induces homeostatic regulation
mechanisms, which in a next step downregulate the
postand presynaptic sensitivity of receptors among other
mechanisms. This downregulation results in an episode
of decreased dopaminergic transmission, which is
associated with the depressive episode of BD. This
hypodopaminergic state activates then again the same homeostatic
mechanisms, which now upregulate the key elements,
resulting in another manic episode and thereby
explaining the cyclic nature of the disease. A desynchronization
of receptors and other key elements in different brain
regions might be a possible explanation for euthymic
(Berk et al. 2007)
The dopaminergic system is involved in
experiencing pleasure, mediating motivation
(Bressan and Crippa
, impulsivity, risk behavior, and cognitive processes
(Seamans and Yang 2004)
. Manipulation of the dopamine
D1 receptor (D1R) in several species results in
working memory deficits
(Floresco and Phillips 2001;
Goldman-Rakic 1999; Paspalas et al. 2013; Puig et al. 2014)
Furthermore, increased D1R expression in the
prefrontal cortex plays a role in impulsivity
(Loos et al. 2010)
cocaine addiction, sucrose preference, and high-ri
behavior (Sonntag et al. 2014
). All these behaviors are
to a certain extent detectable in patients of BD,
including increased risk for substance abuse
(Messer et al.
, increased impulsivity in manic episodes
and McClung 2016)
, or cognitive deficits (Cope et al.
2016). Indeed, elevations in D1R have been observed
in BD patients via positron emission tomography and
single-photon emission computed tomography
et al. 2009; Suhara et al. 1992; Yao et al. 2013)
. Also other
dopamine receptors are altered in BD patients and might
therefore play a role in the pathogenesis of the disease.
The D2R density is elevated in the nucleus accumbens
in bipolar patients with psychotic symptoms
et al. 1995)
. Elevated DA levels in the urine were
additionally observed in BD patients within manic episodes
(Joyce et al. 1995)
. Alterations in the dopaminergic
system through administration of psychostimulants result in
a shift of neurotransmitter levels and manic behavior in
(Cousins et al. 2009)
. DA levels can be affected
through administration of L-DOPA, the precursor of DA,
which is an established medication for Parkinson’s
(Berk et al. 2007)
. L-DOPA administration induced
behavior similar to BD mania in these patients, such
as increased sexual behavior, impulsivity, and risk
(Berk et al. 2007; Claassen et al. 2011; van Praag and
Korf 1975; Raja and Bentivoglio 2012)
. Not all, but some
BD patients treated with different DA agonists, such as
bromocriptine, also experienced manic episodes
et al. 1991; Gerner et al. 1976)
. BD depression can be
treated with such agonists and resulted in an
improvement of depressive symptoms
(Goldberg et al. 2004;
Zarate et al. 2004)
. On the other hand, manic symptoms
of BD patients can be attenuated through administration
of DA antagonists
(Christie et al. 1989; Tohen et al. 2003;
Vieta et al. 2005)
. Furthermore, antidepressants increase
the dopaminergic transmission in the prefrontal cortex
and nucleus accumbens as shown in rodents
(Tanda et al.
