Genetic Evidence for a Neurovestibular Influence on the Mammalian Circadian Pacemaker

Abstract

The mammalian circadian timing system (CTS) exerts endogenous temporal control over virtually every biochemical, physiological, and neurobiological process. Recent studies have suggested an interrelationship between the neurovestibular system, specifically the macular otoconial gravity receptors, and the CTS. To test for a functional relationship between these 2 seemingly disparate neuronal systems, the authors performed a study to evaluate the influence of the vestibular system on 3 fundamental properties of the CTS: entrainment, photic modulation, and period. The present study used a nonrecombinant mutant mouse, the head-tilt mouse (abbr. het), which lacks otoconia and hence gravity reception, to evaluate CTS function in mice lacking vestibular inputs. Circadian rhythms of body temperature (T_b) and locomotor activity (ACT) were recorded continuously by biotelemetry in het mice as well as wild-type (PWT) controls during exposure to 4 photic regimens: 12:12 LD, DD (0 μmoles s^-1 m^-2), constant bright light (LL_B; 0.5 μmoles s^-1 m^-2), and constant dim light (LL_D; 0.02 μmoles s^-1 m^-2). In DD, the circadian period of the T_b and ACT rhythms was significantly longer (p < 0.001) in het than in PWT mice. In addition, the circadian period of T_b and ACT was significantly longer (p < 0.01) in LL_B than in DD for both the het and PWT groups, although increasing ambient illuminance (i.e., DD to LL_B) had a significantly greater (p < 0.01) period-lengthening effect in the PWT group than in the het group. The results of the present study demonstrate for the first time that the vestibular macular gravity receptors influence 2 fundamental properties of the mammalian CTS: (1) the intrinsic circadian pacemaker period and (2) the period-altering response to changes in tonic light intensity. The results of the present study thus provide the first neurobehavioral evidence for a vestibular-circadian interrelationship as well as suggest a novel mechanism underlying the signaling of activity-based nonphotic stimuli to the CTS.

Keywords

head-tilt mouse SCN intergeniculate leaflet body temperature activity nonphotic vestibular

References

Balaban CD and Thayer JF (2001) Neurological bases for balance-anxiety links. J Anxiety Disord 15:53-79.

Bergstrom RA , You Y , Erway LC , Lyon MF , and Schimenti JC (1998) Deletion mapping of the head tilt (het) gene in mice: A vestibular mutation causing specific absence of otoliths. Genetics 150:815-822.

Czeisler CA , Duffy JF , Shanahan TL , Brown EN , Mitchell JF , Rimmer DW , Ronda JM , Silva EJ , Allan JS , Emens JS , et al. (1999) Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284:2177-2181.

Dudley TE , DiNardo LA , and Glass JD (1998) Endogenous regulation of serotonin release in the hamster suprachiasmatic nucleus. J Neurosci 13:5045-5052.

Edgar DM , Martin CE , and Dement WC (1991) Activity feedback to the mammalian circadian pacemaker: Influence on observed measures of rhythm period length. J Biol Rhythms 6:185-199.

Enright JT (1965) The search for rhythmicity in biological time-series. J Theor Biol 8:426-468.

Fuller CA , Sulzman FM , and Moore-Ede MC (1978) Thermoregulation is impaired in an environment without circadian time cues. Science 199:794-796.

Fuller PM , Jones TA , Jones SM , and Fuller CA (2002) Neurovestibular modulation of circadian and homeostatic regulation: Vestibulohypothalamic connection? Proc Natl Acad Sci USA 99:15723-15728.

Fuller PM , Jones TA , Jones SM , and Fuller CA (2004) Evidence for macular gravity receptor modulation of hypothalamic, limbic and autonomic nuclei. Neuroscience 129:461-471.

10.

Glass JD , Grossman GH , Farnbauch L , and DiNardo L (2003) Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus. J Neurosci 23:7451-7460.

11.

Grossman GH , Farnbauch L , and Glass JD (2004) Regulation of serotonin release in the Syrian hamster intergeniculate leaflet region. Neuroreport 1:103-106.

12.

