Inter-regional Communication Mechanisms Mediated by Circadian Clocks in Pathological Conditions of the Brain
DescriptionThe brain has the most complicated structure with diverse microenvironments, and they are tightly controlled for brain functions. Circadian clocks are endogenous oscillators generating cell-autonomous rhythms in various cellular processes. They are distributed across the brain and synchronized to the local macro- and micro-environments by the action of external cues. Circadian clocks in different brain regions also communicate with each other by neuro-circuits and paracrine/humoral cues to coordinate physiological processes. Therefore, once toxic insults to the brain change microenvironments, this affects local circadian clocks. This suggests that altered circadian clocks in the lesions may send signals to nearby areas for further processes. However, how circadian clocks respond to altered microenvironments in pathological conditions, mechanisms of how they communicate with each other, and the effects of these communications on the brain are largely unknown. Our preliminary results with in vitro, ex vivo, and in vivo systems have shown that circadian clocks in both neural cells (e.g., neurons and astrocytes) and brain regions (e.g., the corpus callosum and the SVZ) differentially responded to the pathological conditions. We found that these dynamic changes in circadian clocks generated inter-regional communications via producing and secreting signaling molecules. Based on these findings, we have tried to modulate the communications mediated by circadian clocks with a small-molecule targeting circadian clocks. By stereotactic injection, we directly targeted local circadian clocks in the demyelinating lesions and observed that this changed inter-regional communications between the demyelinating lesions and the nearby brain area SVZ to initiate a natural repair process, remyelination. Based on our preliminary results, we hypothesize that circadian clocks in various brain regions communicate with each other by producing and secreting signaling molecules. This results in inter-regional communications to respond to microenvironmental changes. To test this, we will focus on two major objectives: 1) identify mechanisms of how circadian clocks mediate inter-regional communications in the brain; 2) examine whether targeting local circadian clocks is sufficient to modulate inter-regional communications in the brain. From this project, we will provide evidence that dynamically changed local circadian clocks in response to pathological conditions are not merely detrimental to the brain. These changes can be a part of natural repair systems of the brain through controlling inter-regional communications.
|Effective start/end date||1/01/21 → …|