Neurovestibular modulation of circadian and homeostatic regulation: vestibulohypothalamic connection?

Abstract

Chronic exposure to increased force environments (+G) has pronounced effects on the circadian and homeostatic regulation of body temperature (T(b)), ambulatory activity (Act), heart rate, feeding, and adiposity. By using the Brn 3.1 knockout mouse, which lacks vestibular hair cells, we recently described a major role of the vestibular system in mediating some of these adaptive responses. The present study used the C57BL6JEi-het mouse strain (het), which lacks macular otoconia, to elucidate the contribution of specific vestibular receptors. In this study, eight het and eight WT mice were exposed to 2G for 8 weeks by means of chronic centrifugation. In addition, eight het and eight WT mice were maintained as 1G controls in similar conditions. Upon 2G exposure, the WT exhibited a decrease in T(b) and an attenuated T(b) circadian rhythm. Act means and rhythms also were attenuated. Body mass and food intake were significantly lower than the 1G controls. After 8 weeks, percent body fat was significantly lower in the WT mice (P < 0.0001). In contrast, the het mice did not exhibit a decrease in mean T(b) and only a slight decrease in T(b) circadian amplitude. het Act levels were attenuated similarly to the WT mice. Body mass and food intake were only slightly attenuated in the het mice, and percent body fat, after 8 weeks, was not different in the 2G het group. These results link the vestibular macular receptors with specific alterations in homeostatic and circadian regulation.

Figures

Fig. 1.

Plots of representative Tb data from WT (A) and het (B) mouse. The onset of 2G is preceded by 48 h of 1G; the WT example demonstrates the typical drop in Tb and loss of circadian Tb rhythmicity. Only a small drop in Tb and small attenuation of the circadian Tb rhythm amplitude are seen in the het example. Gray bar, 2G period.

Fig. 2.

Plots of the Tb mean responses (±SE) for the WT (gray line) and het (black line) groups. (A) Twenty-four-hour Tb averages. (B) Tb circadian rhythm amplitudes. The attenuated Tb amplitude response of the het is another indicator that these mice are refractory to the change in gravity loading and suggests, furthermore, that the hypothalamic circadian clock is affected more in the WT mice. Black bar, 2G period.

Fig. 3.

Plots of representative Act data from a WT (A) and het (B) mouse. The onset of 2G is preceded by 48 h of 1G; the WT example demonstrates the typical drop in Act levels and loss of circadian Act amplitude. A similar response was seen in the het mice in both Act levels and circadian Act amplitude. Gray bar, 2G period.

Fig. 4.

Plots of the Act mean responses (±SE) for the WT (gray line) and het (black line) groups. (A) Twenty-four-hour Act averages. (B) Act circadian rhythm amplitudes. Black bar, 2G period.

Fig. 5.

(A) Plot of bm (mean ± SE) of the 1G and 2G WT (gray lines) and het (black lines) mice. Black bar, 2G period. At 2G onset, there is a rapid drop (within the first 72 h) in bm in the WT mice. The 2G het mice showed a significantly smaller drop in bm at 2G onset. The 2G WT mice exhibited a lower bm as compared with their 1G counterparts from weeks 1 to 6 of 2G. The 2G het mice never exhibited a lower bm as compared with their 1G counterparts. (B) Plot of MIFI (±SE) of the 1G and 2G WT (gray lines) and het (black lines) mice. The 2G WT mice exhibited the anticipated anorexic response at 2G onset, and, by week 6 of 2G, the 2G WT mice had a significantly higher MIFI than their 1G counterparts. The 2G het mice exhibited only a small, delayed reduction in MIFI at 2G onset, which recovered to 1G levels for the balance of the 2G period.

Fig. 6.

Plot of MIFI vs. percent body fat. The 2G WTs exhibited the anticipated metabolic shift: an increase in MIFI and a decrease in percent and absolute body fat. The het mice demonstrated a significantly different metabolic relationship at 1G, and this relationship was not altered with chronic 2G exposure.