Halberg F , Tong YL , and Johnson EA (1967) Circadian system phase: An aspect of temporal morphology; procedures and illustrative examples. In The Cellular Aspects of Biorhythms, von Mayersbachn H , ed, pp 20-48, Berlin, Springer-Verlag.

13.

Harrington ME (1997) The ventral lateral geniculate nucleus and the intergeniculate leaflet: Interrelated structures in the visual and circadian systems. Neurosci Biobehav Rev 21:705-727.

14.

Horowitz SS , Blanchard JH , and Morin LP (2004) Intergeniculate leaflet and ventral lateral geniculate nucleus afferent connections: An anatomical substrate for functional input from the vestibulo-visuomotor system. J Comp Neurol 2:227-245.

15.

Janik D and Mrosovsky N (1994) Intergeniculate leaflet lesions and behaviorally-induced shifts of circadian rhythms. Brain Res 1-2:174-182.

16.

Jones SM , Erway LC , Bergstrom RA , Schimenti JC , and Jones TA (1999) Vestibular responses to linear acceleration are absent in otoconia-deficient C57BL/6JEihet mice. Hear Res 135:56-60.

17.

Kerman IA , McAllen RM , and Yates BJ (2000) Patterning of sympathetic nerve activity in response to vestibular stimulation. Brain Res Bull 53:11-16.

18.

Lewandowski MH and Usarek A (2002) Effects of intergeniculate leaflet lesions on circadian rhythms in the mouse. Behav Brain Res 128:13-17.

19.

Morin LP (1999) Serotonin and the regulation of mammalian circadian rhythmicity. Ann Med 31:12-33.

20.

Morin LP and Blanchard J (1991) Depletion of brain serotonin by 5,7-DHT modifies hamster circadian rhythm response to light. Brain Res 566:173-185.

21.

Morin LP , Michels KM , Smale L , and Moore RY (1990) Serotonin regulation of circadian rhythmicity. Ann NY Acad Sci 600:418-426.

22.

Morin LP and Pace L (2002) The intergeniculate leaflet, but not the visual midbrain, mediates hamster circadian rhythm response to constant light. J Biol Rhythms 17:217-226.

23.

Mrosovsky N (1996) Locomotor activity and non-photic influences on circadian clocks. Biol Rev Cambridge Philos Soc 71:343-372.

24.

Murakami DM , Erkman L , Hermanson O , Rosenfeld MG , and Fuller CA (2002) Evidence for vestibular regulation of autonomic functions in a mouse genetic model. Proc Natl Acad Sci USA 99:17078-17082.

25.

Pickard GE (1994) Intergeniculate leaflet ablation alters circadian rhythms in the mouse. Neuroreport 5:2186-2168.

26.

Pickard GE , Ralph MR , and Menaker M (1987) The intergeniculate leaflet partially mediates effects of light on circadian rhythms. J Biol Rhythms 2:35-56.

27.

Rosbash M and Takahashi JS (2002) Circadian rhythms: The cancer connection. Nature 420:373-374.

28.

Rossiter CD , Hayden NL , Stocker SD , and Yates BJ (1996) Changes in outflow to respiratory pump muscles produced by natural vestibular stimulation. J Neurophysiol 76:3274-3284.

29.

Rummel JA (1974) Combined linear-nonlinear chronobiologic windows by least squares resolve neighboring components in a physiologic rhythm spectrum. In Biorhythms and Human Reproduction, Ferrin M , Halberg F , Richart RM , and Vande Weile RL , eds, pp 53-82, New York, John Wiley.

30.

Rusak B , Meijer JH , and Harrington ME (1989) Hamster circadian rhythms are phase-shifted by electrical stimulation of the geniculo-hypothalamic tract. Brain Res 2:283-291.

31.

Sweet H (1980) Head tilt. Mouse News Ltr 63:19.

32.

Toh KL , Jones CR , He Y , Eide EJ , Hinz WA , Virshup DM , Ptacek LJ , and Fu YH (2001) An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291:1040-1043.

33.

Wright KP Jr , Hughes RJ , Kronauer RE , Dijk DJ , and Czeisler CA (2001) Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans. Proc Natl Acad Sci USA 98:14027-14032.