. Alterations of functional DA transporter (DAT)
levels, particularly reduced availability, were confirmed
in BD patients via positron emission tomography
et al. 2011)
, in postmortem tissue
(Rao et al. 2012; Young
and Dulcis 2015)
and cell culture experiments
et al. 2005)
A knock-down of DAT in mice with reduced DAT
functioning to approximately 10% of wild-type level resulted
in mania-like behavior, such as hyperactivity in novel
(Zhuang et al. 2001)
, increased risk
behavior in the Iowa Gambling Task (IGT)
(Young et al. 2011)
impaired decision making with a preference for high
reward combined with high risk in the IGT
Enkhuizen et al. 2014b)
, and a similar hyperexploratory behavior
in the BPM as observed in humans but with less straight
movements compared to BD patients
et al. 2014a; Perry et al. 2009; Young et al. 2010)
. But DAT
knock-down mice fail to mimic the observed
sensorimotor deficits in PPI observed in humans (Ra
et al. 2003
). Alpha-methyl-p-tyrosine induced depletion
of DA and was able to attenuate some of the behavioral
abnormalities of the DAT knock-down mice
Enkhuizen et al. 2014a)
, similar to the effect of chronic valproate
(van Enkhuizen et al. 2013a)
, whereas both
treatments did not affect the exploration behavior. To sum
up, this animal model is able to resemble various
behavioral aspects of human BD mania
(Cassidy et al. 1998;
van Enkhuizen et al. 2015a)
. Interestingly, photoperiod
length can influence the DAT level in the brain of rats
(Dulcis et al. 2013)
, thereby again connecting the
dopaminergic system and the circadian rhythm (see
“Circadian rhythm”) with the pathophysiology of BD. Possible
critiques of the DAT knock-down mice are the clearly
too low DAT expression compared with unmedicated BD
patients, which is approximately 80% of healthy subjects
(Anand et al. 2011; Young and Dulcis 2015)
and that this
animal model mimics only BD mania and not depression
(van Enkhuizen et al. 2015a)
. Mania-like behavior, such as
(Giros et al. 1996; Ralph et al. 2001)
sensorimotor deficits in PPI (Ralph et al. 2001), can also be
induced through a complete knock-out of the DAT gene
in mice. The pointed hyperactivity of these mice could be
attenuated through the D1R antagonist SCH23390
et al. 2001)
. PPI deficits could be diminished through
clozapine and quetiapine, which are atypical antipsychotics
used as an effective treatment for BD mania and
(Powell et al. 2008)
, acting as antagonists of the
(Brust et al. 2015; Masri et al. 2008)
. However, the
DAT knock-down and knock-out mice were also used as
animal models for ADHD
(Leo and Gainetdinov 2013)
(Gainetdinov et al. 2001)
. This is no
surprise considering the fact that DA transmission is also
involved in the pathogenesis of these disorders
(Gainetdinov et al. 2001; Giros et al. 1996; Leo and Gainetdinov
2013; Sharma et al. 2016; Zhuang et al. 2001)
Nevertheless, we want to point out that it is important to create
specific animal models, which are able to model more
facets of the complex behavior of each of these disorders and
the cyclical nature of BD especially.
One different approach to recreate the cyclical nature
of BD within one animal through manipulating the
dopaminergic system was realized by Freund and
colleagues, using an inducible lentiviral vector system.
Over-expression of D1R in the medial prefrontal cortex
of rats resulted in increased sexual behavior, increased
sucrose preference, impulsivity, and increased
drugrelated behavior (
Sonntag et al. 2014
). The increased D1R
expression in the medial prefrontal cortex was
accompanied by decreased D2R expression in the nucleus
accumbens. Even more interestingly, just the
termination of this viral over-expression was sufficient enough to
induce depressive-like behavior in the triadic paradigm
of learned helplessness, reduced activity, and
diminished sucrose preference (Freund et al. 2016).
Termination of D1R over-expression furthermore increased levels
of cAMP response element-binding protein (CREB) in
eus accumbens (Freund et al. 2016
). This animal
model is therewith one of the few models, which is able
to recreate the cyclical nature of BD. It furthermore
supports the hypothesis that the homeostatic regulation of
DA transmission plays a key role in the pathogenesis of
(Berk et al. 2007)
Animal models that manipulate dopaminergic
pathways mainly increased dopaminergic transmission and
therewith induced mania-like behavior (Table 1).
Inducible viral over-expression of D1R allowed investigating
behavior after the termination of the ov
(Freund et al. 2016
). Results indicate that while increased
dopaminergic transmission is associated with
manialike behavior the termination of increased
dopaminergic transmission induces depressive-like behavior. Exact
mechanisms leading to the observed behavioral changes
are still unclear. Autoregulatory mechanism might have
downregulated D1R expression during the viral
overexpression causing reduced dopaminergic transmission
after the termination of the over-expression. This
explanation would be in line with Berk’s dopamine hypothesis
(Berk et al. 2007)
. While this approach might be
a promising new way to create an animal model for BD,
further studies, e.g., on the models’ susceptibility to
treatment like lithium are necessary for better understanding
of the underlying mechanisms.
