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The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms

Nature Neuroscience volume 9, pages 398–407 (2006)Cite this article

Abstract

Circadian rhythms of behavior and physiology can be entrained by daily cycles of restricted food availability, but the pathways that mediate food entrainment are unknown. The dorsomedial hypothalamic nucleus (DMH) is critical for the expression of circadian rhythms and receives input from systems that monitor food availability. Here we report that restricted feeding synchronized the daily rhythm of DMH activity in rats such that c-Fos expression in the DMH was highest at scheduled mealtime. During food restriction, unlesioned rats showed a marked preprandial rise in locomotor activity, body temperature and wakefulness, and these responses were blocked by cell-specific lesions in the DMH. Furthermore, the degree of food entrainment correlated with the number of remaining DMH neurons, and lesions in cell groups surrounding the DMH did not block entrainment by food. These results establish that the neurons of the DMH have a critical role in the expression of food-entrainable circadian rhythms.

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Figure 1: Restricted daytime food availability shifts the daily rhythm of c-Fos in the DMH.
Figure 2: Camera lucida drawings of ibotenic acid–induced brain lesions in the DMH.
Figure 3: DMH lesions attenuate food-anticipatory locomotor activity and block the preprandial rise in body temperature.
Figure 4: DMH lesions block food entrainment of locomotor activity, body temperature and wakefulness.
Figure 5: DMH lesions block food entrainment measured in constant darkness.
Figure 6: Food entrainment correlates with the number of remaining DMH neurons.

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References

  1. Krieger, D.T. Food and water restriction shifts corticosterone, temperature, activity and brain amine periodicity. Endocrinology 95, 1195–1201 (1974).

    Article  CAS  Google Scholar 

  2. Bolles, R.C. & Stokes, L.W. Rat's anticipation of diurnal and a-diurnal feeding. J. Comp. Physiol. Psychol. 60, 290–294 (1965).

    Article  CAS  Google Scholar 

  3. Boulos, Z., Rosenwasser, A.M. & Terman, M. Feeding schedules and the circadian organization of behavior in the rat. Behav. Brain Res. 1, 39–65 (1980).

    Article  CAS  Google Scholar 

  4. Stephan, F.K. Limits of entrainment to periodic feeding in rats with suprachiasmatic lesions. J. Comp. Physiol. [A] 143, 401–410 (1981).

    Article  Google Scholar 

  5. Stephan, F.K. Phase shifts of circadian rhythms in activity entrained to food access. Physiol. Behav. 32, 663–671 (1984).

    Article  CAS  Google Scholar 

  6. Stephan, F.K. Resetting of a feeding-entrainable circadian clock in the rat. Physiol. Behav. 52, 985–995 (1992).

    Article  CAS  Google Scholar 

  7. Inouye, S.I. Restricted daily feeding does not entrain circadian rhythms of the suprachiasmatic nucleus in the rat. Brain Res. 232, 194–199 (1982).

    Article  CAS  Google Scholar 

  8. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    Article  CAS  Google Scholar 

  9. Hara, R. et al. Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus. Genes Cells 6, 269–278 (2001).

    Article  CAS  Google Scholar 

  10. Stokkan, K.A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

    Article  CAS  Google Scholar 

  11. Schibler, U., Ripperger, J. & Brown, S.A. Peripheral circadian oscillators in mammals: time and food. J. Biol. Rhythms 18, 250–260 (2003).

    Article  Google Scholar 

  12. Lamont, E.W., Diaz, L.R., Barry-Shaw, J., Stewart, J. & Amir, S. Daily restricted feeding rescues a rhythm of period2 expression in the arrhythmic suprachiasmatic nucleus. Neuroscience 132, 245–248 (2005).

    Article  CAS  Google Scholar 

  13. Krieger, D.T., Hauser, H. & Krey, L.C. Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity. Science 197, 398–399 (1977).

    Article  CAS  Google Scholar 

  14. Stephan, F.K. Entrainment of activity to multiple feeding times in rats with suprachiasmatic lesions. Physiol. Behav. 46, 489–497 (1989).

    Article  CAS  Google Scholar 

  15. Stephan, F.K. Circadian rhythm dissociation induced by periodic feeding in rats with suprachiasmatic lesions. Behav. Brain Res. 7, 81–98 (1983).

