Role of circadian clock on astrocyte and dementia

Abstract

The circadian clock is a system that helps organisms to adapt to changes of the external environment by day and night cycle caused by the earth's rotation. The circadian clock is preserved from the cellular level, and is regulated through the transcriptional translational feedback loop (TTFL) of the core clock genes such as Bmal1 or Nr1d1. The circadian clock at the cellular level can further lead to the circadian clock at the tissue or organism level. In mammals, suprachiasmatic nucleus (SCN), which exists in the hypothalamus, is the master circadian clock and responsible for transmitting and synchronizing circadian clock signals. Recently, it has been proposed that the circadian gene expression pattern at the cellular or tissue level is related to time dependent functional regulation of each cell type or tissue. Therefore, studies on the regulation of cellular or tissue physiology have been attempted by assessing circadian oscillating transcripts of specific cell type or tissue sample. In addition, studies on the role of the circadian clock on pathophysiology can be attempted by measuring the circadian rhythm characteristics at the organism level such as behavioral activity monitoring or multiple cortisol assessments. At the first part, I investigated circadian transcriptome in mouse cortical astrocyte culture to find crucial gene and/or pathway for regulating astrocyte physiology at cellular level. I found 412 circadian oscillating transcripts in astrocyte and found several enriched biological mechanisms such as cellular migration, glutathione metabolism, and calcium signaling pathways. I further narrowed candidate oscillating transcripts possibly regulating astrocyte physiology. Finally, I could get 38 candidate transcripts which include several transcripts already studied as possible regulator of astrocyte physiology or brain functions. I further assessed Tmem44 as a novel candidate. Tmem44 downregulation affected circadian rhythm, decreased cellular migration, and metabolic activity in astrocytes. Further research will be performed to identify the role of Tmem44 and other candidates on astrocyte physiology in vitro and in vivo. At the second part, I assessed role of circadian rhythm on pathophysiology of neurodegenerative disorder at organism level. I investigated the associations between behavioral circadian rhythm, neurodegeneration, and cognition in patients with mild cognitive impairment and mild dementia. I extracted behavioral circadian rhythm characteristics from longitudinal activity data measured by wrist actigraphy. As a result, I found that MESOR, which corresponds to the rhythm-adjusted mean activity, associated positively with frontal/executive function. Furthermore, L5 onset time, which corresponds to the time of rest period onset, associated positively with medial temporal lobe grey matter (MTL GM) volume and memory function, particularly in amyloid-negative participants. Additional path analysis revealed that MTL GM volume partially mediates the relationship between L5 onset time and memory function in amyloid-negative participants. Together, these studies suggest potential role of circadian rhythm on regulation of astrocyte physiology at cellular level and dementia pathophysiology at organism level.