Stressful life events in combination with genetic factors
are a risk factor for the onset of psychiatric disorders
(Afifi et al. 2009; Bebbington et al. 1984; Costello 1982;
Kendler et al. 1999; Paykel 1978; Schmitt et al. 2014;
Surtees et al. 1986)
. Environmental risk factors, causing
these stressful experiences, are for example neglect
during childhood, maternal loss, economic problems,
family violence, abuse, sexual maltreatment, and many more
(Bernstein et al. 2003; Brown et al. 2009; Kaufman and
Charney 2001; Marangoni et al. 2016; Mullen et al. 1996)
In fact almost two-third of BD patients sustained at least
one negative or goal-attainment life event 6 months prior
to the index or first occurred episode
(Simhandl et al.
. Especially the first period of life plays an
important role in the development of children
Different types of maltreatment including physical,
sexual, and emotional abuse or neglect in the early period of
life (i.e., early live stress, ELS) are associated with mood
(Afifi et al. 2009; Green et al. 2010; Hovens
et al. 2010; Leverich et al. 2002; McLaughlin et al. 2010)
ELS in humans can lead to impaired cognitive
functioning, exemplified in worse academic performance,
impaired intellectual ability, language difficulties, and
(Cohen et al. 2008; De Bellis et al. 2009; van den
Dries et al. 2010; Loman et al. 2009; Nelson et al. 2007)
The risk to develop anxiety, depression, and psychoses
in adulthood is particularly increased through ELS
(Bebbington et al. 2004; Gilbert et al. 2009; Kaufman and
Charney 2001; Mullen et al. 1996)
and it is more likely
that these illnesses are treatment resistant
(Bryer et al.
1987; Nemeroff et al. 2003; Vetulani 2013)
longlasting effects can occur through high or chronic levels of
stress, because they might affect brain development and
thereby mental health
(Anda et al. 2006; De Bellis et al.
1999a; De Bellis et al. 1999b; Lupien et al. 2009; Maniglio
2009; McLaughlin et al. 2010; Pechtel and Pizzagalli 2011;
Pirkola et al. 2005; Spataro et al. 2004; Teicher 2002)
32 percent of psychiatric disorders can be explained by
childhood adverse experiences
(Green et al. 2010;
Pechtel and Pizzagalli 2011)
. These experiences influence also
the overall lifespan, because humans, who experienced
more than six traumatic events in their childhood, have
an increased risk of dying approximately 20 years earlier
(Anda et al. 2009; Brown et al. 2009)
The mother–infant interaction is very important not
only for humans, but also for primates, rodents, or
mammals in general for the development of the offspring
and includes much more than just supply with nutrition
(Gutman and Nemeroff 2002; Harlow and Zimmermann
1959; Heim and Nemeroff 2002; Kaffman and Meaney
2007; Mason and Berkson 1975; Meaney 2001;
Tractenberg et al. 2016)
. Stressful events in the early period of
life produce long-lasting effects on brain development
(Caldji et al. 1998, 2000a; Francis and Meaney
1999; Romeo et al. 2003; Tractenberg et al. 2016)
comparable to the effects observed in humans.
ELS in rodents can be induced as early as the prenatal
period by stressing the pregnant damn, e.g., by restrain.
Observed behavioral consequences of adult rats, which
were prenatally stressed, can be identified as
depressivelike, namely anhedonia, increased helplessness, indicated
through increased immobility time in the forced swim
test, increased anxiety behavior in the open field test,
impaired cognition, decreased exploratory behavior, and
(Fatima et al. 2017; Frye and
Wawrzycki 2003; Hao et al. 2010; Jia et al. 2015; Lin et al. 2012;
Lin and Wang 2014; Wakshlak and Weinstock 1990)
Similar long-lasting effects on social behavior could be
observed in prenatally stressed rhesus macaques (Clarke
and Schneider 1993).
