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Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture.

Yu X, Zecharia A, Zhang Z, Yang Q, Yustos R, Jager P, Vyssotski AL, Maywood ES, Chesham JE, Ma Y, Brickley SG, Hastings MH, Franks NP, Wisden W - Curr. Biol. (2014)

Bottom Line: We found that hdc gene expression varies with time of day.Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms.We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.

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HDC-ΔBmal1 Mice Have a Functionally Normal Circadian Clock(A) Representative wheel-running actograms from homozygous loxBmal1 mice and HDC-ΔBmal1 mice. Mice were initially entrained to 12 h white light, 12 h dim red light (LD) and then transferred to continuous dim red light (DD) or continuous white light (LL).(B) HDC-ΔBmal1 mice (n = 6) and littermate controls (n = 8) did not have differing circadian periods or amplitudes during LD, LL, or DD (bars represent SEM; p > 0.05).(C and D) Immunocytochemical analysis shows that the circadian rhythm of BMAL1 (green) and PER2 (green) expression is unaffected in the SCN of HDC-ΔBmal1 mice. Sections are counterstained to show all cell nuclei with DAPI. The scale bar represents 0.5 mm.
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fig2: HDC-ΔBmal1 Mice Have a Functionally Normal Circadian Clock(A) Representative wheel-running actograms from homozygous loxBmal1 mice and HDC-ΔBmal1 mice. Mice were initially entrained to 12 h white light, 12 h dim red light (LD) and then transferred to continuous dim red light (DD) or continuous white light (LL).(B) HDC-ΔBmal1 mice (n = 6) and littermate controls (n = 8) did not have differing circadian periods or amplitudes during LD, LL, or DD (bars represent SEM; p > 0.05).(C and D) Immunocytochemical analysis shows that the circadian rhythm of BMAL1 (green) and PER2 (green) expression is unaffected in the SCN of HDC-ΔBmal1 mice. Sections are counterstained to show all cell nuclei with DAPI. The scale bar represents 0.5 mm.

Mentions: HDC-ΔBmal1 knockout mice had an unchanged behavioral circadian rhythm and phase, compared with littermate controls, as assessed by wheel running in free-running conditions of constant darkness (DD) (unpaired two-tailed t test, p > 0.05) (Figures 2A and 2B) [25]. In free-running constant light (LL), both genotypes were more variable in period length than in LD or DD (Figure 2A). However, the amplitude of the peak period was lower and more variable in LL than in LD and DD, indicating the mice were equally less active in LL than in LD or DD, regardless of genotype (Figures 2A and 2B). Within the SCN, the circadian variation in BMAL1 and PER2 proteins was unchanged between HDC-ΔBmal1 knockout mice and littermate controls (Figures 2C and 2D); there was little variation in BMAL1 staining intensity in the SCN between ZT6 and ZT18 (Figure 2C), highlighting that although BMAL1 is the core component of the clock, its levels change little during the circadian cycle. CLOCK and BMAL1 are often constitutively bound to E boxes. The critical rhythm for BMAL1-CLOCK activity arises from PER-CRY, which arrives to inhibit, and then dissociates from, the BMAL1-CLOCK complex [33]. PER2 staining in the SCN of both groups of mice increased at ZT18 compared with ZT6 (Figure 2D). Thus, the HDC-ΔBmal mice had an unaffected SCN molecular clock and circadian pace making.


Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture.

Yu X, Zecharia A, Zhang Z, Yang Q, Yustos R, Jager P, Vyssotski AL, Maywood ES, Chesham JE, Ma Y, Brickley SG, Hastings MH, Franks NP, Wisden W - Curr. Biol. (2014)

HDC-ΔBmal1 Mice Have a Functionally Normal Circadian Clock(A) Representative wheel-running actograms from homozygous loxBmal1 mice and HDC-ΔBmal1 mice. Mice were initially entrained to 12 h white light, 12 h dim red light (LD) and then transferred to continuous dim red light (DD) or continuous white light (LL).(B) HDC-ΔBmal1 mice (n = 6) and littermate controls (n = 8) did not have differing circadian periods or amplitudes during LD, LL, or DD (bars represent SEM; p > 0.05).(C and D) Immunocytochemical analysis shows that the circadian rhythm of BMAL1 (green) and PER2 (green) expression is unaffected in the SCN of HDC-ΔBmal1 mice. Sections are counterstained to show all cell nuclei with DAPI. The scale bar represents 0.5 mm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4252164&req=5

fig2: HDC-ΔBmal1 Mice Have a Functionally Normal Circadian Clock(A) Representative wheel-running actograms from homozygous loxBmal1 mice and HDC-ΔBmal1 mice. Mice were initially entrained to 12 h white light, 12 h dim red light (LD) and then transferred to continuous dim red light (DD) or continuous white light (LL).(B) HDC-ΔBmal1 mice (n = 6) and littermate controls (n = 8) did not have differing circadian periods or amplitudes during LD, LL, or DD (bars represent SEM; p > 0.05).(C and D) Immunocytochemical analysis shows that the circadian rhythm of BMAL1 (green) and PER2 (green) expression is unaffected in the SCN of HDC-ΔBmal1 mice. Sections are counterstained to show all cell nuclei with DAPI. The scale bar represents 0.5 mm.
Mentions: HDC-ΔBmal1 knockout mice had an unchanged behavioral circadian rhythm and phase, compared with littermate controls, as assessed by wheel running in free-running conditions of constant darkness (DD) (unpaired two-tailed t test, p > 0.05) (Figures 2A and 2B) [25]. In free-running constant light (LL), both genotypes were more variable in period length than in LD or DD (Figure 2A). However, the amplitude of the peak period was lower and more variable in LL than in LD and DD, indicating the mice were equally less active in LL than in LD or DD, regardless of genotype (Figures 2A and 2B). Within the SCN, the circadian variation in BMAL1 and PER2 proteins was unchanged between HDC-ΔBmal1 knockout mice and littermate controls (Figures 2C and 2D); there was little variation in BMAL1 staining intensity in the SCN between ZT6 and ZT18 (Figure 2C), highlighting that although BMAL1 is the core component of the clock, its levels change little during the circadian cycle. CLOCK and BMAL1 are often constitutively bound to E boxes. The critical rhythm for BMAL1-CLOCK activity arises from PER-CRY, which arrives to inhibit, and then dissociates from, the BMAL1-CLOCK complex [33]. PER2 staining in the SCN of both groups of mice increased at ZT18 compared with ZT6 (Figure 2D). Thus, the HDC-ΔBmal mice had an unaffected SCN molecular clock and circadian pace making.

Bottom Line: We found that hdc gene expression varies with time of day.Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms.We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.

Show MeSH
Related in: MedlinePlus