    Article  CAS  Google Scholar 

  16. Stephan, F.K., Swann, J.M. & Sisk, C.L. Entrainment of circadian rhythms by feeding schedules in rats with suprachiasmatic lesions. Behav. Neural Biol. 25, 545–554 (1979).

    Article  CAS  Google Scholar 

  17. Watts, A.G., Swanson, L.W. & Sanchez-Watts, G. Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J. Comp. Neurol. 258, 204–229 (1987).

    Article  CAS  Google Scholar 

  18. Watts, A.G. & Swanson, L.W. Efferent projections of the suprachiasmatic nucleus: II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat. J. Comp. Neurol. 258, 230–252 (1987).

    Article  CAS  Google Scholar 

  19. Chou, T.C. et al. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23, 10691–10702 (2003).

    Article  CAS  Google Scholar 

  20. Lu, J. et al. Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation. J. Neurosci. 21, 4864–4874 (2001).

    Article  CAS  Google Scholar 

  21. Thompson, R.H. & Swanson, L.W. Organization of inputs to the dorsomedial nucleus of the hypothalamus: a reexamination with Fluorogold and PHAL in the rat. Brain Res. Brain Res. Rev. 27, 89–118 (1998).

    Article  CAS  Google Scholar 

  22. Elmquist, J.K., Elias, C.F. & Saper, C.B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232 (1999).

    Article  CAS  Google Scholar 

  23. Chou, T.C. et al. Afferents to the ventrolateral preoptic nucleus. J. Neurosci. 22, 977–990 (2002).

    Article  CAS  Google Scholar 

  24. Simerly, R.B. & Swanson, L.W. The organization of neural inputs to the medial preoptic nucleus of the rat. J. Comp. Neurol. 246, 312–342 (1986).

    Article  CAS  Google Scholar 

  25. Thompson, R.H., Canteras, N.S. & Swanson, L.W. Organization of projections from the dorsomedial nucleus of the hypothalamus: a PHA-L study in the rat. J. Comp. Neurol. 376, 143–173 (1996).

    Article  CAS  Google Scholar 

  26. Elmquist, J.K., Ahima, R.S., Elias, C.F., Flier, J.S. & Saper, C.B. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc. Natl. Acad. Sci. USA 95, 741–746 (1998).

    Article  CAS  Google Scholar 

  27. Choi, S., Wong, L.S., Yamat, C. & Dallman, M.F. Hypothalamic ventromedial nuclei amplify circadian rhythms: do they contain a food-entrained endogenous oscillator? J. Neurosci. 18, 3843–3852 (1998).

    Article  CAS  Google Scholar 

  28. Inouye, S.T. Ventromedial hypothalamic lesions eliminate anticipatory activities of restricted daily feeding schedules in the rat. Brain Res. 250, 183–187 (1982).

    Article  CAS  Google Scholar 

  29. Krieger, D.T. Ventromedial hypothalamic lesions abolish food-shifted circadian adrenal and temperature rhythmicity. Endocrinology 106, 649–654 (1980).

    Article  CAS  Google Scholar 

  30. Saper, C.B., Lu, J., Chou, T.C. & Gooley, J. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 28, 152–157 (2005).

    Article  CAS  Google Scholar 

  31. Mistlberger, R. & Rusak, B. Food anticipatory circadian rhythms in paraventricular and lateral hypothalamic lesioned rats. J. Biol. Rhythms 3, 277–292 (1988).

    Article  Google Scholar 

  32. Landry, G.J., Simon, M., Webb, I.C. & Mistlberger, R.E. Persistence of a behavioral food anticipatory circadian rhythm following dorsomedial hypothalamic ablation in rats. Am. J. Physiol. published online January 19 2006 (10.1152/ajpregu.00874.2005).

  33. Abe, M. et al. Circadian rhythms in isolated brain regions. J. Neurosci. 22, 350–356 (2002).

    Article  CAS  Google Scholar 

  34. Angeles-Castellanos, M., Aguilar-Roblero, R. & Escobar, C. c-Fos expression in hypothalamic nuclei of food-entrained rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R158–R165 (2004).

    Article  CAS  Google Scholar 

  35. Zigman, J.M. & Elmquist, J.K. Minireview: from anorexia to obesity—the yin and yang of body weight control. Endocrinology 144, 3749–3756 (2003).

