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Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, Arey RN, Enwright JF, Jacobsen JP, Kumar S, Remillard EM, Caron MG, Deisseroth K, McClung CA - Mol. Psychiatry (2015)

Bottom Line: Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis.To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state.Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.

ABSTRACT
Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

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Related in: MedlinePlus

Behavioural mood-cycling across the light-dark cycleAnxiety-like (a, b) and depressive-like (c, d) behaviours were measured during the day (ZT 6-10) and night (ZT 18-22) in wild-type (WT) and ClockΔ19 mutant mice. (a) ClockΔ19 mutant mice exhibited a significant increase in entries into the centre of the open field during the day (main effect of genotype, F1,28=11.72, p=0.0019; post-hoc, p<0.01) that decreased to WT levels at night (genotype by time interaction, F1,28=4.19, p=0.05). ClockΔ19 mice also spent more time in the centre of the open field during the day (main effect of genotype, F1,28=6.17, p=0.02; post-hoc, p<0.05) with differences no longer apparent at night.(b) This daytime specific anxiolytic profile was also found in the light-dark test, where ClockΔ19 mice entered the light chamber significantly more than WT controls during the day (main effect of genotype, F1,28=4.23, p=0.049; post-hoc, p<0.05) but significantly decreased exploration to WT levels at night (genotype by time interaction, F1,28=5.35, p=0.03; post-hoc student’s t-test, p=0.06, ClockΔ19 day vs. night). ClockΔ19 mice also spent more time in the light chamber of the light/dark box during the day (main effect of genotype, F1,28=4.29, p=0.048; post-hoc, p<0.05), with a significant decrease to WT levels at night (genotype by time interaction, F1,28=5.03, p=0.03; post-hoc student’s t-test, p=0.049, ClockΔ19 day vs. night). (c) ClockΔ19 mice exhibited decreased depressive-like behaviors during the day as evidenced by increased struggling time in the forced swim test (main effect of genotype, F1,28=44.7, p<0.0001; post-hoc, p<0.0001) and (d) an increased preference for a 1% sucrose solution (main effect of genotype F1,27=5.46, p=0.027; post-hoc, p<0.05). Differences in depressive-like behaviours were no longer evident at night as ClockΔ19mutant mice significantly decreased struggling time to near WT levels in the forced swim test (c:genotype by time interaction, F1,28=7.84, p=0.0092; post-hoc, p<0.0001) and no longer showed a preference for sucrose relative to WT mice (d). Day and night cohorts, n=8–9/group.
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Figure 1: Behavioural mood-cycling across the light-dark cycleAnxiety-like (a, b) and depressive-like (c, d) behaviours were measured during the day (ZT 6-10) and night (ZT 18-22) in wild-type (WT) and ClockΔ19 mutant mice. (a) ClockΔ19 mutant mice exhibited a significant increase in entries into the centre of the open field during the day (main effect of genotype, F1,28=11.72, p=0.0019; post-hoc, p<0.01) that decreased to WT levels at night (genotype by time interaction, F1,28=4.19, p=0.05). ClockΔ19 mice also spent more time in the centre of the open field during the day (main effect of genotype, F1,28=6.17, p=0.02; post-hoc, p<0.05) with differences no longer apparent at night.(b) This daytime specific anxiolytic profile was also found in the light-dark test, where ClockΔ19 mice entered the light chamber significantly more than WT controls during the day (main effect of genotype, F1,28=4.23, p=0.049; post-hoc, p<0.05) but significantly decreased exploration to WT levels at night (genotype by time interaction, F1,28=5.35, p=0.03; post-hoc student’s t-test, p=0.06, ClockΔ19 day vs. night). ClockΔ19 mice also spent more time in the light chamber of the light/dark box during the day (main effect of genotype, F1,28=4.29, p=0.048; post-hoc, p<0.05), with a significant decrease to WT levels at night (genotype by time interaction, F1,28=5.03, p=0.03; post-hoc student’s t-test, p=0.049, ClockΔ19 day vs. night). (c) ClockΔ19 mice exhibited decreased depressive-like behaviors during the day as evidenced by increased struggling time in the forced swim test (main effect of genotype, F1,28=44.7, p<0.0001; post-hoc, p<0.0001) and (d) an increased preference for a 1% sucrose solution (main effect of genotype F1,27=5.46, p=0.027; post-hoc, p<0.05). Differences in depressive-like behaviours were no longer evident at night as ClockΔ19mutant mice significantly decreased struggling time to near WT levels in the forced swim test (c:genotype by time interaction, F1,28=7.84, p=0.0092; post-hoc, p<0.0001) and no longer showed a preference for sucrose relative to WT mice (d). Day and night cohorts, n=8–9/group.