Prenatal stress is associated with alterations in the
(Diz-Chaves et al. 2012, see “Immune
and HPA axis (Koehl et al. 1999), decreased
neurogenesis in the hippocampus
(Fatima et al. 2017;
Lemaire et al. 2000; Lin and Wang 2014)
, and reduced
(Jia et al. 2015; Lin and Wang 2014)
addition, the metabotropic glutamate receptor 1 (mGluR1)
is increased in the hippocampus and prefrontal cortex
and mGluR5 is increased in the striatum of prenatally
stressed rats (Jia et al. 2015). Glutamate transporter
expression is increased in adult prenatally stressed rats
and therefore affects the whole glutamate
neurotransmission long term, but only in the frontal cortex and
(Adrover et al. 2015)
. The glutamatergic
system plays a critical role in the regulation of
(D’Sa and Duman 2002; Manji et al. 2001)
Chronic lithium and valproate treatment can
downregulate the synaptic expression of ionotropic glutamate
receptors in hippocampal neurons of rats
(Du et al. 2004;
Gray et al. 2003)
and the antidepressant imipramine has
the opposite effect
(Einat and Manji 2006; Gray et al.
. In addition, pharmacological inhibition of
ionotropic glutamate receptors via several competitive and
noncompetitive inhibitors attenuated
amphetamineinduced hyperactivity in mice
Interestingly, a contrary effect occurs through manipulating the
GluR6. Knock-out mice for the GluR6 gene exhibited
mania-like behavior, indicated through hyperactivity,
heightened responsivity to amphetamine, increased
risktaking behavior, more aggressive, less immobility time in
the forced swim test, and less anxiety behavior
et al. 2008)
. Lithium was able to attenuate these
(Shaltiel et al. 2008)
. Prenatal stress
is in addition able to alter the circadian rhythm and
corticosterone secretion through disturbance of the HPA
axis in adult prenatally stressed rats
(Koehl et al. 1999)
One function of the HPA axis is the synthesis of cortisol,
a glucocorticoid; especially, maternal glucocorticoid is
crucial for fetal development, because it affects
synaptic connections, density, and differentiation of
postnatal development of the fetal hippocampus
(Fatima et al.
2017; Trejo et al. 2000)
. An overall decrease in the
number of neurons and overall size could be observed in fetal
hippocampus of rhesus macaques, whose mothers were
administrated excessive amounts of glucocorticoids
during pregnancy (Uno et al. 1990). Similar effects of
inhibited hippocampal neurogenesis, decreased hippocampal
volume, and elevated cortisol levels were observed in
juvenile rhesus macaques prenatally stressed via
environmental alterations of the photoperiod
(Coe et al. 2003)
Hippocampal Bcl-2 expression is also affected, namely
decreased, in juvenile prenatally stressed offspring rats,
exhibiting depressive-like behavior
(Guan et al. 2013)
Interestingly lithium, which attenuates mania-like
behavior in animal models, increases the Bcl-2 level
et al. 1999; Manji et al. 2000)
, indicating one way of
lithium’s therapeutic effects. In return, chronic stress
during pregnancy affects not only the unborn pup, but also
the mother. Stressed mother rats exhibit depressive-like
behavior in the forced swim test, less maternal care, and a
decrease in spine density in the medial prefrontal cortex
(Leuner et al. 2014)
Not only prenatal but also postnatal stress, for
example, induced through maternal separation of the pups
from their mother for a defined amount of time (e.g.,
2–4 h per day for up to 3 weeks) can result in long-lasting
behavioral alterations. Early maternal separation (EMS)
results in ELS and induces a conserved neural response,
including a protest response and the feeling of despair in
humans and animals
. The mother’s
behavior has an influence on the brain development of the
neonate. Hippocampal development, memory, spatial
and social learning, and the response to stress of the
HPA axis is affected by maternal licking and grooming
of the offspring (
Lévy et al. 2003
; Lippmann et al. 2007;
Liu et al. 1997
, 2000; Vetulani 2013). This mother infant
interaction has as well a physiological effect in rats and
an interruption can result in alterations of the heart rate,
hormone levels, and interestingly the circadian rhythm
(Hofer 1970, 1975, 1976; Kuhn et al. 1990; Meaney et al.
