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Table 1 Summary of manipulable risk factors for BD and their influence on BD-relevant behavior

From: Animal models for bipolar disorder: from bedside to the cage


BD-relevant behavior



Circadian rhythm

ClockΔ19 mutant mice


Altered sleep pattern

(Coque et al. 2011; van Enkhuizen et al. 2013b; McClung 2013; McClung et al. 2005; Mukherjee et al. 2010; Roybal et al. 2007)

Altered sleep pattern

Enhanced DA release

Greater preference for rewarding stimuli

Decreased anxiety behavior

Less depressive-like behavior

Impaired PPI

CLOCK knock-down mice

Abnormal circadian rhythms


Less anxiety

Hyperactivity in novel environment but decreased overall hyperactivity

Increased depression-like behavior and helplessness

GSK-3β haploinsufficient mutant mice

Reduced exploration

Affect gene transcription, neurogenesis, and apoptosis

(Besing et al. 2015; O’Brien et al. 2004, 2011; Prickaerts et al. 2006)

Less helplessness

Normal overall activity

GSK-3β over-expression mice


Alterations of dopaminergic system


Less helplessness

Reduced habituation

Increased acoustic startle response

ERK1 knock-out mice


Shift of activity rhythm

(Engel et al. 2008)

Enhanced goal-directed activity

Increased risk taking and impulsivity

Increased reward seeking

BDNF haploinsufficient mutant mice


Decreased BDNF level following DA overactivity

(Kernie et al. 2000; Lyons et al. 1999; Magariños et al. 2011)

Increased aggression

Elevated appetite

Decreased hippocampal volume

CA3 dendritic arborizations resemble stressed wild-type mice

Bcl-2 heterozygous knock-out mice

Increased anxiety

Decreased Bcl-2 level

(DeVries et al. 2001; Einat et al. 2005; Lien et al. 2008; Rondi-Reig et al. 1997; Rondi-Reig and Mariani 2002)

Increased reward seeking

Acts protective against deleterious stress-induced neuronal endangerment

Increased amphetamine sensitization

DBP heterozygotous knock-out mice



(Le-Niculescu et al. 2008)

Diminished response to amphetamine

Environmental stress induce hyperactivity

Sleep deprivation



(Benedetti et al. 2008; Gessa et al. 1995; Hicks et al. 1979; Malkoff-Schwartz et al. 1998; Morden et al. 1968)

Increased aggression

Increased exploratory behavior


High-frequency stimulation of the lateral hypothalamus


Affects sleep–wake cycle

(Abulseoud et al. 2015; Abulseoud et al. 2014)

Increased grooming


Reduced resting phases

Photoperiod lengths

Anxiety behavior

Neurotransmitter switching

(Dulcis et al. 2013)


(DA ↔ somatostatin)

Sensitization models

Administration of psychostimulants (amphetamine, cocaine)


Increased synaptic DA and NE levels

(Borison et al. 1978; Davies et al. 1974; Frey et al. 2006; Fries et al. 2015; Gould et al. 2001; Kilbey and Ellinwood 1977; Macêdo et al. 2012, 2013; Post 1992; Post 1990; Queiroz et al. 2015; Rezin et al. 2014; Rygula et al. 2015; Seiden et al. 1993; Zheng et al. 2013)

Increased aggression

Disturbance of homeostatic mechanisms


Increased hedonic behavior

Alterations in BDNF level

Disturbed sleep–wake cycle

Declined cognitive performance

Deficient PPI response

Withdrawal following chronically psychostimulant administration


Supersensitivity of serotoninergic neurons a decrease in NE

(Barr et al. 1999; Barr and Phillips 1999, 2002; Baumann and Rothman 1998; Markou and Koob 1991; Marszalek-Grabska et al. 2016; Mutschler and Miczek 1998; Paulson et al. 1991; Schindler et al. 1994; Schwartz et al. 1982; Wise and Munn 1995)

