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Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours.

Keers R, Pedroso I, Breen G, Aitchison KJ, Nolan PM, Cichon S, Nöthen MM, Rietschel M, Schalkwyk LC, Fernandes C - PLoS ONE (2012)

Bottom Line: Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations.Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour.One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.

View Article: PubMed Central - PubMed

Affiliation: MRC SGDP Centre, Institute of Psychiatry, King's College London, London, United Kingdom.

ABSTRACT

Background: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.

Methodology: Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder.

Principal findings: Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009).

Conclusions: Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.

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Related in: MedlinePlus

Immobility in the forced swim test is attenuated in after hours mice.Results from the forced swim test indicate no significant difference in immobility in trial 1 but the increase in immobility observed in trial 2 was not seen in Afh/Afh mice. (Data shown is mean ± SEM). **, P<0.01 results from posthoc t-tests comparing immobility in trial 1 vs. trial 2 in Afh/Afh. Afh/+ and +/+ mice.
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pone-0038263-g003: Immobility in the forced swim test is attenuated in after hours mice.Results from the forced swim test indicate no significant difference in immobility in trial 1 but the increase in immobility observed in trial 2 was not seen in Afh/Afh mice. (Data shown is mean ± SEM). **, P<0.01 results from posthoc t-tests comparing immobility in trial 1 vs. trial 2 in Afh/Afh. Afh/+ and +/+ mice.

Mentions: In Trial 1 of the forced swim test 26 of the 37 animals tested showed immobility. The 11 mice that failed to show immobility did not differ significantly by genotype (χ2 = 0.42, P = 0.80). There were no effects of genotype on latency to immobility and although Afh/Afh appeared to show longer periods of immobility than both Afh/+ and +/+ mice, this difference did not reach statistical significance (t = 1.80, P = 0.08, Figure 3).


Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours.

Keers R, Pedroso I, Breen G, Aitchison KJ, Nolan PM, Cichon S, Nöthen MM, Rietschel M, Schalkwyk LC, Fernandes C - PLoS ONE (2012)

Immobility in the forced swim test is attenuated in after hours mice.Results from the forced swim test indicate no significant difference in immobility in trial 1 but the increase in immobility observed in trial 2 was not seen in Afh/Afh mice. (Data shown is mean ± SEM). **, P<0.01 results from posthoc t-tests comparing immobility in trial 1 vs. trial 2 in Afh/Afh. Afh/+ and +/+ mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376117&req=5

pone-0038263-g003: Immobility in the forced swim test is attenuated in after hours mice.Results from the forced swim test indicate no significant difference in immobility in trial 1 but the increase in immobility observed in trial 2 was not seen in Afh/Afh mice. (Data shown is mean ± SEM). **, P<0.01 results from posthoc t-tests comparing immobility in trial 1 vs. trial 2 in Afh/Afh. Afh/+ and +/+ mice.
Mentions: In Trial 1 of the forced swim test 26 of the 37 animals tested showed immobility. The 11 mice that failed to show immobility did not differ significantly by genotype (χ2 = 0.42, P = 0.80). There were no effects of genotype on latency to immobility and although Afh/Afh appeared to show longer periods of immobility than both Afh/+ and +/+ mice, this difference did not reach statistical significance (t = 1.80, P = 0.08, Figure 3).

Bottom Line: Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations.Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour.One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.

View Article: PubMed Central - PubMed

Affiliation: MRC SGDP Centre, Institute of Psychiatry, King's College London, London, United Kingdom.

ABSTRACT

Background: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.

Methodology: Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder.

Principal findings: Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009).

Conclusions: Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.

Show MeSH
Related in: MedlinePlus