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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

Manipulation BD-relevant behavior Neurobiology References
Circadian rhythm
ClockΔ19 mutant mice Hyperactivity 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 Hyperactivity Alterations of dopaminergic system  
Less helplessness
Reduced habituation
Increased acoustic startle response
ERK1 knock-out mice Hyperactivity Shift of activity rhythm (Engel et al. 2008)
Enhanced goal-directed activity
Increased risk taking and impulsivity
Increased reward seeking
BDNF haploinsufficient mutant mice Hyperactivity 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 Hypoactivity   (Le-Niculescu et al. 2008)
Diminished response to amphetamine
Environmental stress induce hyperactivity
Sleep deprivation Hyperactivity   (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 Hyperactivity 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) Hyperactivity 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 Hypoactivation 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 Hypoactivity Increased CREB in nucleus accumbens (Freund et al. 2016)
Anhedonic behavior
DAT knock-down mice Hyperactivity in novel environments Hyperdopaminergia (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 Hyperactivity   
Sensorimotor deficits within PPI
GluR6 knock-out mice Hyperactivity   (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 Hypoactivity 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