1991; Stahl et al. 2002; Stanton and Levine 1990; Vetulani
. Rats exposed to chronic EMS exhibited
hypoactivity, increased stereotypic behavior, abnormal anxiety
behavior, abnormal HPA axis functioning, and
heightened response to an acute stressor and an elevated
acoustic startle response in adulthood
(Caldji et al. 2000b; Huot
et al. 2001; Kalinichev et al. 2002; Ladd et al. 2000, 2004;
Lippmann et al. 2007; McIntosh et al. 1999; Wigger and
. Antidepressant treatment can attenuate
these depressive-like behaviors induced by EMS
et al. 2013; Couto et al. 2012; El Khoury et al. 2006; Huot
et al. 2001; MacQueen et al. 2003)
. The BDNF levels were
decreased over a long period of time in the hippocampus
of adult rats exposed to EMS (Lippmann et al. 2007), as
well as in rats that were chronically stressed
(Smith et al.
. Prolonged stress experiments indicate that
inhibition of BDNF could cause neuronal atrophy or that BDNF
is required for neuronal remodeling
(Duman et al. 2016;
Magariños et al. 2011)
. Indeed, long-lasting reduced
BDNF levels in the hippocampus were associated with
learning and memory deficits, as well as depressive-like
(Duman and Monteggia 2006; Huot et al. 2002;
Lippmann et al. 2007)
. Furthermore, BDNF
expression can be increased through chronic
antidepressant treatment in rat hippocampus
(Nibuya et al. 1995;
Russo-Neustadt et al. 2000)
. In return, a single direct
injection of BDNF into the hippocampus led to an
antidepressant effect, indicated through comparable
performances in the forced swim test and learned helplessness
paradigm of rats chronically treated with antidepressants
(Shirayama et al. 2002)
. This behavioral effect could not
be recapitulated in mice with reduced BDNF expression
(Saarelainen et al. 2003), suggesting that BDNF signaling
is necessary for the antidepressant effect.
Interestingly, stress affects the dopaminergic system
through stimulating dopaminergic transmission in the
VTA of stressed rats
(Di Chiara et al. 1999; Horger and
Roth 1996; Nieoullon and Coquerel 2003; Yadid et al.
, which again links alterations in the
dopaminergic system and stress to BD. In addition, humans and
rodents are not only in these early stages of life highly
vulnerable to stress, but also in adolescence. During this
important time of brain development, neuroplasticity in
stress regulatory circuits and HPA axis functioning are
(Andersen 2003; Andersen and Teicher 2008;
Eiland and Romeo 2013; Wulsin et al. 2016)
chronic stress exposure to rats in the late adolescence
results in depressive-like behavior in adulthood (Wulsin
et al. 2016). But the effects of environmental stressors
can be so powerful to induce depressive-like phenotypes
even in adult, normally raised rats. These stressors can be
provided through several behavioral paradigms, such as
the forced swim test
(Porsolt et al. 1977)
, tail suspension
(Steru et al. 1985)
, and learned helplessness
and Seligman 1976)
. Similar behavioral abnormalities,
which can be described as depressive-like behavior, such
as reduced locomotor and exploratory behavior,
aggression, sexual behavior, elevated anxiety and submissive
behavior, social avoidance, disrupted circadian rhythms,
and immune function, can be induced through repeated
exposure to social defeat in rats
(Berton et al. 1998;
Crawford et al. 2013; Hollis et al. 2010; Hollis and Kabbaj 2014;
Meerlo et al. 1996; Ruis et al. 1999; Stefanski 2000; Tidey
and Miczek 1997; Tornatzky and Miczek 1993)
prominent stressor, sleep deprivation, was already
discussed in “Circadian rhythm” and can result in
manialike behavior in rodents
(Malkoff-Schwartz et al. 1998)
Environmental stress has been widely used to create
animal models for depression. Paradigms like maternal
eparation (Tractenberg et al. 2016
) or social defeat
are well-established models that have revealed
several neurobiological mechanisms that connect stress
and the onset of depression. It is to mention, however,
that we cannot distinguish between uni- and bipolar
depressive-like behavior in these models. The
administration of antidepressants in these models provides mixed
(Harrison and Baune 2014)
but to our knowledge
it did not result in the induction of mania-like behavior
as sometimes seen in patients with BD. Lithium was able
to prevent ELS-associated changes in the brain
and Mathé 2002)
Environmental stressors can also induce mania-like
behavior, e.g., by affecting circadian rhythms
(MalkoffSchwartz et al. 1998). A combination of circadian rhythm
manipulation and environmental stressors
(comparable to Le-Niculescu et al. 2008; see “Circadian rhythm”)
might therefore be useful to create a switch between both
behavioral phases in animal models.