Mentions: Previously we found that ClockΔ19 mice exhibited a robust manic-like phenotype when tested during the daytime3, however, we had yet to explore how behaviour may change over the light-dark cycle. Consistent with previous findings3, ClockΔ19 mice exhibited reduced anxiety-related behaviour during the daytime as indicated by increased exploration of the centre of the open field (center entries, p<0.01; center time, p<0.05; Figure 1a) and light chamber of the light/dark box (light entries, p<0.05; light time, p<0.05; Figure 1b). ClockΔ19 mice also exhibited an antidepressive-like phenotype in the forced swim test (FST; p<0.0001; Figure 1c) and sucrose-preference test (p<0.05;Figure 1d), two well-validated behavioural assays that measure motivational and anhedonic facets of depressive-like behavior, respectively. Quite surprisingly, however, the behavioural profile of ClockΔ19 mutant mice was time-dependent as manic-related behaviours were normalized to near wild-type (i.e. euthymic-like) levels during the night time, resulting in a cyclic pattern in mood-related states over the light-dark cycle (night, mutant vs. WT: open field, light/dark, and sucrose preference test, p’s>0.05; mutant, day vs. night: light/dark test, p<0.05; FST, p<0.0001; Figure 1a–d). To confirm that behavioral changes were not due to locomotor changes across the light-dark cycle (day vs. night: WT, p=0.04; mutants, p<0.05; Supplementary Figure 1a), the data were re-analyzed to control for locomotor differences in the open field and light/dark test and yielded a consistent pattern of results (day, mutant vs. WT: open field, p<0.01; light/dark, p<0.05; night, mutant vs. WT: p’s>0.05; Supplementary Figure 1b,c).


Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, Arey RN, Enwright JF, Jacobsen JP, Kumar S, Remillard EM, Caron MG, Deisseroth K, McClung CA - Mol. Psychiatry (2015)

Behavioural mood-cycling across the light-dark cycleAnxiety-like (a, b) and depressive-like (c, d) behaviours were measured during the day (ZT 6-10) and night (ZT 18-22) in wild-type (WT) and ClockΔ19 mutant mice. (a) ClockΔ19 mutant mice exhibited a significant increase in entries into the centre of the open field during the day (main effect of genotype, F1,28=11.72, p=0.0019; post-hoc, p<0.01) that decreased to WT levels at night (genotype by time interaction, F1,28=4.19, p=0.05). ClockΔ19 mice also spent more time in the centre of the open field during the day (main effect of genotype, F1,28=6.17, p=0.02; post-hoc, p<0.05) with differences no longer apparent at night.(b) This daytime specific anxiolytic profile was also found in the light-dark test, where ClockΔ19 mice entered the light chamber significantly more than WT controls during the day (main effect of genotype, F1,28=4.23, p=0.049; post-hoc, p<0.05) but significantly decreased exploration to WT levels at night (genotype by time interaction, F1,28=5.35, p=0.03; post-hoc student’s t-test, p=0.06, ClockΔ19 day vs. night). ClockΔ19 mice also spent more time in the light chamber of the light/dark box during the day (main effect of genotype, F1,28=4.29, p=0.048; post-hoc, p<0.05), with a significant decrease to WT levels at night (genotype by time interaction, F1,28=5.03, p=0.03; post-hoc student’s t-test, p=0.049, ClockΔ19 day vs. night). (c) ClockΔ19 mice exhibited decreased depressive-like behaviors during the day as evidenced by increased struggling time in the forced swim test (main effect of genotype, F1,28=44.7, p<0.0001; post-hoc, p<0.0001) and (d) an increased preference for a 1% sucrose solution (main effect of genotype F1,27=5.46, p=0.027; post-hoc, p<0.05). Differences in depressive-like behaviours were no longer evident at night as ClockΔ19mutant mice significantly decreased struggling time to near WT levels in the forced swim test (c:genotype by time interaction, F1,28=7.84, p=0.0092; post-hoc, p<0.0001) and no longer showed a preference for sucrose relative to WT mice (d). Day and night cohorts, n=8–9/group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492925&req=5

