Suprachiasmatic Nucleus Grafts Restore Circadian Behavioral Rhythms of Genetically Arrhythmic Mice

Apr 18, 2003Current biology : CB

Grafts of the brain’s internal clock restore daily activity patterns in mice with disrupted rhythms

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Abstract

Transplantation of mouse fetal SCN tissue into the hypothalamus restores free-running circadian behavioral rhythmicity in mutant mice.

Mice lacking normal CLOCK protein or CRYPTOCHROMES show no circadian rhythmicity in behavior.
Transplanted SCN tissue can evoke circadian rhythms even when peripheral oscillators are absent.
The periodicity of the rhythms is influenced by the genetic makeup of the grafted SCN.
Functional circadian oscillators are only present in the grafted region of the hypothalamus in deficient mice.

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The mammalian master clock driving circadian rhythmicity in physiology and behavior resides within the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN neurons contain a molecular oscillator composed of a set of clock genes that acts in intertwined negative and positive feedback loops [1]. In addition, all peripheral tissues analyzed thus far have been shown to contain circadian oscillators [2]. This raises the question of whether the central circadian pacemaker in the SCN is sufficient to evoke behavioral rhythms or whether peripheral circadian clockworks are also required. Mice with a mutated CLOCK protein (a transcriptional activator of E box-containing clock and clock output genes) or lacking both CRYPTOCHROMES, mCRY1 and mCRY2 proteins (inhibitors of E box-mediated transcription), lack circadian rhythmicity in behavior [3,4]. Here, we show that transplantation of mouse fetal SCN tissue into the hypothalamus restores free-running circadian behavioral rhythmicity in Clock mutant or mCry1/mCry2 double knockout mice. The periodicity of the emerged rhythms is determined by the genetic constitution (i.e., wild-type or mCry2 knockout) of the grafted SCN. Since transplanted mCry1/mCry2-deficient mice do not have functional circadian oscillators [5] other than those present in the grafted hypothalamus region, these findings suggest that the SCN can generate circadian behavioral rhythms in the absence of distant peripheral oscillators in the brain or elsewhere.

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Suprachiasmatic Nucleus Grafts Restore Circadian Behavioral Rhythms of Genetically Arrhythmic Mice

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