During the past few years, it became more and more
evident that the immune system plays an important role in
psychiatric disorders including BD. First speculations
started after epidemiological studies revealed that BD
occurs more often in people born between December
(Fuller Torrey et al. 1996)
, indicating that
an infection of the mother during the winter months
could contribute to the risk to develop BD. Indeed,
several years later it was confirmed that an influenza
infection during pregnancy increases the risk for the offspring
to develop BD by fourfold
(Parboosing et al. 2013)
patients furthermore show an increased cerebrospinal
fluid-to-serum ratio, which could be an indicator for a
dysfunctional blood–brain barrier
(Patel and Frey 2015;
Zetterberg et al. 2014)
. However, not only the immune
system predisposed to develop BD, but also changes
in the immune system have been shown in patients
diagnosed with BD. A persistent and low-grade
proinflammatory state, which is more intense during mood
episodes, especially manic episodes, and less intense in
(Brietzke et al. 2009b;
Modabbernia et al. 2013)
has been revealed in these patients. Even
euthymia has been associated with detectable peripheral
(Brietzke et al. 2009a, 2009b)
In support of these findings is the increased mortality
rate of BD patients
(Anda et al. 2009; Brown et al. 2009;
Crump et al. 2013)
. Apart from suicide, this elevated
mortality rate can be explained by additional natural
causes of death associated with increased
(Crump et al. 2013; Hoang et al. 2011; Kupfer 2005)
Furthermore, the immunological response to stress is
altered in patients with BD (Wieck et al. 2014). There are
some findings showing that the number of past episodes
could even be a key factor to understand the evolution
of immunological changes in BD. In a study conducted
by Maes and colleagues, they have found that the
number of past depressive episodes positively correlates with
(Maes et al. 2012)
elevated levels of pro-inflammatory cytokines were
reported in BD patients
(Goldstein et al. 2009; Haarman
et al. 2014; Stertz et al. 2013)
. Interestingly, lithium is able
to attenuate pro-inflammatory cytokines
(Boufidou et al.
2004; Green and Nolan 2012; Himmerich et al. 2013;
Patel and Frey 2015; Rowse et al. 2012; Wang et al. 2009;
Zhang et al. 2009)
In animal models, maternal immune activation (MIA)
and its consequences for the offspring has been
intensively studied in the last two decades
Thereby, the immune system of the pregnant damn
has mainly been stimulated with the human influenza
(Cotter et al. 1995; Kneeland and Fatemi 2013)
the immunostimulant Polyinosinic:polycytidylic acid
(poly I:C) (Eßlinger et al. 2016; Rose et al. 2017; Shi et a
), or bacterial lipopolysaccharide
(Bakos et al. 2004;
Fernández de Cossío et al. 2017)
gestational stages. In adult animals that had been exposed to
MIA sensorimotor gating, i.e., latent inhibition and the
US-preexposure effect are disrupted, impairments in
working memory are evident and the locomotor response
to amphetamine is increased
(Meyer et al. 2005)
Furthermore, a reduction in social interactions in addition
to increased repetitive and stereotypic behavior has been
(Fernández de Cossío et al. 2017; Rose et al.
