Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice
MM Sidor, SM Spencer, K Dzirasa, PK Parekh, KM Tye, MR Warden, RN Arey, JF Enwright, JPR Jacobsen, S Kumar, EM Remillard, MG Caron, K Deisseroth and CA McClung
Molecular Psychiatry (2015) 20, 1479–1480; doi:10.1038/mp.2015.8; published online 17 February 2015
Correction to: Molecular Psychiatry (2015) 20, 1406–1419; doi:10.1038/mp.2014.167; published online 6 January 2015
As the result of an editing error, the image in Figure 2e was duplicated in Figure 2f. The correct version of Figure 2 appears below. The publisher regrets the error.
Figure 2.
Time-specific alterations in VTA dopaminergic activity in ClockΔ19 mice. (a) Two-way analysis of variance of firing rate found a significant genotype effect (F1,112 = 12.67, P = 0.0006). Post hoc tests revealed significant differences in the firing rate of dopaminergic neurons during the first 6 h of the light cycle and the last 6 h of the dark cycle (P < 0.05 using Student’s t-test; n = 14/14/16/12 and 14/14/17/12 for the number of dopaminergic neurons analyzed in WT (n = 8) and ClockΔ19 mice (n = 9), respectively). (b) Two-way analysis of variance of bursting rate found a significant genotype effect (F1,112 = 8.6, P = 0.004) with post hoc analyses revealing significant differences in the bursting rate of dopaminergic neurons during the first 6 h of the dark cycle (P < 0.05, by Student’s t-test; n = 14/14/16/12 and 14/14/17/12 for the number of dopaminergic neurons analyzed in WT and ClockΔ19 mice, respectively). (c) Relative abundance of TH mRNA normalized to the expression of Gapdh. Two-way analysis of variance revealed a significant genotype effect (F1,45 = 9.42, P = 0.004) with a specific increase in TH expression at ZT4 in ClockΔ19 mice (P < 0.05, n = 3–5 animals per genotype per time point). Diurnal variation was significant in wild-type (WT) mice (CircWave: F2,27 = 10.63, P = 0.0004) but not in ClockΔ19 mutants (P > 0.05). (d) A significant main effect of time was found for total TH (F3,28 = 5.34, P = 0.005), with an increase in ClockΔ19 mouse TH levels at ZT9 (P < 0.01). Diurnal variation was statistically significant in mutants (CircWave: F2,17 = 5.15, P = 0.02). (e) There was a significant effect of time on phosphorylated TH (ser 40) protein (F3,32 = 6.50, P = 0.002), with ClockΔ19 mice exhibiting a specific increase in THser40 levels at ZT9 (P < 0.05, Student’s t-test). Diurnal variation in THser40 was statistically significant in mutants (Circwave: F2,17 = 7.18, P = 0.005). (f) No differences in phosphorylated THser31 protein levels were found at any time point measured. Inset depicts average protein levels over 24 h. (e, f) Dopamine synthesis assay. (g) Dopamine synthesis was significantly increased in ClockΔ19 mutant mice as measured by L-Dopa in the nucleus accumbens after NSD-1015 administration during the light phase, at ZT4 (t9 = 2.546, P = 0.03). (h) Dopamine synthesis was unaltered in the dorsal striatum of ClockΔ19 mutants (P > 0.05, n = 5–8 per group; dark phase = ZT16). White and dark bars below graph represent daytime and nighttime measurements, respectively.