    Article  CAS  Google Scholar 

  36. Fulwiler, C.E. & Saper, C.B. Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res. 319, 229–259 (1984).

    Article  CAS  Google Scholar 

  37. Davidson, A.J., Cappendijk, S.L. & Stephan, F.K. Feeding-entrained circadian rhythms are attenuated by lesions of the parabrachial region in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R1296–R1304 (2000).

    Article  CAS  Google Scholar 

  38. Comperatore, C.A. & Stephan, F.K. Effects of vagotomy on entrainment of activity rhythms to food access. Physiol. Behav. 47, 671–678 (1990).

    Article  CAS  Google Scholar 

  39. Moreira, A.C. & Krieger, D.T. The effects of subdiaphragmatic vagotomy on circadian corticosterone rhythmicity in rats with continuous or restricted food access. Physiol. Behav. 28, 787–790 (1982).

    Article  CAS  Google Scholar 

  40. Fei, H. et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 94, 7001–7005 (1997).

    Article  CAS  Google Scholar 

  41. Elmquist, J.K., Bjorbaek, C., Ahima, R.S., Flier, J.S. & Saper, C.B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547 (1998).

    Article  CAS  Google Scholar 

  42. Mitchell, V. et al. Comparative distribution of mRNA encoding the growth hormone secretagogue-receptor (GHS-R) in Microcebus murinus (Primate, lemurian) and rat forebrain and pituitary. J. Comp. Neurol. 429, 469–489 (2001).

    Article  CAS  Google Scholar 

  43. Mistlberger, R.E. & Marchant, E.G. Enhanced food-anticipatory circadian rhythms in the genetically obese Zucker rat. Physiol. Behav. 66, 329–335 (1999).

    Article  CAS  Google Scholar 

  44. Sherin, J.E., Shiromani, P.J., McCarley, R.W. & Saper, C.B. Activation of ventrolateral preoptic neurons during sleep. Science 271, 216–219 (1996).

    Article  CAS  Google Scholar 

  45. Lu, J., Greco, M.A., Shiromani, P. & Saper, C.B. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J. Neurosci. 20, 3830–3842 (2000).

    Article  CAS  Google Scholar 

  46. Akiyama, M. et al. Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice. Eur. J. Neurosci. 20, 3054–3062 (2004).

    Article  Google Scholar 

  47. Mieda, M. et al. Orexin neurons function in an efferent pathway of a food-entrainable circadian oscillator in eliciting food-anticipatory activity and wakefulness. J. Neurosci. 24, 10493–10501 (2004).

    Article  CAS  Google Scholar 

  48. Morrison, S.F. Central pathways controlling brown adipose tissue thermogenesis. News Physiol. Sci. 19, 67–74 (2004).

    Google Scholar 

  49. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic Press, San Diego, 1998).

    Google Scholar 

  50. Gooley, J.J., Lu, J., Fischer, D. & Saper, C.B. A broad role for melanopsin in nonvisual photoreception. J. Neurosci. 23, 7093–7106 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Q. Ha and M. Ha for superb technical assistance. This research was supported by grants from the US National Institutes of Health to C.B.S. (HL60292) and J.J.G. (MH67413).

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Authors and Affiliations

  1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Joshua J Gooley, Ashley Schomer & Clifford B Saper

  2. Division of Sleep Medicine and Program in Neuroscience, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Joshua J Gooley & Clifford B Saper

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  1. Joshua J Gooley
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Correspondence to Clifford B Saper.

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Supplementary information

Supplementary Fig. 1

The daily rhythm of c–Fos in the DMH realigns with a restricted daytime meal. (PDF 388 kb)

Supplementary Fig. 2

DMH lesions block the preprandial rise in locomotor activity, body temperature, and wakefulness. (PDF 2156 kb)

Supplementary Fig. 3

Camera lucida drawings of ibotenic acid–induced lesions in the hypothalamus. (PDF 975 kb)

Supplementary Fig. 4

Lesions in the VMHdm do not abolish food entrainment. (PDF 538 kb)

Supplementary Fig. 5

Parabrachial nucleus lesions do not block food entrainment. (PDF 726 kb)

Supplementary Fig. 6

The DMH plays a critical role in the expression of SCN− and food–entrainable rhythms. (PDF 969 kb)

Supplementary Methods (PDF 100 kb)

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Gooley, J., Schomer, A. & Saper, C. The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nat Neurosci 9, 398–407 (2006). https://doi.org/10.1038/nn1651

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