Figure 1: Behavioural mood-cycling across the light-dark cycleAnxiety-like (a, b) and depressive-like (c, d) behaviours were measured during the day (ZT 6-10) and night (ZT 18-22) in wild-type (WT) and ClockΔ19 mutant mice. (a) ClockΔ19 mutant mice exhibited a significant increase in entries into the centre of the open field during the day (main effect of genotype, F1,28=11.72, p=0.0019; post-hoc, p<0.01) that decreased to WT levels at night (genotype by time interaction, F1,28=4.19, p=0.05). ClockΔ19 mice also spent more time in the centre of the open field during the day (main effect of genotype, F1,28=6.17, p=0.02; post-hoc, p<0.05) with differences no longer apparent at night.(b) This daytime specific anxiolytic profile was also found in the light-dark test, where ClockΔ19 mice entered the light chamber significantly more than WT controls during the day (main effect of genotype, F1,28=4.23, p=0.049; post-hoc, p<0.05) but significantly decreased exploration to WT levels at night (genotype by time interaction, F1,28=5.35, p=0.03; post-hoc student’s t-test, p=0.06, ClockΔ19 day vs. night). ClockΔ19 mice also spent more time in the light chamber of the light/dark box during the day (main effect of genotype, F1,28=4.29, p=0.048; post-hoc, p<0.05), with a significant decrease to WT levels at night (genotype by time interaction, F1,28=5.03, p=0.03; post-hoc student’s t-test, p=0.049, ClockΔ19 day vs. night). (c) ClockΔ19 mice exhibited decreased depressive-like behaviors during the day as evidenced by increased struggling time in the forced swim test (main effect of genotype, F1,28=44.7, p<0.0001; post-hoc, p<0.0001) and (d) an increased preference for a 1% sucrose solution (main effect of genotype F1,27=5.46, p=0.027; post-hoc, p<0.05). Differences in depressive-like behaviours were no longer evident at night as ClockΔ19mutant mice significantly decreased struggling time to near WT levels in the forced swim test (c:genotype by time interaction, F1,28=7.84, p=0.0092; post-hoc, p<0.0001) and no longer showed a preference for sucrose relative to WT mice (d). Day and night cohorts, n=8–9/group.
Mentions: Previously we found that ClockΔ19 mice exhibited a robust manic-like phenotype when tested during the daytime3, however, we had yet to explore how behaviour may change over the light-dark cycle. Consistent with previous findings3, ClockΔ19 mice exhibited reduced anxiety-related behaviour during the daytime as indicated by increased exploration of the centre of the open field (center entries, p<0.01; center time, p<0.05; Figure 1a) and light chamber of the light/dark box (light entries, p<0.05; light time, p<0.05; Figure 1b). ClockΔ19 mice also exhibited an antidepressive-like phenotype in the forced swim test (FST; p<0.0001; Figure 1c) and sucrose-preference test (p<0.05;Figure 1d), two well-validated behavioural assays that measure motivational and anhedonic facets of depressive-like behavior, respectively. Quite surprisingly, however, the behavioural profile of ClockΔ19 mutant mice was time-dependent as manic-related behaviours were normalized to near wild-type (i.e. euthymic-like) levels during the night time, resulting in a cyclic pattern in mood-related states over the light-dark cycle (night, mutant vs. WT: open field, light/dark, and sucrose preference test, p’s>0.05; mutant, day vs. night: light/dark test, p<0.05; FST, p<0.0001; Figure 1a–d). To confirm that behavioral changes were not due to locomotor changes across the light-dark cycle (day vs. night: WT, p=0.04; mutants, p<0.05; Supplementary Figure 1a), the data were re-analyzed to control for locomotor differences in the open field and light/dark test and yielded a consistent pattern of results (day, mutant vs. WT: open field, p<0.01; light/dark, p<0.05; night, mutant vs. WT: p’s>0.05; Supplementary Figure 1b,c).

Bottom Line: Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis.To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state.Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.

ABSTRACT
Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Show MeSH
Related in: MedlinePlus