Circadian Alterations in a Murine Model of Hypothalamic Glioma

Abstract

The mammalian circadian system is controlled by a central oscillator located in the suprachiasmatic nuclei (SCN) of the hypothalamus, in which glia appears to play a prominent role. Gliomas originate from glial cells and are the primary brain tumors with the highest incidence and mortality. Optic pathway/hypothalamic gliomas account for 4–7% of all pediatric intracranial tumors. Given the anatomical location, which compromises both the circadian pacemaker and its photic input pathway, we decided to study whether the presence of gliomas in the hypothalamic region could alter circadian behavioral outputs. Athymic nude mice implanted with LN229 human glioma cells showed an increase in the endogenous period of the circadian clock, which was also less robust in terms of sustaining the free running period throughout 2 weeks of screening. We also found that implanted mice showed a slower resynchronization rate after an abrupt 6 h advance of the light-dark (LD) cycle, advanced phase angle, and a decreased direct effect of light in general activity (masking), indicating that hypothalamic tumors could also affect photic sensitivity of the circadian clock. Our work suggests that hypothalamic gliomas have a clear impact both on the endogenous pacemaking of the circadian system, as well as on the photic synchronization of the clock. These findings strongly suggest that the observation of altered circadian parameters in patients might be of relevance for glioma diagnosis.

Circadian Regulation Patterns With Distinct Immune Landscapes in Gliomas Aid in the Development of a Risk Model to Predict Prognosis and Therapeutic Response

“…Over the past several decades the connection between circadian clocks and tumorigenesis has been well studied. Abnormal rhythms are associated with high-grade brain tumors ( 15 , 16 ). Specifically, disruption of the circadian clock pharmacologically (REV-ERB agonists) or genetically (CLOCK and BMAL1 short hairpin RNAs) impairs glioma stem cell (GSC) stemness in GBM and causes GSC cell-cycle arrest and apoptosis ( 17 , 18 ).…”

Circadian regulation of sleep in a pre-clinical model of Dravet syndrome: dynamics of sleep stage and siesta re-entrainment

“…p < 0.05 was considered as statistically significant. IV index was calculated as previously described [43,44]. Briefly, IV is the ratio of the mean square of the difference between all the successive hours on each day, and the same calculation around the overall mean:…”

Identification of key modules and hub genes in glioblastoma multiforme based on co‐expression network analysis

“…Correspondingly, the main KEGG pathways in the turquoise module‐demonstrated enrichment included circadian rhythm entrainment, glutamatergic synapses, axonal guidance, GABAergic synapses, dopaminergic synapses, retrograde endogenous cannabinoid signalling, MAPK signalling pathway and extracellular matrix (ECM)–receptor interaction. Changes in circadian rhythm parameters in the mouse model were found to be associated with glioma diagnosis [34]. Netrin‐1, an axonal guidance molecule, has been reported to be associated with invasive and angiogenic phenotypes [35].…”