Hepatocellular Carcinoma in Mice Affects Neuronal Activity and Glia Cells in the Suprachiasmatic Nucleus

Abstract

Background: Chronic liver diseases such as hepatic tumors can affect the brain through the liver–brain axis, leading to neurotransmitter dysregulation and behavioral changes. 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. It generates circadian rhythms in physiology and behavior and controls their entrainment to the surrounding light/dark cycle. Neuron–glia interactions are crucial for the functional integrity of the SCN. Under pathological conditions, oxidative stress can compromise these interactions and thus circadian timekeeping and entrainment. To date, little is known about the impact of peripheral pathologies such as hepatocellular carcinoma (HCC) on SCN. Materials and Methods: In this study, HCC was induced in adult male mice. The key neuropeptides (vasoactive intestinal peptide: VIP, arginine vasopressin: AVP), an essential component of the molecular clockwork (Bmal1), markers for activity of neurons (c-Fos), astrocytes (GFAP), microglia (IBA1), as well as oxidative stress (8-OHdG) in the SCN were analyzed by immunohistochemistry at four different time points in HCC-bearing compared to control mice. Results: The immunoreactions for VIP, Bmal1, GFAP, IBA1, and 8-OHdG were increased in HCC mice compared to control mice, especially during the activity phase. In contrast, c-Fos was decreased in HCC mice, especially during the late inactive phase. Conclusions: Our data suggest that HCC affects the circadian system at the level of SCN. This involves an alteration of neuropeptides, neuronal activity, Bmal1, activation of glia cells, and oxidative stress in the SCN.