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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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Daytime-specific tyrosine hydroxylase inhibition reverses manic-like behavioursClockΔ19 mice and wild-type (WT) littermates received an intraperitoneal injection of either 0.9% saline (vehicle) or AMPT (100mg/kg) during the day (ZT 6-10) or night (ZT 18-22) and were tested for anxiety- and depressive-related behaviours 60–90 min later. Daytime cohorts (a–f): (a) Two-way ANOVA revealed a significant interaction of genotype and treatment (F1,20=6.66, p=0.01) on distance traveled in a novel environment where vehicle-treated ClockΔ19 mice exhibited hyperactivity (p<0.05) which decreased to WT levels following AMPT treatment (p<0.05). Vehicle-treated ClockΔ19 mice also showed the expected decrease in anxiety-like behaviour compared to vehicle-treated WT littermates as indicated by increased exploration of the anxiogenic (b) open arms of the elevated plus maze (main effect of genotype: F1,20=5.09, p=0.03), (c) centre of the open field (main effect of genotype: F1,15=16.22, p=0.001; post-hoc p<0.001), and (d) light chamber of the light/dark box (interaction between genotype and treatment: F1,15=6.12, p=0.03; post-hoc p<0.05 for vehicle treated groups) and displayed (e, f) decreased depressive-like behaviour in the forced swim test (e) as indicated by increased time spent struggling (F1,16=8.73, p=0.009; post-hoc p<0.05) and an increased preference for sucrose (f) in the sucrose preference test (genotype effect:F1,25=3.24, p=0.08). Importantly, AMPT treatment significantly reversed ClockΔ19 mice manic-behavioural features to WT levels (a–e). Main effect of treatment in (a) reported above; (b) F1,20=10.48, p=0.004, post-hoc p<0.05; (c) F1,15=7.6, p=0.01, post-hoc p<0.001; (d) F1,15=19.18, p=0.0005, post-hoc p<0.001; (e) F1,16=6.55, p=0.02, post-hoc p<0.05. (g–k) Night time cohorts. Vehicle-treated ClockΔ19 mice did not exhibit manic-related behavioural features when tested at night, nor did AMPT treatment effect behaviour in ClockΔ19 mice or WT littermates. Daytime cohorts, n=5–6/group; Daytime sucrose preference test and night time light/dark test, n=7/8; Night time cohorts, n=5–8/group.
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Figure 5: Daytime-specific tyrosine hydroxylase inhibition reverses manic-like behavioursClockΔ19 mice and wild-type (WT) littermates received an intraperitoneal injection of either 0.9% saline (vehicle) or AMPT (100mg/kg) during the day (ZT 6-10) or night (ZT 18-22) and were tested for anxiety- and depressive-related behaviours 60–90 min later. Daytime cohorts (a–f): (a) Two-way ANOVA revealed a significant interaction of genotype and treatment (F1,20=6.66, p=0.01) on distance traveled in a novel environment where vehicle-treated ClockΔ19 mice exhibited hyperactivity (p<0.05) which decreased to WT levels following AMPT treatment (p<0.05). Vehicle-treated ClockΔ19 mice also showed the expected decrease in anxiety-like behaviour compared to vehicle-treated WT littermates as indicated by increased exploration of the anxiogenic (b) open arms of the elevated plus maze (main effect of genotype: F1,20=5.09, p=0.03), (c) centre of the open field (main effect of genotype: F1,15=16.22, p=0.001; post-hoc p<0.001), and (d) light chamber of the light/dark box (interaction between genotype and treatment: F1,15=6.12, p=0.03; post-hoc p<0.05 for vehicle treated groups) and displayed (e, f) decreased depressive-like behaviour in the forced swim test (e) as indicated by increased time spent struggling (F1,16=8.73, p=0.009; post-hoc p<0.05) and an increased preference for sucrose (f) in the sucrose preference test (genotype effect:F1,25=3.24, p=0.08). Importantly, AMPT treatment significantly reversed ClockΔ19 mice manic-behavioural features to WT levels (a–e). Main effect of treatment in (a) reported above; (b) F1,20=10.48, p=0.004, post-hoc p<0.05; (c) F1,15=7.6, p=0.01, post-hoc p<0.001; (d) F1,15=19.18, p=0.0005, post-hoc p<0.001; (e) F1,16=6.55, p=0.02, post-hoc p<0.05. (g–k) Night time cohorts. Vehicle-treated ClockΔ19 mice did not exhibit manic-related behavioural features when tested at night, nor did AMPT treatment effect behaviour in ClockΔ19 mice or WT littermates. Daytime cohorts, n=5–6/group; Daytime sucrose preference test and night time light/dark test, n=7/8; Night time cohorts, n=5–8/group.