. Even depressive-like behavior including increased
anxiety and helplessness (Meyer et al. 2005; Ronovsky
et al. 2016
) has been shown. Thereby, depressive-like
behavior has also been reported in the second generation
(Ronovsky et al. 2017)
. Taken together, MIA
results in the development of several behavioral deficits
that are associated with psychiatric disorders. Given
the strong effect on sensorimotor gating and deficits in
social behavior, MIA in animal models has mainly been
associated with a schizophrenia-like phenotype
et al. 2005)
or autism-related characteristics
de Cossío et al. 2017)
. An animal model for BD using
MIA has never been proposed. At the same time,
deficits in sensory gating have been implicated in patients
with BD (Cheng et al. 2016), specifically during the acute
(Kohl et al. 2013)
. Similarly, impairments
in working memory
(Dickinson et al. 2017)
(Hoertnagl et al. 2014)
have been reported in
patients with BD and animals after MIA
Cossío et al. 2017; Meyer et al. 2005)
. Further findings on
an increased striatal DA release following MIA
(Zuckerman et al. 2003) are in line with the hypothesis that
dopaminergic pathways are disrupted in BD (see
“Dopaminergic pathways”) and further support the fact that
MIA might be useful to also create animal models for
BD. Less research on disrupted behavior after an acute or
chronic activation of the immune system in adult animals
has been conducted. Nevertheless, there is evidence that
even in adulthood activation of the immune system can
induce depressive-like behavior and anxiety
Dantzer 2016; Wachholz et al. 2017)
. So far no reports on
adult immune activation and mania-associated
behaviors in animal models exist. An animal model of mania
(induced by amphetamine; see “Sensitization models
and neurotransmitters in general”), however, showed
increased cytokine levels in plasma and brain, which
could together with the mania-like behavior be reversed
by lithium treatment
(Valvassori et al. 2015)
. Even adult
animals therefore show depressive-like behavior when
manipulating the immune system and a mania-like
phenotype in adult animals is associated with increased
Taken together, there is growing evidence that the
immune system plays an important role in BD. Animal
models with an immune activation early in development
(i.e., prenatally) show several behavioral changes that are
associated with depression and mania. So far, however,
no cycling between these two behavioral states has been
shown after manipulation of the immune system and
MIA has never been considered as a manipulation to
create an animal model for BD.
BD was to some extent already described by ancient
Greek scholars like Hippocrates and Aristoteles
and Marneros 2001)
. Nevertheless, our current
knowledge in the 21st century about the disorder is still limited.
Given the fact that lithium, one of the top choice
treatment options (Sani et al. 2017), was discovered by animal
, animal models for the disorder can
be a very useful tool to advance our knowledge. Indeed,
several models have either confirmed findings from
patients or even extended these findings by explaining the
underlying neurobiological mechanisms. In this review,
we could confirm that several affected areas and risk
factors can be found in human patients as well as animal
models for BD. Thereby, it can be noticed that all sections
described here are connected with each other. Disruptions
of circadian rhythms influence the dopaminergic
(Coque et al. 2011; McClung et al. 2005; Mukherjee
et al. 2010; Roybal et al. 2007)
. DA in turn is well known
as a key player in reward behavior and therewith drug
use (Cooper et al. 2017). Substance abuse disorder is
correlated with a stressful environment and stress increases
the risk for relapse
(Goldstein et al. 2008)
stress and addiction induce similar epigenetic and
(Cadet 2016; Moonat and Pandey
2012; Palmisano and Pandey 2017; Spanagel et al. 2014)
Stress has an influence on the immune system
(Stefanski 2000) and the immune system on the other hand is
connected with pathways related to circadian rhythm
(Dumbell et al. 2016)
. Manipulation in animal models
therewith often results in an interplay of several affected
factors. It therewith resembles the human condition and
it strengthens the model. At the same time, when several
mechanisms are affected, the exact mechanism
underlying BD is hard to investigate. It is clear that BD is not
caused by a single factor. Therefore animal models that
cover a broad range of the disruptions observed in human
patients might need manipulations in several areas. At the
same time, single-factor manipulations would be the best
way to confirm correlations between observed changes
and the manipulation. Due to the complex etiology,
biology and disease pattern of psychiatric diseases, animal
models with targeted mutations involve some limitations.
