الوصف

Chronic liver diseases, such as hepatic tumors can affect the brain, via the liver-brain axis, leading to neurotransmitter dysregulation and behavioral alteration. Cancer patients suffer from fatigue, which can be associated with sleep disturbances. Sleep is regulated via two interlocked mechanisms: homeostatic regulation and the circadian system. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is the key component of the circadian system, controlling circadian rhythms in behavior. The glia-neuron interactions is a crucial element in timekeeping integrity of the SCN. Astrocytes have been shown to modulate SCN-related behavioral rhythms, independently on neurons. Under pathological conditions, oxidative stress can compromise SCN astrocytes and thus the integrity of timekeeping. To date, little is known about the impact of peripheral pathologies such as the hepatocellular carcinoma (HCC) on SCN glial cells. To close this gap, we chemically induced HCC in male mice and analyzed rhythms of spontaneous locomotor activity using on-cage infrared detectors (E-Motion), and markers for oxidative stress (8-OHdG) and activity of neurons (c-FOS), astrocytes (GFAP) and microglia (IBA1) in the SCN by immunohistochemistry. Tumor bearing mice were kept under a standard photoperiod [12h light/12h darkness, Zeitgeber time (ZT) 00 ] and sacrificed at four different time points, two in the rest/light phase (ZT02, ZT08) and two in the dark/activity phase (ZT14, ZT20). Although rhythmic locomotor activity was preserved in HCC-bearing mice, amplitude and total locomotor activity, in particular during the activity phase, were reduced compared to control mice. This indicates that the liver tumor affects the circadian system and dampens activity, which is reminiscent of cancer-related fatigue. Furthermore, immunoreaction for GFAP, IBA1, and 8-OHdG was increased in HCC mice compared to control mice during light and dark phase. This indicates that HCC leads to a general activation of astrocytes, microglia and oxidative stress in the SCN. c-FOS immunoreaction was not different at ZT02, but decreased at ZT08 and increased expression at ZT20 in the SCN of HCC mice compared to control mice, indicating an effect of the tumor on rhythmic SCN neuronal activity. In summary, our data suggest that the liver tumor leads to a damped rhythmic locomotor activity, induces oxidative stress and affects activity of neurons and glial cells in the SCN.

URL

DOI

الملخص

الكلمات الدالة