Mentions: Finally, we sought to determine if daytime increases in TH activity are necessary to produce a switch to a manic-like state inClockΔ19 mice through direct pharmacological inhibition of TH activity. Mice were administered Alpha-methyl-DL-p-tyrosine methyl ester hydrochloride (AMPT) either during the day, at a time corresponding to peak levels of dopaminergic activity in ClockΔ19 mice, or during the dark phase when no difference in dopaminergic activity is observed. As expected, vehicle-treated ClockΔ19 mice exhibited a hyperactive phenotype (p<0.05; Figure 5a) and an overall anxiolytic behavioural profile compared to WT mice during the daytime as characterized by increased exploration of the open arms of the EPM (main effect of genotype, p=0.03; Figure 5b), centre of the open field (p<0.001; Figure 5c) and light chamber of the light/dark test (p<0.05;Figure 5d). ClockΔ19 mice also exhibited an anti-depressive phenotype during the daytime as demonstrated by increased time spent struggling in the FST (p<0.05; Figure 5e) and an increased preference for sucrose (main effect of genotype, p=0.08;Figure 5f). Importantly, all behavioural components of the ClockΔ19 mouse manic-like phenotype were reversed to WT levels with daytime AMPT treatment (p’s<0.05, vehicle vs. AMPT; Figure 5a–e). AMPT did not alter general locomotor activity (p>0.05; Supplementary Figure 12a,b) except in the light/dark test where it decreased overall distance traveled in ClockΔ19 mice (p<0.01; Supplementary Figure 12c). In this case, data were also plotted as %distance traveled and yielded similar results to those reported above (p<0.01; Supplementary Figure 12d). Conversely, AMPT had no behavioural effects when administered during the dark phase (p’s>0.05, vehicle vs. AMPT;Figure 6g–k and Supplementary Figure 12e–g), when ClockΔ19 mice were found to be in a euthymic-like state.


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)

Daytime-specific tyrosine hydroxylase inhibition reverses manic-like behavioursClockΔ19 mice and wild-type (WT) littermates received an intraperitoneal injection of either 0.9% saline (vehicle) or AMPT (100mg/kg) during the day (ZT 6-10) or night (ZT 18-22) and were tested for anxiety- and depressive-related behaviours 60–90 min later. Daytime cohorts (a–f): (a) Two-way ANOVA revealed a significant interaction of genotype and treatment (F1,20=6.66, p=0.01) on distance traveled in a novel environment where vehicle-treated ClockΔ19 mice exhibited hyperactivity (p<0.05) which decreased to WT levels following AMPT treatment (p<0.05). Vehicle-treated ClockΔ19 mice also showed the expected decrease in anxiety-like behaviour compared to vehicle-treated WT littermates as indicated by increased exploration of the anxiogenic (b) open arms of the elevated plus maze (main effect of genotype: F1,20=5.09, p=0.03), (c) centre of the open field (main effect of genotype: F1,15=16.22, p=0.001; post-hoc p<0.001), and (d) light chamber of the light/dark box (interaction between genotype and treatment: F1,15=6.12, p=0.03; post-hoc p<0.05 for vehicle treated groups) and displayed (e, f) decreased depressive-like behaviour in the forced swim test (e) as indicated by increased time spent struggling (F1,16=8.73, p=0.009; post-hoc p<0.05) and an increased preference for sucrose (f) in the sucrose preference test (genotype effect:F1,25=3.24, p=0.08). Importantly, AMPT treatment significantly reversed ClockΔ19 mice manic-behavioural features to WT levels (a–e). Main effect of treatment in (a) reported above; (b) F1,20=10.48, p=0.004, post-hoc p<0.05; (c) F1,15=7.6, p=0.01, post-hoc p<0.001; (d) F1,15=19.18, p=0.0005, post-hoc p<0.001; (e) F1,16=6.55, p=0.02, post-hoc p<0.05. (g–k) Night time cohorts. Vehicle-treated ClockΔ19 mice did not exhibit manic-related behavioural features when tested at night, nor did AMPT treatment effect behaviour in ClockΔ19 mice or WT littermates. Daytime cohorts, n=5–6/group; Daytime sucrose preference test and night time light/dark test, n=7/8; Night time cohorts, n=5–8/group.