Therefore, it is unlikely that one genetic alteration within
an animal model will be able to recapitulate all facets of
human DSM-defined disorder symptomatology
(Kaiser and Feng 2015)
. DSM-defined disorders often
contain similar phenotypical features, which can be based on
diverse biological factors. Nevertheless, most established
animal models for BD use one manipulation to model just
a partial list of symptoms (concentrating on either mania
or depressive-like symptoms). This approach facilitates to
connect behavioral outcomes to specific pathways and is
an important tool to advance our knowledge of certain
aspects. Nevertheless, the diverse character of behavior
and even switch of behavior observed in patients is not
considered in these models. Specifically for the
investigation of this switch and its neurobiology, it is crucial to
create animal models presenting mania- as well as
(Nestler and Hyman 2010)
. So far, very
few models were able to show a switch between
maniaand depressive-like behaviors. Sensitization models show
mania-like behavior following repeated administration
of psychostimulants (see “Sensitization models and
neurotransmitters in general”) and depressive-like behavior
(Antelman et al. 1998; Barr et al. 1999;
Baumann and Rothman 1998; Marszalek-Grabska et al.
2016; Persico et al. 1995; Schwartz et al. 1982)
psychostimulants target several neurotransmitter systems
and therefore information on the neurobiology of BD we
got from these models is limited. New techniques, namely
the use of viral vector to induce genetic material into
specific cells, might be promising for the development of new
BD animal models reproducing the cyclic character of the
disorder. D1R over-expression on glutamatergic cells in
the medial prefrontal cortex induces mania-like behavior,
while the single termination of this over-expression was
sufficient enough to result in depressive-like behavior. It
has to be noted, however, that this switch in behavior is
not spontaneous as reported in BD patients. Apart from
manipulating the dopaminergic system, circadian rhythms
and the immune system seem to be promising targets for
the development of animal models for BD. Investigating
the neurobiology behind the induction of mania- or
depressive-like behavior by extending or shortening the
length of day might provide us with the switch between
the two phases and will induce both phases one after the
other in one animal. Similarly, inducing an increased state
of inflammation followed by a decreased state of
inflammation might reveal an animal model for BD showing the
characteristic switch between mood phases.
As always, further research is needed. New technology,
however, either in the field of animal research as well as
for examining human patients is being established.
Combining these techniques with new insights especially in
the fields of immunology and circadian rhythms provides
us with new tools to develop better models.
ADHD: attention-deficit hyperactivity disorder; Bcl-2: B-cell lymphoma 2; BD:
bipolar disorder; BDNF: brain-derived neurotrophic factor; BPM: behavioral
pattern monitor; Clock: circadian locomotor output cycles kaput; CREB:
cAMP response element-binding protein; D1R: dopamine D1 receptor; D2R:
dopamine D2 receptor; DA: dopamine; DAT: dopamine transporter; ELS: early
life stress; EMS: early maternal separation; ERK: extracellular-signal-regulated
kinase; GSK-3β: glycogen synthase kinase-3 beta; HPA:
hypothalamic–pituitary–adrenal; IGT: Iowa Gambling Task; mGluR: metabotropic glutamate
receptor; MIA: maternal immune activation; NE: norepinephrine; poly I: C:
polyinosinic:polycytidylic acid; PPI: prepulse inhibition; REV-ERBα: nuclear
receptor subfamily1, group D, member1; VTA: ventral tegmental area.
NF and DKEB both contributed equally in writing this review. Both authors
read and approved the final manuscript.
All authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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