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A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity

Nature Neuroscience volume 9, pages 212–219 (2006)Cite this article

Abstract

The suprachiasmatic nucleus (SCN) drives circadian rhythms of locomotor behavior by releasing factors that act on receptor sites near the third ventricle. Here we show that cardiotrophin-like cytokine (CLC) satisfies multiple criteria for a circadian regulator of locomotor activity. In the mouse, CLC is expressed in a subpopulation of SCN vasopressin neurons with a circadian rhythm that peaks during the daily period of locomotor quiescence. CLC receptors flank the third ventricle, and acute infusion of CLC into the third ventricle produced a transient blockade of locomotor activity without affecting the circadian clock. The hypothalamic infusion of neutralizing antibodies to the CLC receptor produced extra daily locomotor activity at the time when CLC is maximally expressed. These results suggest that CLC is probably an SCN output signal important for shaping daily rhythms of behavior; moreover, they indicate an unexpected role for a cytokine in adult brain function.

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Figure 1: Exclusive expression of Clc mRNA in a subpopulation of SCN vasopressin neurons.
Figure 2: Clc-expressing neurons in the SCN express core circadian-clock components.
Figure 3: Circadian regulation of Clc mRNA in the SCN.
Figure 4: The Clc gene is probably a direct molecular output of the SCN circadian clock.
Figure 5: Expression of CLC receptor components around the third ventricle in the adult mouse hypothalamus.
Figure 6: Administration of CLC into the third ventricle of hamsters rapidly and reversibly inhibits locomotor activity without affecting circadian clock function.
Figure 7: Chronic blockade of periventricular GP130 signaling leads to a reversible increase in locomotor activity during the circadian rest period.

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Acknowledgements

We thank M. Liu for technical assistance, L. Zakhary for advice on in situ hybridization and D. Knutti and K.-F. Storch for comments on the manuscript. Confocal images were obtained at the Harvard Center for Neurodegeneration and Repair. This work was supported by the US National Institute of Neurological Disorders and Stroke (C.J.W.), a Howard Hughes Medical Institute predoctoral fellowship (S.K.) and a Stuart H.Q. and Victoria Quan Fellowhip (S.K.).

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Authors and Affiliations

  1. Department of Neurobiology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Sebastian Kraves & Charles J Weitz

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  1. Sebastian Kraves
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Correspondence to Charles J Weitz.

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Supplementary information

Supplementary Fig. 1

In situ hybridization to coronal mouse brain sections showing constitutive expression of clc mRNA in the anterodorsal thalamus [Franklin, K. B. & Paxinos, G. The mouse brain in stereotaxic coordinates. (Academic Press, 1997)] over a circadian cycle. (PDF 152 kb)

Supplementary Fig. 2

Cells expressing clc mRNA are located in the dorsal division of the mouse SCN and distributed throughout its rostrocaudal axis. (PDF 114 kb)

Supplementary Fig. 3

Induction of clc mRNA by light in the mouse SCN. (PDF 111 kb)

Supplementary Fig. 4

Blockade of locomotor activity by activation of hypothalamic CLC receptors does not reflect a generalized inhibition of behavior. (PDF 79 kb)

Supplementary Methods (PDF 124 kb)

Supplementary Note (PDF 43 kb)

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Kraves, S., Weitz, C. A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity. Nat Neurosci 9, 212–219 (2006). https://doi.org/10.1038/nn1633

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