Increased anxiety


Increased negative contrast

Reduced DA responsiveness

Decreased motivation

Dopaminergic pathways

Increased D1R expression in the prefrontal cortex

Increased impulsivity

Decreased D2R in nucleus accumbens

(Freund et al. 2016; Sonntag et al. 2014)

Increased sexual behavior

Hedonic behavior

Addictive behavior

Termination of previous D1R over-expression


Increased CREB in nucleus accumbens

(Freund et al. 2016)

Anhedonic behavior


DAT knock-down mice

Hyperactivity in novel environments


(Dulcis et al. 2013; van Enkhuizen et al. 2014b; van Enkhuizen et al. 2014a; Giros et al. 1996; Ralph et al. 2001; Ralph-Williams et al. 2003; Young et al. 2010, 2011; Zhuang et al. 2001)

Increased risk behavior

Hyperexploratory behavior

Less anxiety

Impaired decision making with a preference for high reward combined with high risk

DAT knock-out mice



Sensorimotor deficits within PPI

GluR6 knock-out mice



(Shaltiel et al. 2008)

Increased risk taking

Elevated aggression

Heightened responsivity to amphetamine

Less anxiety

Environmental stressors

Prenatal stress

Hyperactivity in novel environment

Incomplete development of hippocampus and reduced weight of the prefrontal cortex and nucleus accumbens

(Clarke and Schneider 1993; Coe et al. 2003; Diz-Chaves et al. 2012; Fatima et al. 2017; Frye and Wawrzycki 2003; Guan et al. 2013; Hao et al. 2010; Jia et al. 2015; Koehl et al. 1999; Lemaire et al. 2000; Lin et al. 2012; Lin and Wang 2014; Uno et al. 1990; Wakshlak and Weinstock 1990)

Hypersensitivity to amphetamine


Increased helplessness

Alterations in HPA axis and neurotransmitter levels in early development

Increased anxiety

Impaired cognition including working memory deficits

Reduced BDNF levels

Decreased exploratory behavior

Decreased Bcl-2 level

Diminished neurogenesis

Increased mGluR1 and mGluR2

Altered immune system

Stimulating dopaminergic transmission

Social withdrawal

Postnatal stress


Hippocampal development, memory, spatial and social learning, response to stress of the HPA axis

(Caldji et al. 2000b; Duman et al. 2016; Duman and Monteggia 2006; Huot et al. 2002; Huot et al. 2001; Kalinichev et al. 2002; Ladd et al. 2000, 2004; Lippmann et al. 2007; Magariños et al. 2011; McIntosh et al. 1999; Wigger and Neumann 1999)

Increased stereotypies

Increased anxiety behavior

Heightened response to acute stressor

Decreased BDNF level

Elevated PPI response

Neuronal atrophy

Stimulating dopaminergic transmission

Chronic stress (through, e.g., repeated social defeat)

Depressive-like behavior

Disrupted circadian rhythms and immune function

(Berton et al. 1998; Crawford et al. 2013; Hollis et al. 2010; Hollis and Kabbaj 2014; Leuner et al. 2014; Maier and Seligman 1976; Meerlo et al. 1996; Porsolt et al. 1977; Ruis et al. 1999; Steru et al. 1985; Tidey and Miczek 1997; Tornatzky and Miczek 1993; Wulsin et al. 2016)


Reduced exploration

Reduced aggression


Elevated anxiety

Submissive behavior

Social avoidance

Immune system

Maternal immune activation

Increased locomotor response to amphetamine

Increased inflammation

(Bakos et al. 2004; Cotter et al. 1995; Eßlinger et al. 2016; Fernández de Cossío et al. 2017; Kneeland and Fatemi 2013; Meyer et al. 2005; Remus and Dantzer 2016; Ronovsky et al. 2017; Rose et al. 2017; Shi et al. 2003; Wachholz et al. 2017; Zuckerman et al. 2003)

Increased striatal DA release

Increased repetitive and stereotypic behavior

Increased anxiety


Disrupted sensorimotor gating

Impaired working memory