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Figure 5: Daytime-specific tyrosine hydroxylase inhibition reverses manic-like behavioursClockΔ19 mice and wild-type (WT) littermates received an intraperitoneal injection of either 0.9% saline (vehicle) or AMPT (100mg/kg) during the day (ZT 6-10) or night (ZT 18-22) and were tested for anxiety- and depressive-related behaviours 60–90 min later. Daytime cohorts (a–f): (a) Two-way ANOVA revealed a significant interaction of genotype and treatment (F1,20=6.66, p=0.01) on distance traveled in a novel environment where vehicle-treated ClockΔ19 mice exhibited hyperactivity (p<0.05) which decreased to WT levels following AMPT treatment (p<0.05). Vehicle-treated ClockΔ19 mice also showed the expected decrease in anxiety-like behaviour compared to vehicle-treated WT littermates as indicated by increased exploration of the anxiogenic (b) open arms of the elevated plus maze (main effect of genotype: F1,20=5.09, p=0.03), (c) centre of the open field (main effect of genotype: F1,15=16.22, p=0.001; post-hoc p<0.001), and (d) light chamber of the light/dark box (interaction between genotype and treatment: F1,15=6.12, p=0.03; post-hoc p<0.05 for vehicle treated groups) and displayed (e, f) decreased depressive-like behaviour in the forced swim test (e) as indicated by increased time spent struggling (F1,16=8.73, p=0.009; post-hoc p<0.05) and an increased preference for sucrose (f) in the sucrose preference test (genotype effect:F1,25=3.24, p=0.08). Importantly, AMPT treatment significantly reversed ClockΔ19 mice manic-behavioural features to WT levels (a–e). Main effect of treatment in (a) reported above; (b) F1,20=10.48, p=0.004, post-hoc p<0.05; (c) F1,15=7.6, p=0.01, post-hoc p<0.001; (d) F1,15=19.18, p=0.0005, post-hoc p<0.001; (e) F1,16=6.55, p=0.02, post-hoc p<0.05. (g–k) Night time cohorts. Vehicle-treated ClockΔ19 mice did not exhibit manic-related behavioural features when tested at night, nor did AMPT treatment effect behaviour in ClockΔ19 mice or WT littermates. Daytime cohorts, n=5–6/group; Daytime sucrose preference test and night time light/dark test, n=7/8; Night time cohorts, n=5–8/group.
Mentions: Finally, we sought to determine if daytime increases in TH activity are necessary to produce a switch to a manic-like state inClockΔ19 mice through direct pharmacological inhibition of TH activity. Mice were administered Alpha-methyl-DL-p-tyrosine methyl ester hydrochloride (AMPT) either during the day, at a time corresponding to peak levels of dopaminergic activity in ClockΔ19 mice, or during the dark phase when no difference in dopaminergic activity is observed. As expected, vehicle-treated ClockΔ19 mice exhibited a hyperactive phenotype (p<0.05; Figure 5a) and an overall anxiolytic behavioural profile compared to WT mice during the daytime as characterized by increased exploration of the open arms of the EPM (main effect of genotype, p=0.03; Figure 5b), centre of the open field (p<0.001; Figure 5c) and light chamber of the light/dark test (p<0.05;Figure 5d). ClockΔ19 mice also exhibited an anti-depressive phenotype during the daytime as demonstrated by increased time spent struggling in the FST (p<0.05; Figure 5e) and an increased preference for sucrose (main effect of genotype, p=0.08;Figure 5f). Importantly, all behavioural components of the ClockΔ19 mouse manic-like phenotype were reversed to WT levels with daytime AMPT treatment (p’s<0.05, vehicle vs. AMPT; Figure 5a–e). AMPT did not alter general locomotor activity (p>0.05; Supplementary Figure 12a,b) except in the light/dark test where it decreased overall distance traveled in ClockΔ19 mice (p<0.01; Supplementary Figure 12c). In this case, data were also plotted as %distance traveled and yielded similar results to those reported above (p<0.01; Supplementary Figure 12d). Conversely, AMPT had no behavioural effects when administered during the dark phase (p’s>0.05, vehicle vs. AMPT;Figure 6g–k and Supplementary Figure 12e–g), when ClockΔ19 mice were found to be in a euthymic-like state.

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